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Guidelines

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011)

Pediatric Infectious Diseases Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
APHP-Henri Mondor Hospital, Hematology Department and Université Paris Est-Créteil, France
Norwich Medical School, University of East Anglia, Norwich. UK
Division of Infectious Diseases, University of Genova, IRCCS San Martino-IST, Genova, Italy
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Switzerland
Division of Infectious Diseases, University of Genova, IRCCS San Martino-IST, Genova, Italy
Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands;Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands;Hasselt University, Diepenbeek, Belgium
Center for Infectious Diseases and Travel Medicine, Department of Medicine, University Hospital, Albert-Ludwigs University, Freiburg, Germany
National Research Center for Hematology, Moscow, Russia
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Switzerland
Pediatric Infectious Diseases Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Department of Medicine, Section of Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey
Vol. 98 No. 12 (2013): December, 2013 https://doi.org/10.3324/haematol.2013.091330

Abstract

The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4th European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.

Introduction

There is a growing problem of antimicrobial resistance among the pathogens isolated from hematology patients and hematopoietic stem cell transplant (HSCT) recipients in many centers, and this increasingly influences the choice of empirical therapy.1 Resistance also affects the choice of ‘targeted’ therapy once a pathogen has been isolated, identified and subjected to susceptibility testing. In some cases, treatment options are very limited, and the emergence and proliferation of multiresistant Gram-negative organisms – both Enterobacteriaceae and non-fermenters – is forcing the renewed use of old antibiotics, notably colistin/polymyxin B and fosfomycin2–6 and of tigecycline. Similarly, the emergence of Gram-positive pathogens resistant to β-lactams and glycopeptides is leading to the use of linezolid, daptomycin and tigecycline in hematology patients.

These agents have not been extensively trialed in hematology patients; rather, their use is predicated on the lack of alternatives. Additional concern is that onco-hematological patients, and especially allogeneic HSCT recipients receive a lot of drugs (e.g., cyclosporine, mycophenolate mofetil, triazoles, antivirals) and they are likely more prone to drug-drug interactions than other populations. We should therefore reinforce the caution about the use of these antibiotics. For this reason, the European Conference on Infections in Leukemia (ECIL) group decided to review the published literature on the use of these non-conventional antibacterial agents for use against resistant Gram-negative and -positive pathogens in leukemic patients and HSCT recipients. The resulting draft guidelines, presented here, were discussed by the Expert Group at the ECIL-4 meeting in September 2011 and are based on published studies and expert opinion. Updated slide sets from ECIL-4 covering these aspects are available via the websites of the four organizations involved in ECIL (European Group for Blood and Marrow Transplantation, European Organization for Research and Treatment of Cancer, Immunocompromised Host Society, ECIL and European Leukaemia Net).7,8

Methods

The methodology of the ECIL conferences was described previously;9 the quality of evidence and strength of recommendations were graded according to the criteria of the Infectious Disease Society of America (IDSA)10 (Table 1). A group leader (MA) was proposed by the organizing committee and experts were solicited to form the working group. The group reviewed the published English-language literature and prepared proposals on treatment options for infections due to resistant bacteria. Papers for review were sought using PubMed with the terms “linezolid”, “daptomycin”, “quinupristin/dalfopristin”, “colistin or polymyxin”, “tigecycline”, “fosfomycin”, “telavancin”, “ceftaroline” AND “stem cell transplantation or bone marrow transplant or leukemia or hematological malignancy or cancer”. References cited in the articles identified were also considered.

In respect of ‘Duration of therapy’, the main search terms used were “antibiotic therapy”; “stem cell transplantation or bone marrow transplantation or hematological malignancy or cancer”; “febrile neutropenia” and “duration therapy”, “discontinuation antibiotics” and “microbiologically documented infection”.

Definitions of resistance

A bacterial isolate was considered non-susceptible if it was categorized resistant, intermediate or non-susceptible when using clinical breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), Clinical and Laboratory Standards Institute (CLSI) or the US Food and Drug Administration (FDA). Definitions of ‘MDR’ vary among authors and usually presume resistance to at least two antibiotics used in empiric therapy (34 -generation cephalosporins, carbapenems or piperacillin/tazobactam) or resistance to at least three of the following antibiotic classes: antipseudomonal penicillins, cephalosporins, carbapenems, aminoglycosides and fluoro-quinolones.11–15 According to the recent definition of the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), the isolate is considered MDR if it is non-susceptible to at least one agent in ≥3 therapeutically relevant antimicrobial categories.16

Results of the literature review

Resistant Gram-negative rods

Acquired resistance, now often encompassing carbapenems as well as other drug classes, is a growing problem in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, whereas Stenotrophomonas maltophilia is inherently resistant to most antibiotics except co-trimoxazole (trimetoprim-sulfamethoxazole; TMP-SMX) and ticarcillin-clavulanate. The erosion of carbapenem activity against Enterobacteriaceae and A. baumannii largely reflects the spread of carbapenem-degrading enzymes, dubbed carbapenemases; these enzymes also occur in P. aeruginosa, although multi-resistance in this species, including to carbapenems, more often involves mutational reductions in permeability and up-regulation of efflux.17

Agents that retain some in vitro activity against most carbapenem-resistant Enterobacteriaceae isolates include tigecycline, colistin/polymyxin B, fosfomycin and – more variably – aminoglycosides. Interestingly, some carbapenemase-producing Enterobacteriaceae retain a degree of in vitro susceptibility to carbapenems and, if carbapenems are combined with other agents, they may still provide therapeutic benefit in these cases.18 In general, however, clinical data on the treatment of carbapenem-resistant Enterobacteriaceae infections are very limited and consist mainly of small case-series and brief reports.18–25 The prevalence of resistance in P. aeruginosa from HSCT patients varies across Europe, increasing as one moves south and eastward (ref. “Current etiology and resistance in bacterial bloodstream infections in hematology and oncology patients – literature review and ECIL-4 Surveillance Study.” M. Mikulska, C. Viscoli, C. Orasch, DM. Livermore, D. Averbuch, C. Cordonnier, M. Akova. Submitted for publication). In some centers, 25%–71% of P. aeruginosa isolates are MDR,11,14,15,26–30 leaving colistin/polymyxin B and (maybe) fosfomycin as the only treatment options.

Carbapenem-resistant A. baumannii may remain susceptible to sulbactam,31 a β–lactamase inhibitor that also has clinically relevant intrinsic antimicrobial activity against the organism.

Other antibiotics that show in vitro activity against some A. baumannii are colistin/polymyxin B and tigecycline.31 However, A. baumannii can develop resistance to tigecycline by mutation, with the trait sometimes selected in therapy;32–34 moreover some regionally prevalent MDR strains are non-susceptible to tigecycline.35

Table 1.Infectious Diseases Society of America grading system for ranking recommendations.10

In the case of S. maltophilia, TMP-SMX is considered the treatment of choice, but resistance may arise and the sulfonamide component is poorly tolerated by some patients.36–39 Alternative agents against S. maltophilia proposed by some authors include the β-lactams, ticarcillin-clavulanate and ceftazidime; fluoroquinolones, with moxifloxacin reportedly active in vitro against some ciprofloxacin-resistant isolates from hematological patients;40 minocycline and chloramphenicol. Published cases series are small with variable success and drugs often in combination.37–39 The combination of TMP-SMX with either ticarcillin/clavulanate or with a third-generation cephalosporin (mainly ceftazidime) should be considered in neutropenic or severely ill patients.37,41,42 Review is further complicated because in vitro susceptibility testing for S. maltophilia is problematic, with results contingent on the medium (β-lactams) and temperature (aminoglycosides) used; the correlation with outcome is questionable.39

Treatment options against infections due to MDR Gram-negative rods in leukemic and HSCT patients are summarized in Table 2.

Tigecycline

Tigecycline has a broad-spectrum of in vitro activity against MDR Gram-positive and Gram-negative bacteria, excluding P. aeruginosa, Proteus spp., Providencia spp. and Morganella spp.22,38,54,55 However, evidence of increased mortality, compared to other antibiotic therapies, especially in ventilator-associated pneumonia48 leads to caution in its use. Moreover, a serious drawback, at least for monotherapy in bacteremia, is the low serum level obtained.33 Superinfections with pathogens inherently resistant to tigecycline (P. aeruginosa, Proteus spp., Providencia spp. and Morganella spp.) are another concern.32,56

Table 2.Main characteristics of the new or revisited antibacterial drugs for treatment of infections due to MDR Gram-negative bacteria.

Nevertheless, tigecycline was used at standard dosage, in combination with an anti-pseudomonal drug (β-lactams, quinolones, aminoglycosides) in 110 adult cancer patients (58% with hematological malignancies and 24% post-HSCT) as salvage therapy, for the treatment of refractory pneumonia (60%), bacteremia (17%) or other infections, which were microbiologically documented in 45% of the patients.57 Not all isolates were susceptible, or were tested to the antibiotics administered, concurrently with the tigecycline. Clinical response was achieved in 56% of transplant recipients, being higher in non-pseudomonas than pseudomonas infections (80% vs. 50%, P=0.06). Patients with pneumonia had lower response and higher mortality rates than those with bacteremia (51% vs. 79%, 44% vs. 16% respectively, both P<0.05).57 In another study, tigecycline was used at standard dosages for the treatment of serious hospital-acquired infections caused by MDR bacteria, including 50 patients (24%) with hematological malignancies. Alone or combined with other antibiotics, it showed efficacy in 16/23 (70%) of bacteremia cases and in 7/12 (58%) in whom it was used for empirical treatment of febrile neutropenia.58 Higher-dosage tigecycline regimens potentially may be advantageous in severe infections. A recent randomized study in patients with hospital-acquired pneumonia showed that clinical cure with tigecycline 100 mg twice daily after a loading dose of 200 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg twice daily after a loading dose of 150 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%).59 Tigecycline may also benefit from combination. In a prospective multicenter trial of empirical for febrile neutropenic cancer patients, successful outcomes were reported in 126 of 164 (74%) treated with piperacillin-tazobactam plus tigecycline compared to 90 of 190 (47%) patients treated with piperacillin-tazobactam alone (P<0.01), although there was no difference in mortality. The success rate of the combined regimen was better than the piperacillin-tazobactam alone also in bacteremias (60% vs. 27%, P<0.01) and clinically documented infections (84% vs. 47%, P <0.01).60

Polymyxins

Colistin (polymyxin E) and polymyxin B, which were largely abandoned as systemic treatments from the 1960s and 70s, are now increasingly used as the last-resort treatment options against infections caused by MDR Gram-negative pathogens. Although several studies have presented case series with positive outcomes, treatment with colistin was associated with increased mortality as compared with other appropriate regimens in one retrospective study including a small number of onco-hematological patients.46 In another retrospective study, summarizing the efficacy of colistin in the treatment of infections due to MDR Gram-negative bacteria, multivariate analysis showed that presence of hematological disease, including malignancy, was itself associated with a decreased probability of survival.3 Two retrospective analyses that included patients with (mainly hematological) malignancies who were treated with colistin for MDR P. aeruginosa infections obtained differing results.5,61 In one study, 31-colistin-treated patients (45% with bacteremia, 55% with pneumonia) were compared to those (n= 64) treated with a non-colistin (β-lactam or quinolone) regimen. The colistin regimen achieved a higher rate of clinical response in multiple logistic regression analysis (P=0.026; odds ratio 2.9 (1.5, 7.6), whereas microbiological response (48% vs. 41%) and infection-related death rates (26% vs. 17%) were similar.5 The other study compared 26 patients (84% bacteremic) receiving colistin to 26 patients receiving anti-pseudomonal β–lactams and found similar rates of resolution of infection (77% vs. 65%) and mortality (11% in both groups).61 Nephrotoxicity, which was reported in up to 50% of patients receiving colistin/polymyxin B in older studies, is much less frequent in newer studies, with rates ranging from 10–30%.44 In the two Pseudomonas studies just cited, no significantly increased nephrotoxicity occurred in patients treated with colistin, as compared with other agents (including aminoglycosides), although one patient treated with colistin suffered from seizures.5,61 Among another 38 colistin treatment courses in adults and children with hematological malignancy or HSCT, nephrotoxicity developed in only 11%.62

The use of a 9-million-unit loading dose and high daily dosages (4.5 million units twice daily) of colistin47 may help to overcome the problem of low blood levels that may have been responsible for the suboptimal efficacy of polymyxins in some studies, leading to increased mortality, as well as to the selection of resistant strain variants.3,45,47,63 A recently-published prospective observational study in intensive care unit patients with severe infections due to Gram-negative bacteria susceptible only to colistin recorded clinical cures in 82% of cases when colistin was administered as a 9-million-unit loading dose followed by 9 million units daily, given in two doses, as maintenance therapy.64 Combination of colistin/polymyxin B with other agents to which the bacteria show in vitro sensitivity is strongly encouraged (e.g. with aminoglycosides and/or tigecycline for the treatment of infections due to Klebsiella pneumoniae with KPC carbapenemases).22–24 Nephrotoxicity following combination with aminoglycosides is of concern, though, and renal function should be monitored; moreover, most Enterobacteriaceae with NDM (rather than KPC) carbapenemases are broadly resistant to amino-glycosides.65

Fosfomycin

Fosfomycin is another old, but increasingly revisited, antibiotic with broad-spectrum in vitro activity against Gram-positive and -negative bacteria, excluding Acinetobacter spp. It is used mainly as an oral treatment for community-acquired urinary tract infection (UTI), but intravenous formulations are available in some countries. Several studies estimate 80–90% of Enterobacteriaceae with extended-spectrum β–lactamases (ESBLs) and carbapenemases to be susceptible to fosfomycin,51,66 but other studies report that only 50% of Klebsiella spp. and fewer than 30% of MDR P. aeruginosa to be susceptible.2,6 There are no universally accepted specific species-related susceptibility breakpoints;2 EUCAST has no breakpoints for fosfomycin vs. P. aeruginosa, but notes anecdotal evidence that it may be efficacious, in combination, against strains with minimal inhibitory concentrations (MICs) <128 mg/L.67 Due to the possibility of resistance developing during therapy, fosfomycin should be used in combination with other agents, selected according to the susceptibility results.51,68 Data on the efficacy of intravenous fosfomycin are limited to case reports and small case series51 and there is no published experience of treating invasive infections in onco-hematological and HSCT patients. A retrospective study in HSCT patients showed, that in a multivariate analysis, exposure to fosfomycin (route of administration not specified) was associated with a significantly decreased incidence of veno-occlusive liver disease.69

Sulbactam

Although sulbactam is conventionally used as a β-lactamase inhibitor, it also has inherent antibiotic activity against Acinetobacter spp.31 The package insert of sulbactam says that the maximum daily dose of sulbactam should not exceed 4 g. However, there are reports on dosages of sulbactam (combined with β lactams) of at least 6 g IV in divided dosages, assuming normal renal function.31,70 Furthermore, doses of up to 9–12 g/day were administered for ventilator-associated pneumonia with MDR Acinetobacter.71

Combination therapy in infections due to resistant Gram-negative bacteria

Several meta-analyses of randomized controlled studies, some of them done before the present era of increasing resistance, concluded that there was similar all-cause mortality in febrile neutropenic patients treated with a β-lactam vs. the same β-lactam plus an aminoglycoside as empirical or definitive therapy.72–74 However, owing to the small numbers of cases of infection due to resistant bacteria, a benefit of combination therapy could not be ruled out for those patients who were critically ill or were infected with P. aeruginosa or some other resistant pathogen.72–74

Combination antibiotic therapy also may simply improve the likelihood that at least one component agent is active.75 A retrospective study reviewed patients with hematological malignancies or post-HSCT, who were infected by ESBL- or AmpC-producing Enterobacteriaceae or resistant pseudomonas, most of whom were empirically treated with combination of a β-lactam and an aminoglycoside. Mortality was lower among those patients whose pathogen was sensitive in vitro to either the β-lactam or the aminoglycoside, compared with those whose pathogen was resistant to both (OR, 1.8; 95% CI, 1.3 to 2.5).76

Nevertheless, and in contrast, an early prospective randomized trial in non-neutropenic patients, in the era prior to the emergence of significant imipenem resistance, showed that the combination of imipenem plus netilmicin was no more efficacious than imipenem monotherapy for the treatment of severe infections, but did have increased nephrotoxicity, and did not prevent the emergence of imipenem-resistant P. aeruginosa.77

Some in-vitro data suggest synergy in combining two agents against carbapenemase-producing K. pneumoniae, even when the pathogen is resistant to one of these agents.78,79 Synergy was claimed for a combination of polymyxin B and either rifampin or doxycycline, resulting in at least a four-fold decrease in the MIC of polymyxin B when both drugs were used at physiologically achievable concentrations in one study.78 In another study a combination of fosfomycin with meropenem or colistin was asserted to be synergistic, based on 100-fold more extensive killing than with the more active single agent.79 Nevertheless there is a profound lack of clarity on when and how the various different measures of synergy used in vitro translate into clinical advantage; moreover there must be a concern about publication bias: studies that detect synergy are more likely to be reported and published than those that fail to do so.

Carbapenem-containing regimens were associated with significantly reduced mortality compared to non-carbapenem-containing regimens in a retrospective analysis of 138 patients who received treatment for infections due to carbapenemase-producing K. pneumoniae that showed susceptibility to carbapenems in vitro. Carbapenems may be a reasonable treatment option against carbapenemase-producing K. pneumoniae provided that: (i) the carbapenem MIC for the infecting organism is ≤4 mg/L; (ii) a high-dose prolonged-infusion regimen is administered to drive the pharmacokinetic/pharmacodynamic profile to acceptable exposures; and (iii) this class of agent is administered in combination with another active compound.21 The caveat is that many carbapenemase producers are more substantially resistant, precluding such strategies.

An ertapenem-doripenem combination may be of potential usefulness against KPC-producing K. pneumoniae based on a study in an immunocompetent murine thigh infection model based on the notion that the high affinity of KPC for ertapenem would “trap” the enzyme thus enhancing the activity of doripenem.80

Others have found that various combinations of rifampin, β–lactams, aminoglycosides, quinolones, colistin/polymyxin B, fosfomycin or other agents are synergistic in vitro, or in animal models, against MDR Pseudomonas or Acinetobacter spp.2,31,81,82 Many authors argue that rifampin should be considered for addition to other active antibiotics in the treatment of uncontrolled infection due to MDR bacteria,31,55,78,83–85 though there is little evidence of why rifampicin should improve outcome and no randomized trials to show that it does improve these outcomes. Further obstacles include: (a) there is no relevant in vitro breakpoint for susceptibility to rifampin against Gram-negative bacteria; (b) toxic potential of rifampin; (c) multitude of drug interactions between rifampin and other agents, a main concern especially in onco-hematological patients and allogeneic HSCT recipients who receive a lot of other drugs concomitantly (such as cyclosporine, mycophenolate mofetil, antifungals, antivirals).86

Notably, a randomized, open-label recently published clinical trial, which enrolled 210 patients with life-threatening infections due A. baumannii that were susceptible only to colistin showed that 30-day mortality was not reduced by addition of rifampicin.86

Publication of further observational studies assessing different monotherapies and combinations against MDR Acinetobacter or carbapenem-resistant Gram-negative bacteria is pending.87,88

Resistant Gram-positive pathogens

Treatment options against infections due to resistant Gram-positive bacteria in leukemic and HSCT patients are summarized in Table 3.

Glycopeptide non-susceptible Gram-positive bacteria include vancomycin-resistant enterococci (VRE) and vancomycin-intermediate and hetero-resistant Staphylococcus aureus (VISA and hVISA). There is also evidence that vancomycin MICs at the high end of the normal range for MRSA (2 mg/L) are associated with worse outcomes than MIC of <1 mg/L.104 Infections with VRE are prevalent in onco-hematological and HSCT patients in some countries105–110 but, until now, infections with VISA or hVISA remain rare in this patient population.111–113

Agents showing activity against some glycopeptide non-susceptible Gram-positive pathogens include linezolid, daptomycin, quinupristin/dalfopristin, tigecycline and fosfomycin, as well as the new agents telavancin and ceftaroline. The exact spectra of these agents vary and should be considered before use. Linezolid and tigecycline are almost universally active, whereas quinupristin/dalfopristin for example, does not cover E. faecalis, telavancin is inactive against VanA enterococci and ceftaroline lacks activity against E. faecium and is variable against E. faecalis.

Linezolid is the only one of these antibiotics that has been compared to vancomycin in a relevant prospective double-blind, multicenter equivalence study. This was performed in 605 febrile neutropenic cancer patients with proven (24%) or suspected Gram-positive infections: 94% had hematological malignancy. The study showed equivalent efficacy between vancomycin and linezolid in achieving clinical (87% vs. 86%) and microbiological (58% vs. 50%) success. Mortality rates, too, were similar (5.6% vs. 7.6%), though there were fewer drug-related adverse events with linezolid (17.2% vs. 24%; P=0.04).114 Another prospective, multicenter, open-label, non-comparative, non-randomized study examined the performance of linezolid in 103 neutropenic cancer patients with serious Gram-positive infections, mainly bacteremia. Most patients had VRE resistant to other therapies, or had a history of failure or intolerance to available agents. Linezolid achieved 79% clinical and 86% microbiological cure rates.115

Despite these positive findings, there is a concern about the thrombocytopenia and/or neutropenia found in some studies with linezolid. This side effect was seen in 2–11% of patients,115,116 although two further studies suggested that the incidence was similar to that with vancomycin.114,117 Other uncommon but serious adverse effects associated with linezolid include lactic acidosis, serotonin syndrome, and peripheral and optic neuropathies.118–120

Quinupristin/dalfopristin (QD) was compared to linezolid in a prospective randomized trial in 40 patients with hematological malignancies (a third were post-HSCT, 20% neutropenic) with VRE infections, predominantly bacteremia. Both regimens achieve comparable clinical (43% vs. 58%) and microbiological (71% vs. 90%) cure rates, with similar mortality (10% vs.16%).116 Comparable results were achieved in treating staphylococcal line-associated bacteremia with quinupristin/dalfopristin or vancomycin in a prospective randomized comparative study that included cancer patients.121 The response rate in vancomycin-resistant E. faecium infections, mainly bacteremias, was 55%-68% in two studies that largely included leukemia patients, including those with HSCT and neutropenia,122,123 in one of these studies quinupristin/dalfopristin was combined with minocycline.123 Arthralgia or myalgia developed in 6–36% of patients.99,122 Quinupristin/dalfopristin should preferably be administered via central venous catheter.99,122

Table 3.Main characteristics of the new or revisited antibacterial drugs for treatment of resistant Gram-positive bacteria.

Daptomycin treatment of probable or definite catheter-related bacteremia caused by Gram-positive bacteria resulted in a better overall response rate as compared with matched historical controls treated with vancomycin −68% vs. 32% (P=0.003);124 70% of these patients had hematological malignancy and 13% were post-HSCT. In another retrospective study, treatment with daptomycin led to improvement in 90% of 72 febrile cancer patients (82% with hematologic malignancies, 47% neutropenic) with infections, predominantly bacteremias, due to Gram-positive organisms.125 None of the patients required discontinuation of the daptomycin due to adverse effects.125 The MIC of daptomycin should be checked for staphylococci previously exposed or resistant to glycopeptides, as cross-resistance is possible, due to the thickened cell wall trapping daptomycin.93,95,126 Use in enterococcal bacteremia is off-label and MICs should be carefully checked, as those for E. faecium are commonly around 2–4 mg/L, well above the staphylococcal breakpoint.95 In a small report, only four of nine febrile neutropenic patients with vancomycin-resistant E. faecium bacteremia had clinical and microbiological cure with daptomycin, and only five survived for 30 days.127 In this context the use of daptomycin at 10–12 mg/kg daily-well above the currently licensed 4–6 mg/kg dose - may be justified, especially for high inoculum infections, but clinical data are limited and side effects remain to be evaluated in large-scale clinical trials.95,128,129

Tigecycline shows in vitro activity against glycopeptide-non-susceptible Gram-positive bacteria; studies that considered its activity were outlined above in the section on Gram-negative pathogens.57,58

Other new agents active against some resistant Gram-positive bacteria include lipoglycopeptides (e.g., telavancin) and anti-MRSA β-lactams (e.g. ceftaroline), whilst fosfomycin – an old agent - is active against many MRSA and VRE, especially E. faecalis, at least in vitro.103 As yet, though, there is no published experience with these agents in hematological and neutropenic patients.

Duration of targeted therapy

There are several studies reporting that the duration of treatment for microbiologically documented infections (MDI) is at least 7 days.130–137 Others reported on 10–14 days of therapy.138,139 Some studies required some evidence of bone marrow recovery.138–141 Repeated blood cultures had to be sterile, and control of local infection, if any, needed to be achieved. In a few of the studies patients were afebrile for at least 24 hours138–142 while in the other reports the patients were afebrile for at least 4–5 days.130,133,134,136,143

ECIL-4 recommendations

Based on in vitro susceptibility, the options for targeted treatment of infections due to resistant Gram-negative and Gram-positive bacteria are shown in Table 4. As most of these options have not been assessed in large randomized, prospective studies, at least in hematology populations, their use should be approached with caution and should be carefully discussed with the microbiologists or infectious diseases specialist, taking in account also the risk/benefit balance and safety profile of each drug on an individual basis.

As shown in Table 4, colistin/polymyxin B are the preferred agents for treatment of infections due to β–lactam-resistant Enterobacteriaceae, so long as the organism is susceptible in vitro. A loading dose and high maintenance dose may be required.

Tigecycline has wide in vitro activity, but should be used with caution in bacteremia, as it achieves low blood levels. Alternatives should be considered in patients with severe infections, especially ventilator-associated pneumonia, due to the higher mortality seen in the tigecycline arms of comparative trials,48,144 Resistance can develop on treatment.

Combination therapy, based on in vitro susceptibility tests, should be considered when colistin/polymyxin B, tigecycline, aminoglycosides and fosfomycin are used for the treatment of infections due to resistant Gram-negatives. Addition of rifampin can be considered.

The options for targeted treatment of infections due to resistant Gram-positive bacteria are wider than against Gram-negative bacteria. If linezolid is used, monitoring of bone marrow recovery is important because of the possibility of myelosuppression. Patients with suspected or overt pneumonia should not be treated with daptomycin, which is inactivated in lungs.

In general, the patient should be treated using narrower-spectrum agents active against the pathogen identified, if it is plausible and/or clinically significant, guided by in vitro susceptibility tests, including MICs when available, and based on knowledge on drugs with specific activities (e.g. TMP-SMX for S. maltophilia) AI.

Penicillins and penicillin/β-lactamase inhibitors should be preferred over cephalosporins and carbapenems if they have comparable in vitro activity, spectrum of coverage and drug concentration at site of infection BII. A more drastic narrowing of the antibiotics could be envisaged if a fully-susceptible organism is documented from blood cultures of a stable patient under hospital observation, e.g. step down to an amino- or ureido- penicillin (ampicillin or piperacillin) when an α-haemolytic streptococcus is isolated BIII.

Duration of targeted therapy for microbiologically documented infections

Antibiotic treatment should be continued for at least 7 days, until the infection is microbiologically eradicated and all clinical signs of infection are resolved, with the patient afebrile for at least 4 days BIII. If the patient is still neutropenic and antibiotic therapy is stopped, (s)he should be kept hospitalized under close observation for at least 24–48 hours. If fever recurs, antibiotics should be restarted urgently after obtaining blood cultures and performing other relevant evaluation based on clinical judgment.

Centers that give prophylactic antibacterial agents should consider renewing this regimen upon discontinuation of targeted antibiotic therapy, if the patient is still neutropenic CIII.

Discussion

BSI develops in 13% to 60% of HSCT recipients14,26,108,145–147 and in 21–36% of neutropenic leukemia patients.131,136,146,148–151 Rates in other hematology patients are less well documented.

It is of utmost importance to recognize infections due to resistant bacteria and to target the therapy appropriately, based on: (i) in vitro susceptibility, (ii) knowledge of the best treatment option against the particular species and resistance phenotypes, and (iii) a careful assessment of the risk-benefit balance, according to the expected toxicity of the drug(s). Narrower-spectrum agents should be used whenever possible, so long as they have equivalent activity and efficacy. Pharmacokinetic and pharmacodynamic data in individual situations should also be taken in account.

Table 4.ECIL4 Recommendations: targeted treatment of infections due to resistant Gram-negative and -positive bacteria (based on in vitro susceptibility).

Combinations of antibiotics are often required, as resistance can develop on treatment (e.g., fosfomycin), or because of suboptimal efficacy as monotherapy (e.g., tigecycline). Nevertheless the evidence that combinations improve outcomes or prevent the emergence of resistance is scanty at best, and the relationship of in vitro and in vivo synergy is unclear.

The paucity of new antibacterial drugs expected in the near future should lead us to limit the use of the drugs discussed here to documented infection where there is no other alternative. In this context, a strong collaboration is needed between the hematologist, microbiologist, antimicrobial pharmacist and infectious disease specialist. The best treatment option is uncertain in many cases, and many combinations have not been formally assessed, precluding recommendations based on the principles of “evidence-based medicine”. There is a great need to study and monitor the efficacy of these non-conventional antibiotics in the leukemic population.

Whilst current increases in bacterial resistance among leukemic and HSCT patients restrict treatment choices and force the use of the compounds discussed here, it should never been forgotten that they are poorer therapies than the compounds they replace, with clear evidence that colistin and tigecycline are inferior to other antibiotics if the pathogen is susceptible to them.46,48,144 If the underlying problem is the spread of resistant clones of bacterial among the patients in a unit, the best answer is the reinforcement of infection control, not the use of more exotic and complex antimicrobial chemotherapy. Antimicrobial stewardship, aiming to minimize unnecessary broad spectrum antibiotic use and its associated collateral damage and resistance selection is likewise crucial in the present era of growing resistance.

Acknowledgments

The authors would like to thank the participants of the ECIL 4 meeting:

Hamdi Akan, Murat Akova, Turkey; Diana Averbuch, Israel; Rose-Mary Barnes, United Kingdom; Nicole Blijlevens, The Netherlands; Thierry Calandra, Switzerland; Elio Castagnola, Simone Cesaro, Italy; Catherine Cordonnier, France; Oliver Cornely, Germany; Jean-Hughes Dalle, France; Rafael de la Camara, Spain; Emma Dellow (Gilead Sciences) United Kingdom; Peter Donnelly, The Netherlands; Lubos Dgrona, Slovakia; Hermann Einsele, Germany; Dan Engelhard, Israel; Bertrand Gachot, France; Corrado Girmenia, Italy; Andreas Groll, Germany; Ingeborg Gyssens, The Netherlands; Werner Heinz, Germany; Raoul Herbrecht, France; Hans Hirsch, Switzerland; William Hope, United Kingdom; Petr Hubacek, Czech Republic; Chris Kibbler, United Kingdom; Galina Klyasova, Russia; Sean Knox (Astellas Pharma), United Kingdom; Michal Kouba, Czech Republic; Catherine Lagrou, Belgium; Thomas Lernbecher, Germany; Per Ljungman, Sweden; Johan Maertens, Belgium; Oscar Marchetti, Switzerland; Rodrigo Martino, Spain; Georg Maschmeyer, Germany; Tamas Masszi, Hungary; Suzanne Matthes-Martin, Austria; Małgorzata Mikulska, Alessandra Micozzi, Italy; Bilal Mohty, Switzerland; Patricia Munoz, Spain; David Nadal, Christina Orasch, Switzerland; Zdenek Racil, Czech Republic; Patricia Ribaud, France; Valérie Rizzi-Puechal (Pfizer), France; Emmanouil Roilidis, Greece; Janos Sinko, Hungary; Jan Styzynski, Poland; Alina Tanase, Hungary; Mario Tumbarello, Italy; Paul Verweij, The Netherlands; Claudio Viscoli, Italy; Kate-Nora Ward, United Kingdom; Aafje Warris, The Netherlands; Craig Wood (Merck), USA.

The authors would like to thank Jean-Michel Gosset and the staff of KOBE, group GL Events, Lyon, France, for the organization of the meeting.

Footnotes

  • Funding The ECIL-4 meeting has been supported by unrestricted educational grants from Astellas Pharma, Gilead Sciences, Merck, Novartis and Pfizer.
  • Companion papers European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of emerging resistance: summary of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011). Diana Averbuch, Christina Orasch, Catherine Cordonnier, David M Livermore, Małgorzata Mikulska, Claudio Viscoli, Inge C. Gyssens, Galina Klyasova, Oscar Marchetti, Dan Engelhard, Murat Akova. The role of antibiotic stewardship in limiting antibacterial resistance among hematology patients. Inge C. Gyssens, Winfried V. Kern and David M. Livermore.
  • Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
  • Received May 24, 2013.
  • Accepted October 14, 2013.

References

  1. Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of emerging resistance: summary of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011). Haematologica. 2013; 98(12):1836-47. PubMedhttps://doi.org/10.3324/haematol.2013.091330Google Scholar
  2. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009; 34(2):111-20. PubMedhttps://doi.org/10.1016/j.ijantimicag.2009.03.009Google Scholar
  3. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE. Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents. 2010; 35(2):194-9. PubMedhttps://doi.org/10.1016/j.ijantimicag.2009.10.005Google Scholar
  4. Giamarellou H. Multidrug-resistant Gram-negative bacteria: how to treat and for how long. Int J Antimicrob Agents. 2010; 36(Suppl 2):S50-4. PubMedhttps://doi.org/10.1016/j.ijantimicag.2010.11.014Google Scholar
  5. Hachem RY, Chemaly RF, Ahmar CA, Jiang Y, Boktour MR, Rjaili GA. Colistin is effective in treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in cancer patients. Antimicrob Agents Chemother. 2007; 51(6):1905-11. PubMedhttps://doi.org/10.1128/AAC.01015-06Google Scholar
  6. Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N. What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents. 2011; 37(5):415-9. PubMedhttps://doi.org/10.1016/j.ijantimicag.2011.01.012Google Scholar
  7. Empirical &amp; Targeted Antibiotics in Haematological Cancer Patients. 2011. Google Scholar
  8. Empirical and targeted antibacterial therapy in neutropenic patients. 2013. Google Scholar
  9. Cordonnier C, Calandra T. The first European Conference on Infections in Leukemia: Why and How?. Eur J Cancer. 2007; Supp 5:2-4. Google Scholar
  10. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA. 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; 52(4):e56-93. PubMedhttps://doi.org/10.1093/cid/cir073Google Scholar
  11. Caselli D, Cesaro S, Ziino O, Zanazzo G, Manicone R, Livadiotti S. Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation. Haematologica. 2010; 95(9):1612-5. PubMedhttps://doi.org/10.3324/haematol.2009.020867Google Scholar
  12. Falagas ME, Koletsi PK, Bliziotis IA. The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii and Pseudomonas aeruginosa. J Med Microbiol. 2006; 55(Pt 12):1619-29. PubMedhttps://doi.org/10.1099/jmm.0.46747-0Google Scholar
  13. Johnson LE, D’Agata EM, Paterson DL, Clarke L, Qureshi ZA, Potoski BA. Pseudomonas aeruginosa bacteremia over a 10-year period: multidrug resistance and outcomes in transplant recipients. Transpl Infect Dis. 2009; 11(3):227-34. PubMedhttps://doi.org/10.1111/j.1399-3062.2009.00380.xGoogle Scholar
  14. Mikulska M, Del Bono V, Raiola AM, Bruno B, Gualandi F, Occhini D. Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance. Biol Blood Marrow Transplant. 2009; 15(1):47-53. PubMedGoogle Scholar
  15. Oliveira AL, de Souza M, Carvalho-Dias VM, Ruiz MA, Silla L, Tanaka PY. Epidemiology of bacteremia and factors associated with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2007; 39(12):775-81. PubMedhttps://doi.org/10.1038/sj.bmt.1705677Google Scholar
  16. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012; 18(3):268-81. PubMedhttps://doi.org/10.1111/j.1469-0691.2011.03570.xGoogle Scholar
  17. Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother. 2001; 47(3):247-50. PubMedhttps://doi.org/10.1093/jac/47.3.247Google Scholar
  18. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems?. Clin Microbiol Infect. 2011; 17(8):1135-41. PubMedhttps://doi.org/10.1111/j.1469-0691.2011.03553.xGoogle Scholar
  19. Benenson S, Navon-Venezia S, Carmeli Y, Adler A, Strahilevitz J, Moses AE. Carbapenem-resistant Klebsiella pneumoniae endocarditis in a young adult. Successful treatment with gentamicin and colistin. Int J Infect Dis. 2009; 13(5):e295-8. PubMedhttps://doi.org/10.1016/j.ijid.2009.01.006Google Scholar
  20. Daikos GL, Karabinis A, Paramythiotou E, Syriopoulou VP, Kosmidis C, Avlami A. VIM-1-producing Klebsiella pneumoniae bloodstream infections: analysis of 28 cases. Int J Antimicrob Agents. 2007; 29(4):471-3. PubMedhttps://doi.org/10.1016/j.ijantimicag.2006.11.006Google Scholar
  21. Daikos GL, Petrikkos P, Psichogiou M, Kosmidis C, Vryonis E, Skoutelis A. Prospective observational study of the impact of VIM-1 metallo-beta-lactamase on the outcome of patients with Klebsiella pneumoniae bloodstream infections. Antimicrob Agents Chemother. 2009; 53(5):1868-73. PubMedhttps://doi.org/10.1128/AAC.00782-08Google Scholar
  22. Hirsch EB, Tam VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant infection. J Antimicrob Chemother. 2010; 65(6):1119-25. PubMedhttps://doi.org/10.1093/jac/dkq108Google Scholar
  23. Maltezou HC, Giakkoupi P, Maragos A, Bolikas M, Raftopoulos V, Papahatzaki H. Outbreak of infections due to KPC-2-producing Klebsiella pneumoniae in a hospital in Crete (Greece). J Infect. 2009; 58(3):213-9. PubMedhttps://doi.org/10.1016/j.jinf.2009.01.010Google Scholar
  24. Souli M, Galani I, Antoniadou A, Papadomichelakis E, Poulakou G, Panagea T. An outbreak of infection due to beta-lactamase Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae in a Greek University Hospital: molecular characterization, epidemiology, and outcomes. Clin Infect Dis. 2010; 50(3):364-73. PubMedhttps://doi.org/10.1086/649865Google Scholar
  25. Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012; 25(4):682-707. PubMedhttps://doi.org/10.1128/CMR.05035-11Google Scholar
  26. Collin BA, Leather HL, Wingard JR, Ramphal R. Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients. Clin Infect Dis. 2001; 33(7):947-53. PubMedhttps://doi.org/10.1086/322604Google Scholar
  27. Narimatsu H, Matsumura T, Kami M, Miyakoshi S, Kusumi E, Takagi S. Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients. Biol Blood Marrow Transplant. 2005; 11(6):429-36. PubMedhttps://doi.org/10.1016/j.bbmt.2005.01.010Google Scholar
  28. Ortega M, Rovira M, Almela M, Marco F, de la Bellacasa JP, Martinez JA. Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000. Ann Hematol. 2005; 84(1):40-6. PubMedhttps://doi.org/10.1007/s00277-004-0909-0Google Scholar
  29. Trecarichi EM, Tumbarello M, Caira M, Candoni A, Cattaneo C, Pastore D. Multidrug resistant Pseudomonas aeruginosa bloodstream infection in adult patients with hematologic malignancies. Haematologica. 2011; 96(1):e1-3. PubMedhttps://doi.org/10.3324/haematol.2010.036640Google Scholar
  30. Velasco E, Byington R, Martins CS, Schirmer M, Dias LC, Goncalves VM. Bloodstream infection surveillance in a cancer centre: a prospective look at clinical microbiology aspects. Clin Microbiol Infect. 2004; 10(6):542-9. PubMedhttps://doi.org/10.1111/j.1469-0691.2004.00874.xGoogle Scholar
  31. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008; 21(3):538-82. PubMedhttps://doi.org/10.1128/CMR.00058-07Google Scholar
  32. Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin Infect Dis. 2008; 46(4):567-70. PubMedhttps://doi.org/10.1086/526775Google Scholar
  33. Peleg AY, Potoski BA, Rea R, Adams J, Sethi J, Capitano B. Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report. J Antimicrob Chemother. 2007; 59(1):128-31. PubMedhttps://doi.org/10.1093/jac/dkl441Google Scholar
  34. Schafer JJ, Goff DA, Stevenson KB, Mangino JE. Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumannii. Pharmacotherapy. 2007; 27(7):980-7. PubMedhttps://doi.org/10.1592/phco.27.7.980Google Scholar
  35. Navon-Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acinetobacter baumannii. J Antimicrob Chemother. 2007; 59(4):772-4. PubMedhttps://doi.org/10.1093/jac/dkm018Google Scholar
  36. Ansari SR, Hanna H, Hachem R, Jiang Y, Rolston K, Raad I. Risk factors for infections with multidrug-resistant Stenotrophomonas maltophilia in patients with cancer. Cancer. 2007; 109(12):2615-22. PubMedhttps://doi.org/10.1002/cncr.22705Google Scholar
  37. Falagas ME, Valkimadi PE, Huang YT, Matthaiou DK, Hsueh PR. Therapeutic options for Stenotrophomonas maltophilia infections beyond co-trimoxazole: a systematic review. J Antimicrob Chemother. 2008; 62(5):889-94. PubMedhttps://doi.org/10.1093/jac/dkn301Google Scholar
  38. Nicodemo AC, Paez JI. Antimicrobial therapy for Stenotrophomonas maltophilia infections. Eur J Clin Microbiol Infect Dis. 2007; 26(4):229-37. PubMedhttps://doi.org/10.1007/s10096-007-0279-3Google Scholar
  39. Safdar A, Rolston KV. Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis. 2007; 45(12):1602-9. PubMedhttps://doi.org/10.1086/522998Google Scholar
  40. 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(1):37-9. PubMedGoogle Scholar
  41. Muder RR, Harris AP, Muller S, Edmond M, Chow JW, Papadakis K. Bacteremia due to Stenotrophomonas (Xanthomonas) maltophilia: a prospective, multicenter study of 91 episodes. Clin Infect Dis. 1996; 22(3):508-12. PubMedhttps://doi.org/10.1093/clinids/22.3.508Google Scholar
  42. Poulos CD, Matsumura SO, Willey BM, Low DE, McGeer A. In vitro activities of antimicrobial combinations against Stenotrophomonas (Xanthomonas) maltophilia. Antimicrob Agents Chemother. 1995; 39(10):2220-3. PubMedhttps://doi.org/10.1128/AAC.39.10.2220Google Scholar
  43. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother. 1999; 33(9):960-7. PubMedhttps://doi.org/10.1345/aph.18426Google Scholar
  44. Falagas ME, Kasiakou SK. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006; 10(1):R27. PubMedhttps://doi.org/10.1186/cc3995Google Scholar
  45. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J. 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(7):3284-94. PubMedhttps://doi.org/10.1128/AAC.01733-10Google Scholar
  46. Paul M, Bishara J, Levcovich A, Chowers M, Goldberg E, Singer P. Effectiveness and safety of colistin: prospective comparative cohort study. J Antimicrob Chemother. 2010; 65(5):1019-27. PubMedhttps://doi.org/10.1093/jac/dkq069Google Scholar
  47. Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E, Antoniadou A, Tsangaris I. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009; 53(8):3430-6. PubMedhttps://doi.org/10.1128/AAC.01361-08Google Scholar
  48. Increased Risk of Death with Tygacil (Tigecycline) Compared to Other Antibiotics Used to Treat Similar Infections.Google Scholar
  49. Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis. 2005; 41(Suppl 5):S303-14. PubMedhttps://doi.org/10.1086/431672Google Scholar
  50. Apisarnthanarak A, Mundy LM. Use of high-dose 4-hour infusion of doripenem, in combination with fosfomycin, for treatment of carbapenem-resistant Pseudomonas aeruginosa pneumonia. Clin Infect Dis. 2010; 51(11):1352-4. PubMedhttps://doi.org/10.1086/657249Google Scholar
  51. Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008; 46(7):1069-77. PubMedhttps://doi.org/10.1086/527442Google Scholar
  52. Michalopoulos A, Virtzili S, Rafailidis P, Chalevelakis G, Damala M, Falagas ME. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation. Clin Microbiol Infect. 2010; 16(2):184-6. PubMedhttps://doi.org/10.1111/j.1469-0691.2009.02921.xGoogle Scholar
  53. Roussos N, Karageorgopoulos DE, Samonis G, Falagas ME. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections. Int J Antimicrob Agents. 2009; 34(6):506-15. PubMedhttps://doi.org/10.1016/j.ijantimicag.2009.08.013Google Scholar
  54. Cai Y, Wang R, Liang B, Bai N, Liu Y. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother. 2011; 55(3):1162-72. PubMedhttps://doi.org/10.1128/AAC.01402-10Google Scholar
  55. Neonakis IK, Spandidos DA, Petinaki E. Confronting multidrug-resistant Acinetobacter baumannii: a review. Int J Antimicrob Agents. 2011; 37(2):102-9. PubMedhttps://doi.org/10.1016/j.ijantimicag.2010.10.014Google Scholar
  56. Poulakou G, Kontopidou FV, Paramythiotou E, Kompoti M, Katsiari M, Mainas E. Tigecycline in the treatment of infections from multi-drug resistant gram-negative pathogens. J Infect. 2009; 58(4):273-84. PubMedhttps://doi.org/10.1016/j.jinf.2009.02.009Google Scholar
  57. Chemaly RF, Hanmod SS, Jiang Y, Rathod DB, Mulanovich V, Adachi JA. Tigecycline use in cancer patients with serious infections: a report on 110 cases from a single institution. Medicine (Baltimore). 2009; 88(4):211-20. PubMedhttps://doi.org/10.1097/MD.0b013e3181af01fcGoogle Scholar
  58. Bassetti M, Nicolini L, Repetto E, Righi E, Del Bono V, Viscoli C. Tigecycline use in serious nosocomial infections: a drug use evaluation. BMC Infect Dis. 2010; 10:287. PubMedGoogle Scholar
  59. Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013; 57(4):1756-62. PubMedhttps://doi.org/10.1128/AAC.01232-12Google Scholar
  60. Bucaneve GMA, Prospective, randomised, multi-centre controlled trial on empiric antibiotic therapy in febrile neutropenic cancer patients: piperacillin and tazobactam plus tigecycline versus piperacillin or tazobactam monotherapy. ICAAC 2011. 2011;Abstract L1-1503a. Google Scholar
  61. Durakovic N, Radojcic V, Boban A, Mrsic M, Sertic D, Serventi-Seiwerth R. Efficacy and safety of colistin in the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in patients with hematologic malignancy: a matched pair analysis. Intern Med. 2011; 50(9):1009-13. PubMedhttps://doi.org/10.2169/internalmedicine.50.4270Google Scholar
  62. Averbuch D, Horwitz E, Strahilevitz J, Stepensky P, Goldschmidt N, Gatt ME. Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients. Infection. 2013; 41(5):991-7. PubMedhttps://doi.org/10.1007/s15010-013-0471-6Google Scholar
  63. Beno P, Krcmery V, Demitrovicova A. Bacteraemia in cancer patients caused by colistin-resistant Gram-negative bacilli after previous exposure to ciprofloxacin and/or colistin. Clin Microbiol Infect. 2006; 12(5):497-8. PubMedhttps://doi.org/10.1111/j.1469-0691.2006.01364.xGoogle Scholar
  64. Dalfino L, Puntillo F, Mosca A, Monno R, Spada ML, Coppolecchia S. High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study. Clin Infect Dis. 2012; 54(12):1720-6. PubMedhttps://doi.org/10.1093/cid/cis286Google Scholar
  65. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010; 10(9):597-602. PubMedhttps://doi.org/10.1016/S1473-3099(10)70143-2Google Scholar
  66. Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavromanolakis E, Samonis G. Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob Agents. 2010; 35(3):240-3. PubMedhttps://doi.org/10.1016/j.ijantimicag.2009.10.019Google Scholar
  67. Breakpoint tables for interpretation of MICs and zone diameters. Version 3.1. 2013. Google Scholar
  68. Nilsson AI, Berg OG, Aspevall O, Kahlmeter G, Andersson DI. Biological costs and mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob Agents Chemother. 2003; 47(9):2850-8. PubMedhttps://doi.org/10.1128/AAC.47.9.2850-2858.2003Google Scholar
  69. Hasegawa S, Horibe K, Kawabe T, Kato K, Kojima S, Matsuyama T. Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplant. 1998; 22(12):1191-7. PubMedhttps://doi.org/10.1038/sj.bmt.1701506Google Scholar
  70. Bodey G, Abi-Said D, Rolston K, Raad I, Whimbey E. Imipenem or cefoperazone-sulbactam combined with vancomycin for therapy of presumed or proven infection in neutropenic cancer patients. Eur J Clin Microbiol Infect Dis. 1996; 15(8):625-34. PubMedhttps://doi.org/10.1007/BF01691147Google Scholar
  71. Betrosian AP, Frantzeskaki F, Xanthaki A, Georgiadis G. High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii. Scand J Infect Dis. 2007; 39(1):38-43. PubMedhttps://doi.org/10.1080/00365540600951184Google Scholar
  72. Marcus R, Paul M, Elphick H, Leibovici L. Clinical implications of beta-lactam-amino-glycoside synergism: systematic review of randomised trials. Int J Antimicrob Agents. 2011; 37(6):491-503. PubMedhttps://doi.org/10.1016/j.ijantimicag.2010.11.029Google Scholar
  73. Paul M, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ. 2003; 326(7399):1111. PubMedhttps://doi.org/10.1136/bmj.326.7399.1111Google Scholar
  74. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004; 4(8):519-27. PubMedhttps://doi.org/10.1016/S1473-3099(04)01108-9Google Scholar
  75. Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother. 2010; 54(5):1742-8. PubMedhttps://doi.org/10.1128/AAC.01365-09Google Scholar
  76. Martinez JA, Cobos-Trigueros N, Soriano A, Almela M, Ortega M, Marco F. Influence of empiric therapy with a beta-lactam alone or combined with an aminoglycoside on prognosis of bacteremia due to gram-negative microorganisms. Antimicrob Agents Chemother. 2010; 54(9):3590-6. PubMedhttps://doi.org/10.1128/AAC.00115-10Google Scholar
  77. Cometta A, Baumgartner JD, Lew D, Zimmerli W, Pittet D, Chopart P. Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients. Antimicrob Agents Chemother. 1994; 38(6):1309-13. PubMedhttps://doi.org/10.1128/AAC.38.6.1309Google Scholar
  78. Elemam A, Rahimian J, Doymaz M. In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae. J Clin Microbiol. 2010; 48(10):3558-62. PubMedhttps://doi.org/10.1128/JCM.01106-10Google Scholar
  79. Souli M, Galani I, Boukovalas S, Gourgoulis MG, Chryssouli Z, Kanellakopoulou K. In vitro interactions of antimicrobial combinations with fosfomycin against KPC-2-producing Klebsiella pneumoniae and protection of resistance development. Antimicrob Agents Chemother. 2011; 55(5):2395-7. PubMedhttps://doi.org/10.1128/AAC.01086-10Google Scholar
  80. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011; 55(6):3002-4. PubMedhttps://doi.org/10.1128/AAC.01420-10Google Scholar
  81. Rahal JJ. Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis. 2006; 43(Suppl 2):S95-9. PubMedhttps://doi.org/10.1086/504486Google Scholar
  82. Tripodi MF, Durante-Mangoni E, Fortunato R, Utili R, Zarrilli R. Comparative activities of colistin, rifampicin, imipenem and sulbactam/ampicillin alone or in combination against epidemic multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 carbapenemases. Int J Antimicrob Agents. 2007; 30(6):537-40. PubMedhttps://doi.org/10.1016/j.ijantimicag.2007.07.007Google Scholar
  83. Bassetti M, Repetto E, Righi E, Boni S, Diverio M, Molinari MP. Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii infections. J Antimicrob Chemother. 2008; 61(2):417-20. PubMedhttps://doi.org/10.1093/jac/dkm509Google Scholar
  84. Cirioni O, Ghiselli R, Orlando F, Silvestri C, Mocchegiani F, Rocchi M. Efficacy of colistin/rifampin combination in experimental rat models of sepsis due to a multiresistant Pseudomonas aeruginosa strain. Crit Care Med. 2007; 35(7):1717-23. PubMedhttps://doi.org/10.1097/01.CCM.0000266685.25436.03Google Scholar
  85. Giamarellos-Bourboulis EJ, Sambatakou H, Galani I, Giamarellou H. In vitro interaction of colistin and rifampin on multidrug-resistant Pseudomonas aeruginosa. J Chemother. 2003; 15(3):235-8. PubMedhttps://doi.org/10.1159/000069498Google Scholar
  86. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P. 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; 57(3):349-58. PubMedhttps://doi.org/10.1093/cid/cit253Google Scholar
  87. Clinical and Microbiological Outcomes of Infections Due to Carbapenem-Resistant Gram-Negative Bacteria.Google Scholar
  88. A Prospective Observational Study of Patients With Drug Resistant Acinetobacter Baumannii Bacteremia (ANTI-AB).Google Scholar
  89. Dryden MS. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. J Antimicrob Chemother. 2011; 66(Suppl 4):iv7-iv15. PubMedhttps://doi.org/10.1093/jac/dkr072Google Scholar
  90. MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother. 2003; 51(Suppl 2):ii17-25. PubMedGoogle Scholar
  91. Pea F, Furlanut M, Cojutti P, Cristini F, Zamparini E, Franceschi L. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob Agents Chemother. 2010; 54(11):4605-10. PubMedhttps://doi.org/10.1128/AAC.00177-10Google Scholar
  92. Cafiso V, Bertuccio T, Spina D, Purrello S, Campanile F, Di Pietro C. Modulating activity of vancomycin and daptomycin on the expression of autolysis cell-wall turnover and membrane charge genes in hVISA and VISA strains. PLoS One. 2012; 7(1):e29573. PubMedhttps://doi.org/10.1371/journal.pone.0029573Google Scholar
  93. Cui L, Tominaga E, Neoh HM, Hiramatsu K. Correlation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate staphylococcus aureus. Antimicrob Agents Chemother. 2006; 50(3):1079-82. PubMedhttps://doi.org/10.1128/AAC.50.3.1079-1082.2006Google Scholar
  94. Enoch DA, Bygott JM, Daly ML, Karas JA. Daptomycin. J Infect. 2007; 55(3):205-13. PubMedhttps://doi.org/10.1016/j.jinf.2007.05.180Google Scholar
  95. Livermore DM. Future directions with daptomycin. J Antimicrob Chemother. 2008; 62(Suppl 3):iii41-iii9. PubMedhttps://doi.org/10.1093/jac/dkn371Google Scholar
  96. Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study. Clin Infect Dis. 2012; 54(1):51-8. PubMedhttps://doi.org/10.1093/cid/cir764Google Scholar
  97. Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration &gt;1 mg/L: a matched cohort study. Clin Infect Dis. 2013; 56(11):1562-9. PubMedhttps://doi.org/10.1093/cid/cit112Google Scholar
  98. Arias CA, Contreras GA, Murray BE. Management of multi-drug resistant enterococcal infections. Clin Microbiol Infect. 2010; 16(6):555-62. PubMedhttps://doi.org/10.1111/j.1469-0691.2010.03214.xGoogle Scholar
  99. Delgado G, Neuhauser MM, Bearden DT, Danziger LH. Quinupristin-dalfopristin: an overview. Pharmacotherapy. 2000; 20(12):1469-85. PubMedhttps://doi.org/10.1592/phco.20.19.1469.34858Google Scholar
  100. Vergidis PI, Falagas ME. New antibiotic agents for bloodstream infections. Int J Antimicrob Agents. 2008; 3(Suppl 1):S60-5. Google Scholar
  101. Welte T, Pletz MW. Antimicrobial treatment of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) pneumonia: current and future options. Int J Antimicrob Agents. 2010; 36(5):391-400. PubMedhttps://doi.org/10.1016/j.ijantimicag.2010.06.045Google Scholar
  102. Livermore DM. Tigecycline: what is it, and where should it be used?. J Antimicrob Chemother. 2005; 56(4):611-4. PubMedhttps://doi.org/10.1093/jac/dki291Google Scholar
  103. Falagas ME, Roussos N, Gkegkes ID, Rafailidis PI, Karageorgopoulos DE. Fosfomycin for the treatment of infections caused by Gram-positive cocci with advanced antimicrobial drug resistance: a review of microbiological, animal and clinical studies. Expert Opin Investig Drugs. 2009; 18(7):921-44. PubMedhttps://doi.org/10.1517/13543780902967624Google Scholar
  104. Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006; 166(19):2138-44. PubMedhttps://doi.org/10.1001/archinte.166.19.2138Google Scholar
  105. Avery R, Kalaycio M, Pohlman B, Sobecks R, Kuczkowski E, Andresen S. Early vancomycin-resistant enterococcus (VRE) bacteremia after allogeneic bone marrow transplantation is associated with a rapidly deteriorating clinical course. Bone Marrow Transplant. 2005; 35(5):497-9. PubMedhttps://doi.org/10.1038/sj.bmt.1704821Google Scholar
  106. Dubberke ER, Hollands JM, Georgantopoulos P, Augustin K, DiPersio JF, Mundy LM. Vancomycin-resistant enterococcal bloodstream infections on a hematopoietic stem cell transplant unit: are the sick getting sicker?. Bone Marrow Transplant. 2006; 38(12):813-9. PubMedhttps://doi.org/10.1038/sj.bmt.1705530Google Scholar
  107. Kamboj M, Chung D, Seo SK, Pamer EG, Sepkowitz KA, Jakubowski AA. The changing epidemiology of vancomycin-resistant Enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Biol Blood Marrow Transplant. 2010; 16(11):1576-81. PubMedhttps://doi.org/10.1016/j.bbmt.2010.05.008Google Scholar
  108. Poutsiaka DD, Price LL, Ucuzian A, Chan GW, Miller KB, Snydman DR. Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant. 2007; 40(1):63-70. PubMedhttps://doi.org/10.1038/sj.bmt.1705690Google Scholar
  109. Weinstock DM, Conlon M, Iovino C, Aubrey T, Gudiol C, Riedel E. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2007; 13(5):615-21. PubMedhttps://doi.org/10.1016/j.bbmt.2007.01.078Google Scholar
  110. Zirakzadeh A, Gastineau DA, Mandrekar JN, Burke JP, Johnston PB, Patel R. Vancomycin-resistant enterococcal colonization appears associated with increased mortality among allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2008; 41(4):385-92. PubMedhttps://doi.org/10.1038/sj.bmt.1705912Google Scholar
  111. Ashour HM, el-Sharif A. Microbial spectrum and antibiotic susceptibility profile of gram-positive aerobic bacteria isolated from cancer patients. J Clin Oncol. 2007; 25(36):5763-9. PubMedhttps://doi.org/10.1200/JCO.2007.14.0947Google Scholar
  112. Hososaka Y, Hanaki H, Yanagisawa C, Yamaguchi Y, Matsui H, Nakae T. Nosocomial infection of beta-lactam antibiotic-induced vancomycin-resistant Staphylococcus aureus (BIVR). J Infect Chemother. 2006; 12(4):181-4. PubMedhttps://doi.org/10.1007/s10156-006-0455-xGoogle Scholar
  113. Safdar A, Rolston KV. Vancomycin tolerance, a potential mechanism for refractory gram-positive bacteremia observational study in patients with cancer. Cancer. 2006; 106(8):1815-20. PubMedhttps://doi.org/10.1002/cncr.21801Google Scholar
  114. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis. 2006; 42(5):597-607. PubMedhttps://doi.org/10.1086/500139Google Scholar
  115. Smith PF, Birmingham MC, Noskin GA, Meagher AK, Forrest A, Rayner CR. Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia. Ann Oncol. 2003; 14(5):795-801. PubMedhttps://doi.org/10.1093/annonc/mdg211Google Scholar
  116. Raad I, Hachem R, Hanna H, Afif C, Escalante C, Kantarjian H. Prospective, randomized study comparing quinupristin-dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections. J Antimicrob Chemother. 2004; 53(4):646-9. PubMedhttps://doi.org/10.1093/jac/dkh144Google Scholar
  117. Cohen N, Mihu CN, Seo SK, Chung D, Chou J, Heller G. Hematologic safety profile of linezolid in the early periengraftment period after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2009; 15(10):1337-41. PubMedhttps://doi.org/10.1016/j.bbmt.2009.05.021Google Scholar
  118. Hachem RY, Hicks K, Huen A, Raad I. Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis. 2003; 37(1):e8-11. PubMedhttps://doi.org/10.1086/375689Google Scholar
  119. Joshi L, Taylor SR, Large O, Yacoub S, Lightman S. A case of optic neuropathy after short-term linezolid use in a patient with acute lymphocytic leukemia. Clin Infect Dis. 2009; 48(7):e73-4. PubMedhttps://doi.org/10.1086/597298Google Scholar
  120. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy. 2007; 27(8):1189-97. PubMedhttps://doi.org/10.1592/phco.27.8.1189Google Scholar
  121. Raad I, Bompart F, Hachem R. Prospective, randomized dose-ranging open phase II pilot study of quinupristin/dalfopristin versus vancomycin in the treatment of catheter-related staphylococcal bacteremia. Eur J Clin Microbiol Infect Dis. 1999; 18(3):199-202. PubMedhttps://doi.org/10.1007/s100960050258Google Scholar
  122. Moellering RC, Linden PK, Reinhardt J, Blumberg EA, Bompart F, Talbot GH. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Synercid Emergency-Use Study Group. J Antimicrob Chemother. 1999; 44(2):251-61. PubMedhttps://doi.org/10.1093/jac/44.2.251Google Scholar
  123. Raad I, Hachem R, Hanna H, Girgawy E, Rolston K, Whimbey E. Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin-dalfopristin in combination with minocycline. Antimicrob Agents Chemother. 2001; 45(11):3202-4. PubMedhttps://doi.org/10.1128/AAC.45.11.3202-3204.2001Google Scholar
  124. Chaftari AM, Hachem R, Mulanovich V, Chemaly RF, Adachi J, Jacobson K. Efficacy and safety of daptomycin in the treatment of Gram-positive catheter-related bloodstream infections in cancer patients. Int J Antimicrob Agents. 2010; 36(2):182-6. PubMedhttps://doi.org/10.1016/j.ijantimicag.2010.03.015Google Scholar
  125. Rolston KV, McConnell SA, Brown J, Lamp KC. Daptomycin use in patients with cancer and neutropenia: data from a retrospective registry. Clin Adv Hematol Oncol. 2010; 8(4):90-56. PubMedGoogle Scholar
  126. Gould IM. Clinical activity of anti-Gram-positive agents against methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2011; 66(Suppl 4):iv17-iv21. PubMedhttps://doi.org/10.1093/jac/dkr073Google Scholar
  127. Poutsiaka DD, Skiffington S, Miller KB, Hadley S, Snydman DR. Daptomycin in the treatment of vancomycin-resistant Enterococcus faecium bacteremia in neutropenic patients. J Infect. 2007; 54(6):567-71. PubMedhttps://doi.org/10.1016/j.jinf.2006.11.007Google Scholar
  128. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006; 50(10):3245-9. PubMedhttps://doi.org/10.1128/AAC.00247-06Google Scholar
  129. Rose WE, Rybak MJ, Kaatz GW. Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies. J Antimicrob Chemother. 2007; 60(2):334-40. PubMedhttps://doi.org/10.1093/jac/dkm170Google Scholar
  130. Cometta A, Kern WV, De Bock R, Paesmans M, Vandenbergh M, Crokaert F. Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy. Clin Infect Dis. 2003; 37(3):382-9. PubMedhttps://doi.org/10.1086/376637Google Scholar
  131. Cordonnier C, Herbrecht R, Pico JL, Gardembas M, Delmer A, Delain M. Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study. The French Cefepime Study Group. Clin Infect Dis. 1997; 24(1):41-51. PubMedhttps://doi.org/10.1093/clinids/24.1.41Google Scholar
  132. Eggimann P, Glauser MP, Aoun M, Meunier F, Calandra T. Cefepime monotherapy for the empirical treatment of fever in granulo-cytopenic cancer patients. J Antimicrob Chemother. 1993; 32(Suppl B):151-63. PubMedhttps://doi.org/10.1093/jac/32.suppl_B.151Google Scholar
  133. Raad II, Escalante C, Hachem RY, Hanna HA, Husni R, Afif C. Treatment of febrile neutropenic patients with cancer who require hospitalization: a prospective randomized study comparing imipenem and cefepime. Cancer. 2003; 98(5):1039-47. PubMedhttps://doi.org/10.1002/cncr.11613Google Scholar
  134. Sanz MA, Lopez J, Lahuerta JJ, Rovira M, Batlle M, Perez C. Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob Chemother. 2002; 50(1):79-88. PubMedhttps://doi.org/10.1093/jac/dkf087Google Scholar
  135. Tamura K, Matsuoka H, Tsukada J, Masuda M, Ikeda S, Matsuishi E. Cefepime or carbapenem treatment for febrile neutropenia as a single agent is as effective as a combination of 4th-generation cephalosporin + aminoglycosides: comparative study. Am J Hematol. 2002; 71(4):248-55. PubMedhttps://doi.org/10.1002/ajh.10236Google Scholar
  136. Viscoli C, Cometta A, Kern WV, Bock R, Paesmans M, Crokaert F. Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients. Clin Microbiol Infect. 2006; 12(3):212-6. PubMedhttps://doi.org/10.1111/j.1469-0691.2005.01297.xGoogle Scholar
  137. Lehrnbecher T, Stanescu A, Kuhl J. Short courses of intravenous empirical antibiotic treatment in selected febrile neutropenic children with cancer. Infection. 2002; 30(1):17-21. PubMedhttps://doi.org/10.1007/s15010-002-2094-1Google Scholar
  138. Bash RO, Katz JA, Cash JV, Buchanan GR. Safety and cost effectiveness of early hospital discharge of lower risk children with cancer admitted for fever and neutropenia. Cancer. 1994; 74(1):189-96. PubMedhttps://doi.org/10.1002/1097-0142(19940701)74:1<189::AID-CNCR2820740130>3.0.CO;2-7Google Scholar
  139. Mullen CA, Buchanan GR. Early hospital discharge of children with cancer treated for fever and neutropenia: identification and management of the low-risk patient. J Clin Oncol. 1990; 8(12):1998-2004. PubMedGoogle Scholar
  140. Aquino VM, Buchanan GR, Tkaczewski I, Mustafa MM. Safety of early hospital discharge of selected febrile children and adolescents with cancer with prolonged neutropenia. Med Pediatr Oncol. 1997; 28(3):191-5. PubMedhttps://doi.org/10.1002/(SICI)1096-911X(199703)28:3<191::AID-MPO7>3.0.CO;2-EGoogle Scholar
  141. Aquino VM, Tkaczewski I, Buchanan GR. Early discharge of low-risk febrile neutropenic children and adolescents with cancer. Clin Infect Dis. 1997; 25(1):74-8. PubMedhttps://doi.org/10.1086/514512Google Scholar
  142. Cornelissen JJ, Rozenberg-Arska M, Dekker AW. Discontinuation of intravenous antibiotic therapy during persistent neutropenia in patients receiving prophylaxis with oral ciprofloxacin. Clin Infect Dis. 1995; 21(5):1300-2. PubMedhttps://doi.org/10.1093/clinids/21.5.1300Google Scholar
  143. Horowitz HW, Holmgren D, Seiter K. Stepdown single agent antibiotic therapy for the management of the high risk neutropenic adult with hematologic malignancies. Leuk Lymphoma. 1996; 23(1–2):159-63. PubMedhttps://doi.org/10.3109/10428199609054816Google Scholar
  144. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010; 68(2):140-51. PubMedhttps://doi.org/10.1016/j.diagmicrobio.2010.05.012Google Scholar
  145. Almyroudis NG, Fuller A, Jakubowski A, Sepkowitz K, Jaffe D, Small TN. Pre-and post-engraftment bloodstream infection rates and associated mortality in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2005; 7(1):11-7. PubMedhttps://doi.org/10.1111/j.1399-3062.2005.00088.xGoogle Scholar
  146. Castagnola E, Rossi MR, Cesaro S, Livadiotti S, Giacchino M, Zanazzo G. Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: results from a multi-center Italian study. Pediatr Blood Cancer. 2010; 55(6):1103-7. PubMedhttps://doi.org/10.1002/pbc.22750Google Scholar
  147. Ninin E, Milpied N, Moreau P, Andre-Richet B, Morineau N, Mahe B. Longitudinal study of bacterial, viral, and fungal infections in adult recipients of bone marrow transplants. Clin Infect Dis. 2001; 33(1):41-7. PubMedhttps://doi.org/10.1086/320871Google Scholar
  148. Cordonnier C, Herbrecht R, Buzyn A, Leverger G, Leclercq R, Nitenberg G. Risk factors for Gram-negative bacterial infections in febrile neutropenia. Haematologica. 2005; 90(8):1102-9. PubMedGoogle Scholar
  149. Lech-Maranda E, Seweryn M, Giebel S, Holowiecki J, Piatkowska-Jakubas B, Wegrzyn J. Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG). Int J Infect Dis. 2010; 14(2):e132-40. PubMedGoogle Scholar
  150. Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Klingebiel T, Creutzig U. Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia. 2004; 18(1):72-7. PubMedhttps://doi.org/10.1038/sj.leu.2403188Google Scholar
  151. Viscoli C, Paesmans M, Sanz M, Castagnola E, Klastersky J, Martino P. Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients. Clin Infect Dis. 2001; 32(11):1532-7. PubMedhttps://doi.org/10.1086/320514Google Scholar

Article Information

Vol. 98 No. 12 (2013): December, 2013 : Guidelines
 
DOI
https://doi.org/10.3324/haematol.2013.091330
Pubmed
24323984
Pubmed Central
PMC3856958
 
Published
2013-12-01
Published By
Ferrata Storti Foundation, Pavia, Italy
Print ISSN
0390-6078
Online ISSN
1592-8721
 

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