Antibacterial Resistance in Patients with Hematopoietic Stem Cell Transplantation

Sehnaz Alp1 and Murat Akova2

1 Associate Professor, Hacettepe University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Ankara, Turkey
2 Professor, Hacettepe University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Ankara, Turkey

Corresponding author: Murat Akova. Professor, Hacettepe University, Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Ankara, Turkey. E-mail: akova.murat@gmail.com 

Published: January 1, 2017
Received: July 27, 2016
Accepted: November 11, 2016
Mediterr J Hematol Infect Dis 2017, 9(1): e2017002 DOI 10.4084/MJHID.2017.002
This article is available on PDF format at: 

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Recipients of hematopoietic stem cell transplantation (HSCT) are at substantial risk of bacterial, fungal, viral, and parasitic infections depending on the time elapsed since transplantation, presence of graft-versus-host disease (GVHD), and the degree of immunosuppression. Infectious complications in HSCT recipients are associated with high morbidity and mortality. Bacterial infections constitute the major cause of infectious complications, especially in the early post-transplant period. The emergence of antibacterial resistance complicates the management of bacterial infections in this patient group. Multidrug-resistant bacterial infections in this group of patients have attracted considerable interest and may lead to significant morbidity and mortality. Empirical antibacterial therapy in patients with HSCT and febrile neutropenia has a critical role for survival and should be based on local epidemiology. This review attempts to provide an overview of risk factors and epidemiology of emerging resistant bacterial infections and their management in HSCT recipients.


Hematopoietic stem cell transplantation (HSCT) has become the treatment of choice to cure or improve the outcomes of a wide variety of haematological malignancies and disorders.[1-4] HSCT can be performed by the transfer of hematopoietic stem cells from the donor to the recipient (allogeneic HSCT) or by the return of previously harvested cells of the same individual (autologous HSCT) after administration of conditioning regimens.[4] Myeloablative (MA) conditioning leads to profound pancytopenia, and also breaks down mucosal barriers, which might result in seeding of residing microorganisms of the gastrointestinal system into the bloodstream. Therefore, infectious complications begin to appear in the early post-transplant period. Nonmyeloablative (NMA) conditioning has the advantages of reduced regimen-related toxicity and transplant-related mortality. Therefore, patients being referred for HSCT but not eligible to receive a myeloablative conditioning may have the opportunity to benefit from HSCT. Recipients of NMA allogeneic HSCT experience a heterogeneous duration and degree of pancytopenia according to the administered regimen. NMA regimens with lower mucosal toxicity and myelosuppression provide a low incidence of infectious complications within the early period after transplantation. Immune recovery after NMA regimens was shown to be faster than that was seen following MA regimens, and improved immune reconstitution was associated with lower incidence of life-threatening infectious complications. Even though myelosuppressive potential of NMA regimens seems to be milder than MA regimens, the severity and duration of lymphodepletion is assumed to be similar, because of the implementation of immunosuppressive treatment to prevent graft rejection.[4-8]

Risk factors for bacterial and resistant bacterial infections in patients with HSCT

Infectious complications are the major contributors of morbidity and mortality, especially within one year following HSCT. In the early post-transplant period, presence of neutropenia and mucosal damage predispose patients to infections. Presence and severity of graft-versus-host disease (GVHD) and immunosuppressive treatment for it have a considerable impact on the degree of overall immunosuppression and risk of infection.[4,7] The frequent use of central venous catheters brings about a substantial risk for severe, often recurrent, and potentially lethal infections.[9-11] Recipient factors such as age, comorbidities, and previous exposure to infectious agents prior to transplant, and the type of transplant, due to the distinct duration required for immune reconstitution, also influence the risk of infectious complications.[4]
Initiating broad-spectrum empirical antibacterial therapy results in decreased mortality in febrile neutropenic HSCT recipients. On the other hand, the use of such therapy has the risk of selection of resistant pathogens.[9,12-14] Fluoroquinolone prophylaxis in haematology settings led emerging fluoroquinolone resistance.[15-20] This prophylaxis has also been associated with emerging methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant (MDR) Escherichia coli, and Pseudomonas aeruginosa bacteraemia, and Clostridium difficile infections.[21-25] Consequently, empirical carbapenem use in patients receiving quinolone prophylaxis has increased, a practice may, in turn, result in increased carbapenem-resistant bacterial infections.[16,26] In addition, prolonged and/or repeated hospitalisations, intensive care unit (ICU) stay, severity of illness, healthcare-associated infections, presence of urinary catheter and older age are considered as major risk factors for resistant bacterial infections.[12,26-30] Main risk factors for certain resistant bacterial infections are summarised in the Table 1.

Table 1 Table 1. Risks factor for certain resistant bacterial infections[29]

Antibacterial resistance in patients with HSCT

The data on epidemiology of bacterial infections and their resistance patterns in HSCT recipients mostly reflect isolates from bloodstream infections (BSIs) which are the most frequent microbiologically documented bacterial infections. The rate of BSIs varies between 20-30% of allogeneic and 5% of autologous HSCT recipients, especially within pre-engraftment phase. Even though bacterial pneumonia and skin and soft tissue infections are also common among these patients, microbial aetiology may remain undocumented.[29,31]
During‬ 1960s and 1970s, the incidence of gram-negative infections was high in haematology settings. Nevertheless, the incidence of gram-positive pathogens increased during mid-1980s and 1990s as a result of extensive use of indwelling catheters, early-generation fluoroquinolone prophylaxis and broad-spectrum empirical anti-gram-negative antibacterial therapy.[12,29,32-34] Afterwards, coagulase-negative staphylococci were reported as the most common bacterial etiologic agents isolated from blood cultures in most centres.[10,35] However, recent reports from a number of centres revealed drug-resistant gram-negative pathogens such as ESBL-producing gram-negative bacteria, multidrug resistant (MDR) P. aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and carbapenemase-producing gram-negative bacteria as the causative agents of increasing numbers of infections.[9,12,36-44] In countries where high rates of antibiotic resistance exist, ESBL-producing or MDR gram-negative bacteria contribute up to 13-14% of clinical isolates.[26,28,40,45] A significant increase in the prevalence of resistant gram-positive cocci such as MRSA and vancomycin-resistant enterococci (VRE) have also been reported and stated as the overriding resistant pathogens in some centres.[46,47] Penicillin-resistant viridans streptococci and penicillin-resistant Streptococcus pneumoniae (PRSP) are less common, yet they may be the causative agents of severe infections.[9,10,12,48]
The epidemiology of bacterial infections and their resistance patterns show distinct geographic and inter-centre variability. Being aware of the current data on local epidemiology of predominant pathogens and close monitoring of their resistance patterns are of great importance, especially in empirical antibacterial treatment decisions.[12,29,49,50]
Recent reviews on epidemiology of BSIs in cancer patients, primarily with hematologic malignancies including HSCT recipients, revealed that among all BSI isolates, coagulase-negative staphylococci and Enterobacteriaceae (frequently E. coli) were the most common pathogens followed by P. aeruginosa, S. aureus, viridans streptococci, and enterococci. The approximate rates of these commonly encountered pathogens were: 25% (range: 5-60%) for coagulase-negative staphylococci; 25% (range: 6-54%) for Enterobacteriaceae; 10% (range: 0-30%) for P. aeruginosa; 6% (range: 0-20%) for S. aureus; 5% (range: 0-16%) for viridans streptococci; and 5% (range: 0-38%) for enterococci.[29,49,51]
A brief information on the epidemiology of global resistance data for gram-positive and gram-negative bacteria is given below in each corresponding title. An online website showing the current drug resistance rates and antimicrobial use worldwide is also available at ‘http://resistancemap.cddep.org’.

Gram-Negative Bacteria

E. coli is one of the most frequent pathogens causing bacteraemia in patients with cancer and neutropenia.[49,51-53] Production of one or more extended spectrum beta-lactamases (ESBLs) is the main resistance mechanism against broad-spectrum penicillins and cephalosporins in enteric gram-negative pathogens. Many ESBL-producing E. coli are also resistant to non-beta-lactam antibiotics including aminoglycosides and quinolones with altered resistance mechanisms.[52-54] ESBL-encoding plasmids may also encode resistance to aminoglycosides, tetracyclines, sulphonamides and trimethoprim.[52,55] These plasmids frequently encode an inhibitor-resistant beta-lactamase, which confers resistance to beta-lactam-beta-lactamase inhibitor combinations including amoxicillin-clavulanate and piperacillin-tazobactam.[52,55,56] Aminoglycoside resistance among E. coli and other gram-negative enteric pathogens is determined by aminoglycoside-modifying enzymes which can be encoded on the same plasmid with ESBLs.[52] E. coli was the second most frequent carbapenem-resistant Enterobacteriaceae (CRE) following Klebsiella pneumoniae. In a recent US survey, the incidence of CRE was determined as 2.93 per 100.000 population.[52,57]
One of the most significant carbapenemases described in Enterobacteriaceae is New Delhi metallo-beta-lactamase-1 (NDM-1). This enzyme is prevalent in the Indian subcontinent, but also frequently reported in Balkans and the Middle East.[52,58] The bacteria harbouring this enzyme have spread worldwide and are usually only susceptible to colistin, tigecycline and fosfomycin, although susceptibility to these agents is not universal.[52,59] Since E. coli infections are very frequent in the outpatient settings, it is feared that a progressive increase in the prevalence of NDM-1 producing E. coli may occur.[52,58] Plasmid-mediated colistin resistance (via mcr-1 colistin resistance gene) has recently been described in E. coli isolates worldwide from mainly livestock and less frequently in human samples.[52,60-65] The implications of this finding may be horrendous since the offending plasmid can easily be transferred between E. coli strains and to K. pneumonia and P. aeruginosa.[52,66] As a matter of fact, recent reports already noted the presence of this gene from plasmids in Salmonella and K. pneumoniae.[52,67-70]
Along with ESBLs as the main resistance mechanism to broad-spectrum penicillins and cephalosporins in enteric gram-negative pathogens, carbapenem resistance has become the most important epidemiologic and therapeutic challenge in K. pneumoniae.[52,58] There are mainly 3 classes of carbapenemases involved including KPC (Class A), OXA-48 (Class D) and NDM (Class B) for which different epidemiological reservoirs exist.[52,58,59,71-74] A specific KPC-2 or KPC-3-producing clone has been widely disseminated worldwide contributing the spread of resistance.[52,58] Carbapenem-resistant isolates usually show MDR pattern and are susceptible only to colistin, fosfomycin and tigecycline. However, there is also emergence of resistance against these antibiotics.[52,75,76]
P. aeruginosa strains with high resistance rates to aminoglycosides, ceftazidime, quinolones, piperacillin-tazobactam and carbapenems are usually reported from Southern and Eastern part of Europe.[52,77] Several beta-lactamases have been described for causing resistance and these include AmpC, ESBL (particularly PER-1) and metallo-beta-lactamases.[52,55] Carbapenem resistance in P. aeruginosa is mostly due to porin deficiencies and rarely caused by carbapenemase production.[52,78] Emergence of colistin resistance in P. aeruginosa has also been reported.[52,79]
The most frequent Class A ESBLs found in A. baumannii are PER-, GES- and VEB-type enzymes. These beta-lactamases confer resistance to extended-spectrum cephalosporins, but inhibited by tazobactam and clavulanic acid.[52,78] TEM-, SHV- and CTX-M-type ESBLs are rarely found in A. baumannii. Class B beta-lactamases (metalloenzymes) are also reported in A. baumannii and include IMP-, VIM- and NDM-type enzymes. These beta-lactamases provide activity against not only to carbapenems, but also to broad-spectrum cephalosporins and penicillins.[52,80] Class D, OXA-type carbapenemases are the most widespread carbapenemases in A. baumannii.[52,55] These enzymes cause weak resistance to carbapenems. Thus, high-level resistance usually require other mechanisms involved such as efflux and porin loss.[52,78] The ArmA enzyme is the most frequent methylase which is responsible for high-level resistance to all aminoglycosides in A. baumannii. The gene responsible for this enzyme is often identified among OXA-23-producing A. baumannii strains. Other methylases are also described.[52,78] Overexpression of efflux pumps can provide resistance to quinolones. These pumps also use aminoglycosides, tetracyclines, chloramphenicol and trimethoprim as substrates. Thus, quinolone resistance can be selected by non-quinolone antibiotics as well. Usually several of these mechanisms are present in MDR Acinetobacter isolates.[52]
For treatment of MDR gram-negative infections, especially due to carbapenem-resistant Enterobacteriaceae, Pseudomonas species, and Acinetobacter species, colistin (polymyxin E) has been increasingly used as a therapeutic option, administered as monotherapy or in combination regimens, even though limited data exist on its use in haematology patients and HSCT recipients.[26-28,81,82] There are many reports on successful combination regimens for MDR gram-negative infections.[26,83-85] Colistin plus rifampicin treatment has shown in vitro and in vivo synergistic activity for A. baumannii infections.[86,87] However, in a multicentre, randomized clinical trial, colistin plus rifampicin revealed no difference in infection-related mortality and length of hospital stay in the treatment of serious infections due to extensively drug-resistant A. baumannii as compared to colistin alone, but a significant increase in microbiological eradication rate was determined in the colistin plus rifampicin arm.[88] In a recent study, survival benefit with combination therapy (colistin plus carbapenem or tigecycline plus carbapenem) was demonstrated in patients with KPC-producing K. pneumoniae bacteraemia.[89]

Gram-Positive Bacteria

Methicillin resistance is the hallmark of antimicrobial resistance in S. aureus and coagulase-negative staphylococci.[52] While, vancomycin has long been successfully used for treatment of MRSA infections, emergence of S. aureus strains with vancomycin MICs ≥2 mg/L has coincided with reports of treatment failures.[9,90] Community-acquired MRSA (CA-MRSA) infections have emerged as a global problem since the beginning of the 21st century.[51,90-92] Although CA-MRSA strains initially caused mainly skin and soft tissue infections in healthy individuals and some certain populations such as homeless and imprisoned people, increased rates of bacteraemia both in community and hospital setting; ventilator associated pneumonia; and surgical site infections have recently been reported.[52,94,95] CA-MRSA isolates usually remain susceptible to many non-beta-lactam antibiotics including clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX).[52,96]
Coagulase-negative staphylococci are the most common cause of nosocomial BSIs and are responsible almost one-third of all healthcare-associated bacteraemia. The incidence is highest in those with cancer and neutropenia and those with catheter- and/or prosthetic device-related infections.[29,52,97] Multiple antibiotic resistance is highly encountered among hospital isolates and usually related with methicillin resistance.[52,98] Resistance to vancomycin is very rare, however a 20.8% resistance to teicoplanin was reported from UK, particularly in S. haemolyticus.[98]
Penicillin-resistant pneumococci are more likely to show higher resistance to other classes of antimicrobials. Current figures of resistance in the US include 35% to macrolides, 10% to clindamycin, 30% to TMP-SMX, 18% to doxycycline and 2% to respiratory quinolones.[52,99] Higher rates of macrolide resistance are reported from Europe.[52,100]
Viridans streptococci can cause infective endocarditis, especially in patients with compromised heart valves, and they can also produce bacteraemia and septic shock particularly in patients with neutropenia.[51,52,101] Although these bacteria are susceptible to most antimicrobials, beta-lactam resistance, due to the altered penicillin binding proteins has emerged and may cause a significant problem especially in patients with immunosuppression and bacteraemia.[51,52,102] Ceftriaxone and cefepime resistance has been reported up to 23 and 25%, respectively in strains isolated from hospitalised or cancer patients.[52,103,104] Vancomycin is highly effective on such strains.[52]
Among all enterococci, Enterococcus faecium is the most challenging one in terms of antibacterial resistance and therapy. In the US, enterococci are the second most common bacteria isolated from catheter-related (CR)-BSIs.[52,105] Enterococci are intrinsically resistant to many antimicrobials, but also easily acquire mutations and exogenous genes to develop further resistance.[52,106] While aminopenicillin resistance is rare in E. faecalis, it is encountered around 90% of nosocomial E. faecium isolates.[52,100,106] Beta-lactamase production is infrequently associated with resistance and can be overcome with the use of beta-lactamase inhibitor compounds. The production of PBP5 with low affinity to penicillins is the major culprit for beta-lactam resistance.[52,106] High-level resistance to all aminoglycosides eliminates the synergistic activity of penicillins and vancomycin both of which can enhance activity of aminoglycosides in enterococci with low-to-moderate resistance. High-level aminoglycoside resistance has increased in  both E. faecalis and E. faecium during the last 3 decades.[52,100] Glycopeptide resistance in enterococci is a much bigger problem in the US than in Europe and elsewhere. By 2007, >80% of E. faecium isolates in the US hospitals were reported to be resistant to vancomycin whereas in Europe only Ireland reported a resistance rate of >50%.[52,100,106,107] Similarly, MDR enterococci is much more prevalent in the US. [52,106] Enterococci are the third most frequent agents of bacteraemia in haematological cancer patients and HSCT recipients and may affect up to 12% of all transplant patients. On these patient groups, a shift from E. faecalis to E. faecium has resulted in higher rates of VRE infections.[51,52] However, similar to the general epidemiology, VRE infections constitute a less significant problem in Western European transplant centres with <5% of enterococci being resistant to vancomycin.[52,104] Resistance to linezolid and daptomycin is rarely reported.[52,108]
Newer agents with activity against glycopeptide non-susceptible gram-positive pathogens, such as daptomycin, linezolid, and tigecycline are being increasingly used in various clinical settings.[9,12,27-29,109] One of the major drawbacks of daptomycin is the inactivation of the drug by pulmonary surfactant, which limits its use in treatment of pneumonia. Moreover, treatment failure in staphylococcal central nervous system infection was noticed.[26,110] Even though daptomycin had not been evaluated in controlled trials in haematology patients, its efficacy on gram-positive infections in neutropenic patients has been reported.[26,111,112] The clinical utility of tigecycline is limited by its low peak-serum concentrations, and increased failure and mortality rates.[26,113,114]
C. difficile infection (CDI) is among the major concerns in patients undergoing HSCT. Risk factors for CDI in HSCT patients are specified as exposure to broad-spectrum antimicrobial agents, receipt of chemotherapy prior to conditioning for HSCT, total body irradiation, presence of acute GVHD, and VRE colonisation.[115-118] The outcomes of CDI include increased morbidity and mortality due to increased risk of developing complications such as colitis or toxic megacolon, extended hospital stays, necessity to discontinue the required antibiotics, and increased healthcare costs.[119,120] The emergence of an epidemic strain termed as ‘North American PFGE type 1 or NAP1’ is associated with large outbreaks in Europe and the United States. NAP1 has a genetic alteration that results in enhanced toxin production and has been associated with increased severity of CDI, higher relapse and mortality rates.[9,121,122]
Even though the studies conducted in 1980s and 1990s revealed that orally administered metronidazole and vancomycin showed equal effectiveness for treatment of CDI,[9,123,124] with the emergence of the epidemic strain, reports of higher rates of treatment failure or delayed treatment responses have appeared with metronidazole as compared to oral vancomycin.[125-128] There are variable data on the outcomes of CDI in haematology settings, but treatment response to metronidazole and vancomycin is reported to be similar.[26,129-131] While initiation of treatment for CDI, age, white blood cell count, and serum creatinine level should be taken into consideration as indicators for severe or complicated course.[122,132] For the initial episode of mild-to-moderate CDI, metronidazole is the drug of choice. Vancomycin should be preferred for an initial episode of severe CDI. In case of existence of ileus, megacolon, hypotension or shock, vancomycin at higher doses (500 mg 4 times per day) plus metronidazole can be administered. In recurrent CDI, the recommendations for first recurrence are the same as for initial episode. However, in second recurrence, vancomycin (in a tapered and/or pulsed regimen) is the drug of choice.[132]
The data on alternative treatment options for CDI are limited in haematology patients and HSCT recipients. With the use of fidaxomicin, clinical response and recurrence rates were found to be comparable to that of conventional therapy.[133] However, fidaxomicin was associated with a lower recurrence rate of CDI associated with NAP1 strains.[134] In a recent post hoc analysis, fidaxomicin was found to be superior to vancomycin for treatment of CDI in patients with cancer in terms of shorter time to resolution of diarrhoea, higher cure and sustained response rates, and fewer recurrences.[135]

Screening of MDR Bacteria in Patients with HSCT

Infection prevention and control measures such as hand hygiene, contact barrier precautions, isolation, and appropriate environmental cleaning are crucial to deal with the spread of MDR bacteria in haematology settings.[144-146] Active surveillance can help to identify individuals colonised with MDR pathogens. However, it is not clearly defined whether an active-surveillance for MDR bacteria as an additional strategy to infection control procedures is beneficial to prevent health-care-associated
transmission.[144,147-149] Colonisation may persist for months in the case of severe underlying disorders, prolonged or recurrent antimicrobial exposure, and presence of invasive devices.[144,150] Patient populations for targeted screening, as well as ideal screening method and timing of surveillance, are not definitely determined, but can be chosen among those considered to have risk factors for colonization with MDR pathogens, such as prolonged hospital stay, exposure to antimicrobials, ICU stay or transfer from settings known to have high MDR bacteria rates. Another approach is to obtain surveillance cultures from each patient admitted to the settings with high prevalence of MDR pathogens. While some centres establish weekly surveillance cultures, others choose to obtain cultures at the time of admission and/or whenever risk factors emerge for colonisation of MDR bacteria.[144,150-153]
Screening for MRSA colonisation is not routinely performed, but can be established if MRSA rates remain to be high despite effective implementation of infection control measures. In such circumstances, MRSA surveillance cultures should be obtained on admission and thereafter (e.g. weekly) with or without concomitant decolonization.[144,154-156] VRE surveillance cultures can be considered in case of ongoing spread of VRE in an HSCT unit to identify colonised patients.[144,152]
Active surveillance cultures for MDR-GNBs can be used in units with high rates of MDR-GNB infections. A point prevalence survey is recommended if previously unnoticed cases with CRE are identified by the review of microbiology reports for the preceding 6-12 months.[144,146] In a retrospective nationwide survey from Italy, documented carbapenem-resistant K. pneumoniae (CRKp) colonization before or after HSCT was determined to be followed by infection in 25.8% of autologous HSCT and 39.2% of allogeneic HSCT recipients; and infection-related mortality rates were stated as 16% in autologous HSCT and 64.4% in allogeneic HSCT patients.[44] In endemic settings, screening for CRKp before transplantation prior to hospital admission and weekly after transplantation for those who remain negative in case of isolation of CRKp in that unit is recommended.[157,158] Recent reports have revealed that decolonization with aminoglycosides or colistin could succeed in patients colonised with CRE.[157,159-163] Nevertheless, development of resistance to these agents is of concern, and patients can be recolonized after gastrointestinal decolonization.[158,159,164-166]

Management of Febrile Neutropenia in the Era of Resistant Bacterial Infections

For empirical antibacterial treatment in febrile neutropenia, escalation or de-escalation approach can be used. In escalation strategy, initial therapy targets activity against Enterobacteriaceae and P. aeruginosa, but, ESBL- and carbapenemase-producing gram-negative bacilli and drug-resistant non-fermentative bacteria remain out of empirical coverage. In case of development of clinical deterioration or isolation of a resistant pathogen from clinical samples, the spectrum of antibacterial coverage must be broadened. In de-escalation strategy, initial regimen targets to cover drug-resistant pathogens, and once the microbiological data become available, therapy is de-escalated to an appropriate narrower spectrum. Escalation strategy may be considered for patients followed in a centre where MDR pathogens are rarely seen at the onset of febrile neutropenia and for those without any specific risk factors for resistant bacterial infections. De-escalation strategy may be used for febrile neutropenic patients having risk factors for resistant bacterial infections, such as previous infection or known colonisation with ESBL-producing gram-negative bacteria, residents of a centre where MDR pathogens are common, and also for those presenting with septic shock and pneumonia. Initial regimen in de-escalation strategy may include monotherapy with a carbapenem or combination therapy with an anti-pseudomonal beta-lactam agent and an aminoglycoside/quinolone or combination therapy with colistin and a beta-lactam agent/rifampicin. If risk factors for resistant gram-positive infections are present, early coverage with a glycopeptide or newer agents (linezolid, daptomycin, tigecycline) with activity against glycopeptide non-susceptible gram-positive pathogens should be considered. Patients with suspicion of catheter-related infection, known colonisation with MRSA, VRE, and PRSP, hemodynamic instability, severe sepsis, septic shock, presence of skin and soft tissue infection and pneumonia are accepted as candidates for additional antibiotics against resistant gram-positive pathogens.[12,27-29,51]


The emergence of infections with resistant bacterial pathogens is associated with trends towards poor outcomes, prolonged hospital stay, more frequent ICU admissions, and increased treatment costs in haematology patients.[26,45,136-138] Moreover, the bacterial resistance complicates the use of standard antimicrobial regimens in febrile HSCT recipients. Antimicrobial treatment approach for neutropenic or chronically immunosuppressed HSCT recipients with GVHD necessitates careful evaluation of patients; detailed knowledge on local epidemiological data on antibacterial resistance; close monitoring of the emergence of resistance in bacterial pathogens; and use of robust treatment options in the context of a rational antimicrobial stewardship program.[9,139,140] Convenient infection control measures and appropriate vaccination schedules should be implemented to prevent patients from exposure to pathogens.[9,30,50,141-143] Besides, effective attempts should be provided in the development of new antibacterial agents and immune augmentation strategies to cope with resistant bacterial pathogens.[9


  1. Giralt S. Allogeneic hematopoietic progenitor cell transplantation for the treatment of chronic myelogenous leukemia in the era of tyrosine kinase inhibitors: lessons learned to date. Clin Lymphoma Myeloma 2007; 7 Suppl 3: S102-4. https://doi.org/10.3816/CLM.2007.s.009 PMid:17382018       
  2. Dreger P, Corradini P, Kimby E, et al. Chronic Leukemia Working Party of the EBMT. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21: 12-7. https://doi.org/10.1038/sj.leu.2404441 PMid:17109028         
  3. Davies JK, Guinan EC. An update on the management of severe idiopathic aplastic anaemia in children. Br J Haematol 2007; 136: 549-64. https://doi.org/10.1111/j.1365-2141.2006.06461.x PMid:17214739         
  4. Mackall C, Fry T, Gress R, Peggs K, Storek J, Toubert A. Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant 2009; 44: 457-62. https://doi.org/10.1038/bmt.2009.255 PMid:19861978         
  5. Meijer E, Dekker AW, Lokhorst HM, Petersen EJ, Nieuwenhuis HK, Verdonck LF. Low incidence of infectious complications after nonmyeloablative compared with myeloablative allogeneic stem cell transplantation. Transpl Infect Dis 2004; 6: 171-8. https://doi.org/10.1111/j.1399-3062.2004.00075.x PMid:15762935         
  6. Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Little MT, Corey L, Storb R. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99: 1978-85. https://doi.org/10.1182/blood.V99.6.1978 PMid:11877269     
  7. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Storb R. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002; 8: 512-20. https://doi.org/10.1053/bbmt.2002.v8.pm12374456 PMid:12374456         
  8. Baron F, Sandmaier BM. Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia 2006; 20: 1690-700. https://doi.org/10.1038/sj.leu.2404335 PMid:16871276         
  9. Kontoyiannis DP, Lewis RE, Marr K. The burden of bacterial and viral infections in hematopoietic stem cell transplant. Biol Blood Marrow Transplant 2009; 15(1 Suppl): 128-133. https://doi.org/10.1016/j.bbmt.2008.10.005 PMid:19147091         
  10. Dettenkofer M, Ebner W, Bertz H, Babikir R, Finke J, Frank U, et al. Surveillance of nosocomial infections in adult recipients of allogeneic and autologous bone marrow and peripheral blood stem-cell transplantation. Bone Marrow Transplant 2003; 31: 795-801. https://doi.org/10.1038/sj.bmt.1703920 PMid:12732887         
  11. Engelhart S, Glasmacher A, Exner M, Kramer MH. Surveillance for nosocomial infections and fever of unknown origin among adult hematology-oncology patients. Infect Control Hosp Epidemiol 2002; 23: 244-8. https://doi.org/10.1086/502043 PMid:12026148         
  12. Alp S, Akova M. Management of febrile neutropenia in the era of bacterial resistance. Ther Adv Infect Dis 2013; 1: 37-43. https://doi.org/10.1177/2049936113475610 PMid:25165543 PMCid:PMC4040719     
  13. Harbarth S, Harris AD, Carmeli Y, Samore MH. Parallel analysis of individual and aggregated data on antibiotic exposure and resistance in gram-negative bacilli. Clin Infect Dis 2001; 33: 1462-1468. https://doi.org/10.1086/322677 PMid:11588690         
  14. Mebis J, Goossens H, Berneman ZN. Antibiotic management of febrile neutropenia: current developments and future directions. J Chemother 2010; 22: 5-12. https://doi.org/10.1179/joc.2010.22.1.5 PMid:20227985         
  15. Bousquet A, Malfuson JV, Sanmartin N, Konopacki J, MacNab C, Souleau B, de Revel T, Elouennass M, Samson T, Soler C, Foissaud V, Martinaud C. An 8-year survey of strains identified in blood cultures in a clinical haematology unit. Clin Microbiol Infect 2014; 20: O7-12. https://doi.org/10.1111/1469-0691.12294 PMid:23826912         
  16. Garnica M, Nouér SA, Pellegrino FL, Moreira BM, Maiolino A, Nucci M. Ciprofloxacin prophylaxis in high risk neutropenic patients: effects on outcomes, antimicrobial therapy and resistance. BMC Infect Dis 2013; 13: 356. https://doi.org/10.1186/1471-2334-13-356 PMid:23899356 PMCid:PMC3729823     
  17. Therriault BL, Wilson JW, Barreto JN, Estes LL. Characterization of bacterial infections in allogeneic hematopoietic stem cell transplant recipients who received prophylactic levofloxacin with either penicillin or doxycycline. Mayo Clin Proc 2010; 85: 711-8. https://doi.org/10.4065/mcp.2010.0006 PMid:20675508 PMCid:PMC2912731     
  18. Schelenz S, Nwaka D, Hunter PR. Longitudinal surveillance of bacteraemia in haematology and oncology patients at a UK cancer centre and the impact of ciprofloxacin use on antimicrobial resistance. J Antimicrob Chemother 2013; 68: 1431-8. https://doi.org/10.1093/jac/dkt002 PMid:23396855         
  19. Kern WV, Steib-Bauert M, de With K, Reuter S, Bertz H, Frank U, von Baum H. Fluoroquinolone consumption and resistance in haematology-oncology patients: ecological analysis in two university hospitals 1999-2002. J Antimicrob Chemother 2005; 55: 57-60. https://doi.org/10.1093/jac/dkh510 PMid:15574472         
  20. Castagnola E, Haupt R, Micozzi A, Caviglia I, Testi AM, Giona F, Parodi S, Girmenia C. Differences in the proportions of fluoroquinolone-resistant gram-negative bacteria isolated from bacteraemic children with cancer in two Italian centres. Clin Microbiol Infect 2005; 11: 505-7. https://doi.org/10.1111/j.1469-0691.2005.01114.x PMid:15882204         
  21. Rangaraj G, Granwehr BP, Jiang Y, Hachem R, Raad I. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer 2010; 116: 967-73. https://doi.org/10.1002/cncr.24812 PMid:20052728         
  22. MacDougall C, Powell JP, Johnson CK, Edmond MB, Polk RE. Hospital and community fluoroquinolone use and resistance in Staphylococcus aureus and Escherichia coli in 17 US hospitals. Clin Infect Dis 2005; 41: 435-440. https://doi.org/10.1086/432056 PMid:16028149         
  23. Muto CA, Pokrywka M, Shutt K, Mendelsohn AB, Nouri K, Posey K, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005; 26: 273-280. https://doi.org/10.1086/502539 PMid:15796280         
  24. Park SY, Kang CI, Joo EJ, Ha YE, Wi YM, Chung DR, et al. Risk factors for multidrug resistance in nosocomial bacteremia caused by extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Microb Drug Resist 2012; 18: 518-524. https://doi.org/10.1089/mdr.2012.0067 PMid:22742454         
  25. Pépin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 41: 1254-1260. https://doi.org/10.1086/496986 PMid:16206099         
  26. Trubiano JA, Worth LJ, Thursky KA, Slavin MA. The prevention and management of infections due to multidrug resistant organisms in haematology patients. Br J Clin Pharmacol 2015; 79: 195-207. https://doi.org/10.1111/bcp.12310 PMid:24341410 PMCid:PMC4309626     
  27. Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica 2013; 98: 1826-35. https://doi.org/10.3324/haematol.2013.091025 PMid:24323983 PMCid:PMC3856957     
  28. Averbuch D, Cordonnier C, Livermore DM, Mikulska M, Orasch C, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guideliens of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011). Haematologica 2013; 98: 1836-47. https://doi.org/10.3324/haematol.2013.091330 PMid:24323984 PMCid:PMC3856958     
  29. Mikulska M, Del Bono V, Viscoli C. Bacterial infections in hematopoietic stem cell transplantation recipients. Curr Opin Hematol 2014; 21: 451-8. https://doi.org/10.1097/MOH.0000000000000088 PMid:25295742     
  30. Ruhnke M, Arnold R, Gastmeier P. Infection control issues in patients with haematological malignancies in the era of multidrug-resistant bacteria. Lancet Oncol 2014; 15: e606-19. https://doi.org/10.1016/S1470-2045(14)70344-4     
  31. Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: A practical update. Virulence 2016; 7: 280-97. https://doi.org/10.1080/21505594.2016.1156821 PMid:27002635     
  32. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR, Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: 427-31. https://doi.org/10.1093/cid/ciq147 PMid:21205990      
  33. Ramphal R. Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens. Clin Infect Dis 2004; 39(Suppl 1): S25-31. https://doi.org/10.1086/383048 PMid:15250017      
  34. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis 1999; 29: 490-494. https://doi.org/10.1086/598620 PMid:10530434      
  35. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36: 1103-1110. https://doi.org/10.1086/374339 PMid:12715303      
  36. Aubron C, Poirel L, Fortineau N, Nicolas P, Collet L, Nordmann P. Nosocomial spread of Pseudomonas aeruginosa isolates expressing the metallo-beta-lactamase VIM-2 in a hematology unit of a French hospital. Microb Drug Resist 2005; 11: 254-259. https://doi.org/10.1089/mdr.2005.11.254 PMid:16201928      
  37. Cattaneo C, Quaresmini G, Casari S, Capucci MA, Micheletti M, Borlenghi E, et al. Recent changes in bacterial epidemiology and the emergence of fluoroquinolone-resistant Escherichia coli among patients with haematological malignancies: results of a prospective study on 823 patients at a single institution. J Antimicrob Chemother 2008; 61: 721-728. https://doi.org/10.1093/jac/dkm514 PMid:18218645      
  38. Chen CY, Tang JL, Hsueh PR, Yao M, Huang SY, Chen YC, et al. Trends and antimicrobial resistance of pathogens causing bloodstream infections among febrile neutropenic adults with hematological malignancy. J Formos Med Assoc 2004; 103: 526-532. PMid:15318274     
  39. Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005; 41: 848-854. https://doi.org/10.1086/432803 PMid:16107985      
  40. Gudiol C, Tubau F, Calatayud L, Garcia-Vidal C, Cisnal M, Sánchez-Ortega I, et al. Bacteraemia due to multidrug-resistant gram-negative bacilli in cancer patients: risk factors, antibiotic therapy and outcomes. J Antimicrob Chemother 2011; 66: 657-63. https://doi.org/10.1093/jac/dkq494 PMid:21193475      
  41. Gudiol C, Bodro M, Simonetti A, Tubau F, González-Barca E, Cisnal M, Domingo-Domenech E, Jiménez L, Carratalà J. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect 2013; 19: 474-9. https://doi.org/10.1111/j.1469-0691.2012.03879.x PMid:22524597      
  42. Hakki M, Limaye AP, Kim HW, Kirby KA, Corey L, Boeckh M. Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation. Bone Marrow Transplant 2007; 39: 687-693. https://doi.org/10.1038/sj.bmt.1705653 PMid:17401395      
  43. Oliveira AL, de Souza M, Carvalho-Dias VM, Ruiz MA, Silla L, Tanaka PY, et al. Epidemiology of bacteremia and factors associated with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2007; 39: 775-781. https://doi.org/10.1038/sj.bmt.1705677 PMid:17438585      
  44. Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scimè R, Lombardini L, Viscoli C, Rambaldi A; Gruppo Italiano Trapianto Midollo Osseo (GITMO); Gruppo Italiano Trapianto Midollo Osseo GITMO. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant.2015; 50: 282-8. https://doi.org/10.1038/bmt.2014.231 PMid:25310302      
  45. Gudiol C, Calatayud L, Garcia-Vidal C, Lora-Tamayo J, Cisnal M, Duarte R, Arnan M, Marin M, Carratalà J, Gudiol F. Bacteraemia due to extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) in cancer patients: clinical features, risk factors, molecular epidemiology and outcome. J Antimicrob Chemother 2010; 65: 333-41. https://doi.org/10.1093/jac/dkp411 PMid:19959544      
  46. Morris PG, Hassan T, McNamara M, Hassan A, Wiig R, Grogan L, et al. Emergence of MRSA in positive blood cultures from patients with febrile neutropenia-a cause for concern. Support Care Cancer 2008; 16:1085-1088. https://doi.org/10.1007/s00520-007-0398-5 PMid:18274787      
  47. Weinstock DM, Conlon M, Iovino C, Aubrey T, Gudiol C, Riedel E, et al. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant 2007; 13: 615-621. https://doi.org/10.1016/j.bbmt.2007.01.078 PMid:17448922      
  48. Carratala J, Roson B, Fernandez-Sevilla A, Alcaide F, Gudiol F. Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome. Arch Intern Med 1998; 158: 868-872. https://doi.org/10.1001/archinte.158.8.868 PMid:9570172      
  49. Mikulska M, Viscoli C, Orasch C, Livermore DM, Averbuch D, Cordonnier C, Akova M; Fourth European Conference on Infections in Leukemia Group (ECIL-4), a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect 2014; 68: 321-31. https://doi.org/10.1016/j.jinf.2013.12.006 PMid:24370562      
  50. Tatarelli P, Mikulska M. Multidrug-resistant bacteria in hematology patients: emerging threats. Future Microbiol 2016; 11: 767-80. https://doi.org/10.2217/fmb-2015-0014 PMid:27196948      
  51. Balletto E, Mikulska M. Bacterial Infections in hematopoietic stem cell transplant recipients. Mediterr J Hematol Infect Dis 2015; 7: e2015045. https://doi.org/10.4084/mjhid.2015.045 PMid:26185610 PMCid:PMC4500472   
  52. Akova M. Epidemiology of antimicrobial resistance in bloodstream infections. Virulence 2016; 7: 252-66. https://doi.org/10.1080/21505594.2016.1159366 PMid:26984779    
  53. Kara O, Zarakolu P, Ascioglu S, Etgul S, Uz B, Buyukasik Y, Akova M. Epidemiology and emerging resistance in bacterial bloodstream infections in patients with hematologic malignancies. Infect Dis (Lond) 2015; 47: 686-93. https://doi.org/10.3109/23744235.2015.1051105 PMid:26024284   
  54. Paterson DL. Resistance in gram-negative bacteria: Enterobacteriaceae. Am J Infect Control 2006; 34(5 Suppl 1): S20-8; discussion S64-73.   
  55. Livermore DM. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med 2012; 27: 128-42. https://doi.org/10.3904/kjim.2012.27.2.128 PMid:22707882 PMCid:PMC3372794   
  56. Livermore DM, Hope R, Mushtaq S, Warner M. Orthodox and unorthodox clavulanate combinations against extended-spectrum beta-lactamase producers. Clin Microbiol Infect 2008; 14 Suppl 1: 189-93. https://doi.org/10.1111/j.1469-0691.2007.01858.x PMid:18154546      
  57. Guh AY, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, Wilson LE, Vaeth E, Lynfield R, Shaw KM, Vagnone PM, Bamberg WM, Janelle SJ, Dumyati G, Concannon C, Beldavs Z, Cunningham M, Cassidy PM, Phipps EC, Kenslow N, Travis T, Lonsway D, Rasheed JK, Limbago BM, Kallen AJ. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012-2013. JAMA 2015; 314: 1479-87. https://doi.org/10.1001/jama.2015.12480 PMid:26436831      
  58. Nordmann P, Poirel L. The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect 2014; 20: 821-30. https://doi.org/10.1111/1469-0691.12719 PMid:24930781      
  59. Cornaglia G, Giamarellou H, Rossolini GM. Metallo-ß-lactamases: a last frontier for ß-lactams? Lancet Infect Dis 2011; 11: 381-93. https://doi.org/10.1016/S1473-3099(11)70056-1    
  60. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16): 161-8.   
  61. Hasman H, Hammerum AM, Hansen F, Hendriksen RS, Olesen B, Agersø Y, Zankari E, Leekitcharoenphon P, Stegger M, Kaas RS, Cavaco LM, Hansen DS, Aarestrup FM, Skov RL. Detection of mcr-1 encoding plasmid-mediated colistin-resistant Escherichia coli isolates from human bloodstream infection and imported chicken meat, Denmark 2015. Euro Surveill 2015; 20(49). https://doi.org/10.2807/1560-7917.ES.2015.20.49.30085 PMid:26676364      
  62. Malhotra-Kumar S, Xavier BB, Das AJ, Lammens C, Hoang HT, Pham NT, Goossens H. Colistin-resistant Escherichia coli harbouring mcr-1 isolated from food animals in Hanoi, Vietnam. Lancet Infect Dis. 2016 Mar;16(3):286-7. https://doi.org/10.1016/S1473-3099(16)00014-1    
  63. Malhotra-Kumar S, Xavier BB, Das AJ, Lammens C, Butaye P, Goossens H. Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid. Lancet Infect Dis 2016; 16: 283-4. https://doi.org/10.1016/S1473-3099(16)00012-8    
  64. Falgenhauer L, Waezsada SE, Yao Y, Imirzalioglu C, Käsbohrer A, Roesler U, Michael GB, Schwarz S, Werner G, Kreienbrock L, Chakraborty T; RESET consortium. Colistin resistance gene mcr-1 in extended-spectrum ß-lactamase-producing and carbapenemase-producing gram-negative bacteria in Germany. Lancet Infect Dis 2016; 16: 282-3. https://doi.org/10.1016/S1473-3099(16)00009-8   
  65. Perrin-Guyomard A, Bruneau M, Houée P, Deleurme K, Legrandois P, Poirier C, Soumet C, Sanders P. Prevalence of mcr-1 in commensal Escherichia coli from French livestock, 2007 to 2014. Euro Surveill 2016; 21(6). https://doi.org/10.2807/1560-7917.ES.2016.21.6.30135 PMid:26898350      
  66. Paterson DL, Harris PN. Colistin resistance: a major breach in our last line of defence. Lancet Infect Dis 2016; 16: 132-3. https://doi.org/10.1016/S1473-3099(15)00463-6    
  67. Tse H, Yuen KY. Dissemination of the mcr-1 colistin resistance gene. Lancet Infect Dis 2016; 16: 145-6. https://doi.org/10.1016/S1473-3099(15)00532-0    
  68. Webb HE, Granier SA, Marault M, Millemann Y, den Bakker HC, Nightingale KK, Bugarel M, Ison SA, Scott HM, Loneragan GH. Dissemination of the mcr-1 colistin resistance gene. Lancet Infect Dis 2016; 16: 144-5. https://doi.org/10.1016/S1473-3099(15)00538-1    
  69. Du H, Chen L, Tang YW, Kreiswirth BN. Emergence of the mcr-1 colistin resistance gene in carbapenem-resistant Enterobacteriaceae. Lancet Infect Dis 2016; 16: 287-8. https://doi.org/10.1016/S1473-3099(16)00056-6    
  70. Stoesser N, Mathers AJ, Moore CE, Day NP, Crook DW. Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae. Lancet Infect Dis 2016; 16: 285-6. https://doi.org/10.1016/S1473-3099(16)00010-4    
  71. Cantón R, Akóva M, Carmeli Y, Giske CG, Glupczynski Y, Gniadkowski M, Livermore DM, Miriagou V, Naas T, Rossolini GM, Samuelsen Ø, Seifert H, Woodford N, Nordmann P; European Network on Carbapenemases. Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe. Clin Microbiol Infect 2012; 18: 413-31. https://doi.org/10.1111/j.1469-0691.2012.03821.x PMid:22507109       
  72. Hu L, Zhong Q, Shang Y, Wang H, Ning C, Li Y, Hang Y, Xiong J, Wang X, Xu Y, Qin Z, Parsons C, Wang L, Yu F. The prevalence of carbapenemase genes and plasmid-mediated quinolone resistance determinants in carbapenem-resistant Enterobacteriaceae from five teaching hospitals in central China. Epidemiol Infect 2014; 142: 1972-7. https://doi.org/10.1017/S0950268813002975 PMid:24252194      
  73. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, Cornaglia G, Garau J, Gniadkowski M, Hayden MK, Kumarasamy K, Livermore DM, Maya JJ, Nordmann P, Patel JB, Paterson DL, Pitout J, Villegas MV, Wang H, Woodford N, Quinn JP. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013; 13: 785-96. https://doi.org/10.1016/S1473-3099(13)70190-7    
  74. Tseng IL, Liu YM, Wang SJ, Yeh HY, Hsieh CL, Lu HL, Tseng YC, Mu JJ. Emergence of carbapenemase producing Klebsiella pneumonia and spread of KPC-2 and KPC-17 in Taiwan: A nationwide study from 2011 to 2013. PLoS One 2015; 10: e0138471. https://doi.org/10.1371/journal.pone.0138471 PMid:26384242 PMCid:PMC4575059   
  75. Monaco M, Giani T, Raffone M, Arena F, Garcia-Fernandez A, Pollini S; Network EuSCAPE-Italy, Grundmann H, Pantosti A, Rossolini GM. Colistin resistance superimposed to endemic carbapenem-resistant Klebsiella pneumoniae: a rapidly evolving problem in Italy, November 2013 to April 2014. Euro Surveill 2014; 19(42). https://doi.org/10.2807/1560-7917.ES2014.19.42.20939 PMid:25358041    
  76. Giacobbe DR, Del Bono V, Trecarichi EM, De Rosa FG, Giannella M, Bassetti M, Bartoloni A, Losito AR, Corcione S, Bartoletti M, Mantengoli E, Saffioti C, Pagani N, Tedeschi S, Spanu T, Rossolini GM, Marchese A, Ambretti S, Cauda R, Viale P, Viscoli C, Tumbarello M; ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case-control-control study. Clin Microbiol Infect 2015; 21: 1106.e1-8. https://doi.org/10.1016/j.cmi.2015.08.001  PMid:26278669       
  77. European Centre for Disease Prevention and Control (ECDC). Annual epidemiological report 2014. Antimicrobial resistance and healthcare-associated infections. 2015. Available at: http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistance-annual-epidemiological-report.pdf.
  78. Potron A, Poirel L, Nordmann P. Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology. Int J Antimicrob Agents 2015; 45: 568-85. https://doi.org/10.1016/j.ijantimicag.2015.03.001 PMid:25857949    
  79. Jean SS, Lee WS, Yu KW, Liao CH, Hsu CW, Chang FY, Ko WC, Chen RJ, Wu JJ, Chen YH, Chen YS, Liu JW, Lu MC, Lam C, Liu CY, Hsueh PR. Rates of susceptibility of carbapenems, ceftobiprole, and colistin against clinically important bacteria collected from intensive care units in 2007: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART). J Microbiol Immunol Infect 2015 Jan 10. pii: S1684-1182(15)00021-3.   
  80. Dortet L, Poirel L, Nordmann P. Worldwide dissemination of the NDM-type carbapenemases in gram-negative bacteria. Biomed Res Int 2014; 2014: 249856. https://doi.org/10.1155/2014/249856 PMid:24790993 PMCid:PMC3984790   
  81. Durakovic N, Radojcic V, Boban A, Mrsic M, Sertic D, Serventi-Seiwerth R, Nemet D, Labar B. 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: 1009-13. https://doi.org/10.2169/internalmedicine.50.4270 PMid:21532223    
  82. Micol JB, de Botton S, Guieze R, Coiteux V, Darre S, Dessein R, Leroy O, Yakoub-Agha I, Quesnel B, Bauters F, Beaucaire G, Alfandari S. An 18-case outbreak of drug-resistant Pseudomonas aeruginosa bacteriemia in hematology patients. Haematologica 2006; 91: 1134-8. PMid:16885056      
  83. Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D, Laporta D, Lapinsky S, Ellis P, Mirzanejad Y, Martinka G, Keenan S, Wood G, Arabi Y, Feinstein D, Kumar A, Dodek P, Kravetsky L, Doucette S; Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 2010; 38: 1773-85. https://doi.org/10.1097/CCM.0b013e3181eb3ccd PMid:20639750    
  84. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis 2004; 4: 519-27. https://doi.org/10.1016/S1473-3099(04)01108-9    
  85. Martínez JA, Cobos-Trigueros N, Soriano A, Almela M, Ortega M, Marco F, Pitart C, Sterzik H, Lopez J, Mensa J. 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: 3590-6. https://doi.org/10.1128/AAC.00115-10 PMid:20585123 PMCid:PMC2934963   
  86. Hogg GM, Barr JG, Webb CH. In-vitro activity of the combination of colistin and rifampicin against multidrug-resistant strains of Acinetobacter baumannii. J Antimicrob Chemother 1998; 41: 494-5. https://doi.org/10.1093/jac/41.4.494 PMid:9598783    
  87. Petrosillo N, Chinello P, Proietti MF, Cecchini L, Masala M, Franchi C, Venditti M, Esposito S, Nicastri E. Combined colistin and rifampicin therapy for carbapenem-resistant Acinetobacter baumannii infections: clinical outcome and adverse events. Clin Microbiol Infect 2005; 11: 682-3. https://doi.org/10.1111/j.1469-0691.2005.01198.x PMid:16008625      
  88. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis 2013; 57: 349-58. https://doi.org/10.1093/cid/cit253 PMid:23616495      
  89. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother 2012; 56: 2108-13. https://doi.org/10.1128/AAC.06268-11 PMid:22252816 PMCid:PMC3318350   
  90. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis 2007; 44: 1208-1215. https://doi.org/10.1086/513203 PMid:17407040      
  91. Chuang YY, Huang YC. Molecular epidemiology of community-associated meticillin-resistant Staphylococcus aureus in Asia. Lancet Infect Dis 2013; 13: 698-708. https://doi.org/10.1016/S1473-3099(13)70136-1    
  92. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010; 23: 616-87. https://doi.org/10.1128/CMR.00081-09 PMid:20610826 PMCid:PMC2901661   
  93. Laupland KB, Lyytikäinen O, Søgaard M, Kennedy KJ, Knudsen JD, Ostergaard C, Galbraith JC, Valiquette L, Jacobsson G, Collignon P, Schønheyder HC; International Bacteremia Surveillance Collaborative. The changing epidemiology of Staphylococcus aureus bloodstream infection: a multinational population-based surveillance study. Clin Microbiol Infect 2013; 19: 465-71. https://doi.org/10.1111/j.1469-0691.2012.03903.x PMid:22616816      
  94. Skov RL, Jensen KS. Community-associated meticillin-resistant Staphylococcus aureus as a cause of hospital-acquired infections. J Hosp Infect 2009; 73: 364-70. https://doi.org/10.1016/j.jhin.2009.07.004 PMid:19786313      
  95. Rhee Y, Aroutcheva A, Hota B, Weinstein RA, Popovich KJ. Evolving epidemiology of Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 2015; 36: 1417-22. https://doi.org/10.1017/ice.2015.213 PMid:26372679      
  96. Stryjewski ME, Corey GR. Methicillin-resistant Staphylococcus aureus: an evolving pathogen. Clin Infect Dis. 2014 Jan;58 Suppl 1:S10-9. Hope R, Livermore DM, Brick G, Lillie M, Reynolds R; BSAC Working Parties on Resistance Surveillance. Non-susceptibility trends among staphylococci from bacteraemias in the UK and Ireland, 2001-06. J Antimicrob Chemother 2008; 62 Suppl 2: ii65-74.   
  97. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49: 1-45. https://doi.org/10.1086/599376 PMid:19489710 PMCid:PMC4039170   
  98. Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principle and Practice of Infectious Diseases. 8th ed. Philadelphia (USA): Elsevier Saunders; c2015. Chapter 201, Streptococcus pneumonia; p.2310-27. 
  99. EARS-Net: European Centre for Disease Prevention and Control (ECDC), Antimicrobial resistance interactive database (Internet). Stockholm (Sweden): ECDC (cited 2015 Oct 22). Available from http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/database/Pages/database.aspx.  
  100. Slipczuk L, Codolosa JN, Davila CD, Romero-Corral A, Yun J, Pressman GS, Figueredo VM. Infective endocarditis epidemiology over five decades: a systematic review. PLoS One 2013; 8: e82665. https://doi.org/10.1371/journal.pone.0082665 PMid:24349331 PMCid:PMC3857279   
  101. Cordonnier C, Buzyn A, Leverger G, Herbrecht R, Hunault M, Leclercq R, Bastuji-Garin S; Club de Réflexion sur les Infections en Onco-Hématologie. Epidemiology and risk factors for gram-positive coccal infections in neutropenia: toward a more targeted antibiotic strategy. Clin Infect Dis 2003; 36: 149-58. https://doi.org/10.1086/345435 PMid:12522746      
  102. Pfaller MA, Jones RN, Marshall SA, Edmond MB, Wenzel RP. Nosocomial streptococcal blood stream infections in the SCOPE Program: species occurrence and antimicrobial resistance. The SCOPE Hospital Study Group. Diagn Microbiol Infect Dis 1997; 29: 259-63. https://doi.org/10.1016/S0732-8893(97)00159-4    
  103. Pfaller MA, Marshall SA, Jones RN. In vitro activity of cefepime and ceftazidime against 197 nosocomial blood stream isolates of streptococci: a multicenter sample. Diagn Microbiol Infect Dis 1997; 29: 273-6. https://doi.org/10.1016/S0732-8893(97)00139-9    
  104. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A, Kallen A, Limbago B, Fridkin S; National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013; 34: 1-14. https://doi.org/10.1086/668770 PMid:23221186      
  105. Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol 2012; 10: 266-78. https://doi.org/10.1038/nrmicro2761 PMid:22421879 PMCid:PMC3621121   
  106. O'Driscoll T, Crank CW. Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist 2015; 8: 217-30. PMid:26244026 PMCid:PMC4521680  
  107. Cattoir V, Leclercq R. Twenty-five years of shared life with vancomycin-resistant enterococci: is it time to divorce? J Antimicrob Chemother 2013; 68: 731-42. https://doi.org/10.1093/jac/dks469 PMid:23208830      
  108. Micek ST. Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2007; 45(Suppl 3): S184-190. https://doi.org/10.1086/519471 PMid:17712745      
  109. Wahby KA, Alangaden GJ. Daptomycin failure in a neutropenic leukemia patient with Staphylococcus aureus meningitis. Leuk Lymphoma 2012; 53: 1610-2. https://doi.org/10.3109/10428194.2012.661051 PMid:22390617     
  110. Rolston KV, Besece D, Lamp KC, Yoon M, McConnell SA, White P. Daptomycin use in neutropenic patients with documented gram-positive infections. Support Care Cancer 2014; 22: 7-14. https://doi.org/10.1007/s00520-013-1947-8 PMid:23975231      
  111. Barber GR, Lauretta J, Saez R. A febrile neutropenic patient with Enterococcus gallinarum sepsis treated with daptomycin and gentamicin. Pharmacotherapy 2007; 27: 927-32. https://doi.org/10.1592/phco.27.6.927 PMid:17542774      
  112. Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: a systematic review and meta-analysis. J Antimicrob Chemother 2011; 66: 1963-71. https://doi.org/10.1093/jac/dkr242 PMid:21685488      
  113. Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 2012; 54: 1699-709. https://doi.org/10.1093/cid/cis270 PMid:22467668 PMCid:PMC3404716   
  114. Alonso CD, Treadway SB, Hanna DB, Huff CA, Neofytos D, Carroll KC, Marr KA. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2012; 54: 1053-63. https://doi.org/10.1093/cid/cir1035 PMid:22412059 PMCid:PMC3309884   
  115. Willems L, Porcher R, Lafaurie M, Casin I, Robin M, Xhaard A, Andreoli AL, Rodriguez-Otero P, Dhedin N, Socié G, Ribaud P, Peffault de Latour R. Clostridium difficile infection after allogeneic hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 2012; 18: 1295-301. https://doi.org/10.1016/j.bbmt.2012.02.010 PMid:22387347      
  116. Trifilio SM, Pi J, Mehta J. Changing epidemiology of Clostridium difficile-associated disease during stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 405-9. https://doi.org/10.1016/j.bbmt.2012.10.030 PMid:23219779      
  117. Chakrabarti S, Lees A, Jones SG, Milligan DW. Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow Transplant 2000; 26: 871-6. https://doi.org/10.1038/sj.bmt.1702627 PMid:11081387      
  118. Bergogne-Bérézin E. Treatment and prevention of antibiotic associated diarrhea. Int J Antimicrob Agents 2000; 16: 521-6. https://doi.org/10.1016/S0924-8579(00)00293-4    
  119. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002; 34: 346-53. https://doi.org/10.1086/338260 PMid:11774082      
  120. McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005; 353: 2433-41. https://doi.org/10.1056/NEJMoa051590 PMid:16322603      
  121. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, Bourgault AM, Nguyen T, Frenette C, Kelly M, Vibien A, Brassard P, Fenn S, Dewar K, Hudson TJ, Horn R, René P, Monczak Y, Dascal A. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353: 2442-9. https://doi.org/10.1056/NEJMoa051639 PMid:16322602      
  122. Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr. Prospective randomised trial of metronidazole versus vancomycin for Clostridium difficile-associated diarrhoea and colitis. Lancet 1983; 2: 1043-6. https://doi.org/10.1016/S0140-6736(83)91036-X    
  123. Wenisch C, Parschalk B, Hasenhündl M, Hirschl AM, Graninger W. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis 1996; 22: 813-8. https://doi.org/10.1093/clinids/22.5.813 PMid:8722937      
  124. Musher DM, Aslam S, Logan N, Nallacheru S, Bhaila I, Borchert F, Hamill RJ. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 2005; 40: 1586-90. https://doi.org/10.1086/430311 PMid:15889354      
  125. Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, Frost E, McDonald LC. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366: 1079-84. https://doi.org/10.1016/S0140-6736(05)67420-X    
  126. Al-Nassir WN, Sethi AK, Nerandzic MM, Bobulsky GS, Jump RL, Donskey CJ. Comparison of clinical and microbiological response to treatment of Clostridium difficile-associated disease with metronidazole and vancomycin. Clin Infect Dis 2008; 47: 56-62. https://doi.org/10.1086/588293 PMid:18491964      
  127. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45: 302-7. https://doi.org/10.1086/519265 PMid:17599306      
  128. Schalk E, Bohr UR, König B, Scheinpflug K, Mohren M. Clostridium difficile-associated diarrhoea, a frequent complication in patients with acute myeloid leukaemia. Ann Hematol 2010; 89: 9-14. https://doi.org/10.1007/s00277-009-0772-0 PMid:19533126      
  129. Gorschlüter M, Glasmacher A, Hahn C, Schakowski F, Ziske C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG. Clostridium difficile infection in patients with neutropenia. Clin Infect Dis 2001; 33: 786-91. https://doi.org/10.1086/322616 PMid:11512083      
  130. Parmar SR, Bhatt V, Yang J, Zhang Q, Schuster M. A retrospective review of metronidazole and vancomycin in the management of Clostridium difficile infection in patients with hematologic malignancies. J Oncol Pharm Pract 2014; 20: 172-82. https://doi.org/10.1177/1078155213490004 PMid:23804627      
  131. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31: 431-55. https://doi.org/10.1086/651706 PMid:20307191      
  132. Clutter DS, Dubrovskaya Y, Merl MY, Teperman L, Press R, Safdar A. Fidaxomicin versus conventional antimicrobial therapy in 59 recipients of solid organ and hematopoietic stem cell transplantation with Clostridium difficile-associated diarrhea. Antimicrob Agents Chemother 2013; 57: 4501-5. https://doi.org/10.1128/AAC.01120-13 PMid:23836168 PMCid:PMC3754298   
  133. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364: 422-31. https://doi.org/10.1056/NEJMoa0910812 PMid:21288078      
  134. Cornely OA, Miller MA, Fantin B, Mullane K, Kean Y, Gorbach S. Resolution of Clostridium difficile-associated diarrhea in patients with cancer treated with fidaxomicin or vancomycin. J Clin Oncol 2013; 31: 2493-9. https://doi.org/10.1200/JCO.2012.45.5899 PMid:23715579      
  135. Cattaneo C, Casari S, Bracchi F, Signorini L, Ravizzola G, Borlenghi E, Re A, Manca N, Carosi G, Rossi G. Recent increase in enterococci, viridans streptococci, Pseudomonas spp. and multiresistant strains among haematological patients, with a negative impact on outcome. Results of a 3-year surveillance study at a single institution. Scand J Infect Dis 2010; 42: 324-32. https://doi.org/10.3109/00365540903496569 PMid:20100118      
  136. Haeusler GM, Mechinaud F, Daley AJ, Starr M, Shann F, Connell TG, Bryant PA, Donath S, Curtis N. Antibiotic-resistant gram-negative bacteremia in pediatric oncology patients--risk factors and outcomes. Pediatr Infect Dis J 2013; 32: 723-6. https://doi.org/10.1097/INF.0b013e31828aebc8 PMid:23838774     
  137. Ortega M, Marco F, Soriano A, Almela M, Martínez JA, Mu-oz A, Mensa J.Analysis of 4758 Escherichia coli bacteraemia episodes: predictive factors for isolation of an antibiotic-resistant strain and their impact on the outcome. J Antimicrob Chemother 2009; 63: 568-74. https://doi.org/10.1093/jac/dkn514 PMid:19126669      
  138. Gyssens IC, Kern W, Livermore DM. The Role of Antibiotic Stewardship in Limiting Antibacterial Resistance for Haematology Patients. 4th European Conference on Infections in Leukaemia. Meeting: September 8-10th, 2011. Final version: Feb 14th, 2012. Available at: http://www.ebmt.org/Contents/Resources/Library/ECIL/Documents/Forms/AllItems.aspx
  139. Gudiol C, Carratalà J. Antibiotic resistance in cancer patients. Expert Rev Anti Infect Ther 2014; 12: 1003-16. https://doi.org/10.1586/14787210.2014.920253 PMid:24834465      
  140. Engelhard D, Akova M, Boeckh MJ, et al. Bacterial infection prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 467-70. https://doi.org/10.1038/bmt.2009.257 PMid:19861980      
  141. Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: A global perspective. Biol Blood Marrow Transplant 2009; 15: 1143-1238. https://doi.org/10.1016/j.bbmt.2009.06.019 PMid:19747629 PMCid:PMC3103296   
  142. Boyce JM, Pittet D. Guideline for hand hygiene in health-care settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/Infectious Diseases Society of America. MMWR Recomm Rep 2002; 51(RR-16): 1-45, quiz CE1-4.  
  143. Yokoe D, Casper C, Dubberke E, Lee G, Mu-oz P, Palmore T, Sepkowitz K, Young JA, Donnelly JP; Center for International Blood and Marrow Transplant Research; National Marrow Donor Program; European Blood and Marrow Transplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Disease Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Diseases Canada; Centers for Disease Control and Prevention. Infection prevention and control in health-care facilities in which hematopoietic cell transplant recipients are treated. Bone Marrow Transplant 2009; 44: 495-507. https://doi.org/10.1038/bmt.2009.261 PMid:19861984      
  144. Sehulster L, Chinn RY; CDC; HICPAC. Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 2003; 52(RR-10): 1-42. PMid:12836624      
  145. Centers for Disease Control and Prevention (CDC). Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities. MMWR Morb Mortal Wkly Rep 2009; 58: 256-60. PMid:19300408      
  146. Troché G, Joly LM, Guibert M, Zazzo JF. Detection and treatment of antibiotic-resistant bacterial carriage in a surgical intensive care unit: a 6-year prospective survey. Infect Control Hosp Epidemiol 2005; 26: 161-5. https://doi.org/10.1086/502521 PMid:15756887      
  147. Reddy P, Malczynski M, Obias A, Reiner S, Jin N, Huang J, Noskin GA, Zembower T. Screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae among high-risk patients and rates of subsequent bacteremia. Clin Infect Dis 2007; 45: 846-52. https://doi.org/10.1086/521260 PMid:17806048      
  148. Gardam MA, Burrows LL, Kus JV, Brunton J, Low DE, Conly JM, Humar A. Is surveillance for multidrug-resistant enterobacteriaceae an effective infection control strategy in the absence of an outbreak? J Infect Dis 2002; 186: 1754-60. https://doi.org/10.1086/345921 PMid:12447761      
  149. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control 2007; 35(10 Suppl 2): S165-93. https://doi.org/10.1016/j.ajic.2007.10.006 PMid:18068814      
  150. Yeh KM, Siu LK, Chang JC, Chang FY. Vancomycin-resistant enterococcus (VRE) carriage and infection in intensive care units. Microb Drug Resist 2004; 10: 177-83. https://doi.org/10.1089/1076629041310091 PMid:15256034      
  151. Muto CA, Giannetta ET, Durbin LJ, Simonton BM, Farr BM. Cost-effectiveness of perirectal surveillance cultures for controlling vancomycin-resistant Enterococcus. Infect Control Hosp Epidemiol 2002; 23: 429-35. https://doi.org/10.1086/502080 PMid:12186207      
  152. Jernigan JA, Titus MG, Gröschel DH, Getchell-White S, Farr BM. Effectiveness of contact isolation during a hospital outbreak of methicillin-resistant Staphylococcus aureus. Am J Epidemiol 1996; 143: 496-504. https://doi.org/10.1093/oxfordjournals.aje.a008770 PMid:8610665      
  153. Harbarth S, Fankhauser C, Schrenzel J, Christenson J, Gervaz P, Bandiera-Clerc C, Renzi G, Vernaz N, Sax H, Pittet D. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA 2008; 299: 1149-57. https://doi.org/10.1001/jama.299.10.1149 PMid:18334690      
  154. Robicsek A, Beaumont JL, Paule SM, Hacek DM, Thomson RB Jr, Kaul KL, King P, Peterson LR. Universal surveillance for methicillin-resistant Staphylococcus aureus in 3 affiliated hospitals. Ann Intern Med 2008; 148: 409-18. https://doi.org/10.7326/0003-4819-148-6-200803180-00003 PMid:18347349      
  155. Huang SS, Yokoe DS, Hinrichsen VL, Spurchise LS, Datta R, Miroshnik I, Platt R.Impact of routine intensive care unit surveillance cultures and resultant barrier precautions on hospital-wide methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2006; 43: 971-8. https://doi.org/10.1086/507636 PMid:16983607      
  156. Girmenia C, Viscoli C, Piciocchi A, Cudillo L, Botti S, Errico A, Sarmati L, Ciceri F, Locatelli F, Giannella M, Bassetti M, Tascini C, Lombardini L, Majolino I, Farina C, Luzzaro F, Rossolini GM, Rambaldi A. Management of carbapenem resistant Klebsiella pneumoniae infections in stem cell transplant recipients: an Italian multidisciplinary consensus statement. Haematologica. 2015; 100: e373-6. https://doi.org/10.3324/haematol.2015.125484 PMid:25862702 PMCid:PMC4800687   
  157. Metan G, Akova M. Reducing the impact of carbapenem-resistant Enterobacteriaceae on vulnerable patient groups: what can be done? Curr Opin Infect Dis 2016; 29: 555-60. https://doi.org/10.1097/QCO.0000000000000313 PMid:27584588    
  158. Averbuch D, Engelhard D. Gram-Negative Bacterial Infections After Hematopoietic Stem Cell or Solid Organ Transplantation. In: Ljungman P, Snydman D, Boeckh M (eds). Transplant Infections. Springer International Publishing, Switzerland. 2016: 357-80. https://doi.org/10.1007/978-3-319-28797-3_21    
  159. Machuca I, Gutiérrez-Gutiérrez B, Pérez Cortés S, Gracia-Ahufinger I, Serrano J, Madrigal MD, Barcala J, Rodríguez-López F, Rodríguez-Ba-o J, Torre-Cisneros J. Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother 2016 Jul 26. pii: dkw272. https://doi.org/10.1093/jac/dkw272    
  160. Zuckerman T, Benyamini N, Sprecher H, Fineman R, Finkelstein R, Rowe JM, Oren I. SCT in patients with carbapenem resistant Klebsiella pneumoniae: a single center experience with oral gentamicin for the eradication of carrier state. Bone Marrow Transplant 2011; 46: 1226-30. https://doi.org/10.1038/bmt.2010.279 PMid:21057549      
  161. Saidel-Odes L, Polachek H, Peled N, Riesenberg K, Schlaeffer F, Trabelsi Y, Eskira S, Yousef B, Smolykov R, Codish S, Borer A. A randomized, double-blind, placebo-controlled trial of selective digestive decontamination using oral gentamicin and oral polymyxin E for eradication of carbapenem-resistant Klebsiella pneumoniae carriage. Infect Control Hosp Epidemiol 2012; 33: 14-9. https://doi.org/10.1086/663206 PMid:22173517      
  162. Oren I, Sprecher H, Finkelstein R, Hadad S, Neuberger A, Hussein K, Raz-Pasteur A, Lavi N, Saad E, Henig I, Horowitz N, Avivi I, Benyamini N, Fineman R, Ofran Y, Haddad N, Rowe JM, Zuckerman T. Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial. Am J Infect Control 2013; 41: 1167-72. https://doi.org/10.1016/j.ajic.2013.04.018 PMid:24274912      
  163. Bar-Yoseph H, Hussein K, Braun E, Paul M. Natural history and decolonization strategies for ESBL/carbapenem-resistant Enterobacteriaceae carriage: systematic review and meta-analysis. J Antimicrob Chemother 2016; 71: 2729-39. https://doi.org/10.1093/jac/dkw221 PMid:27317444      
  164. Lübbert C, Faucheux S, Becker-Rux D, Laudi S, Dürrbeck A, Busch T, Gastmeier P, Eckmanns T, Rodloff AC, Kaisers UX. Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience. Int J Antimicrob Agents 2013; 42: 565-70. https://doi.org/10.1016/j.ijantimicag.2013.08.008 PMid:24100228    
  165. Oostdijk EA, Kesecioglu J, Schultz MJ, Visser CE, de Jonge E, van Essen EH, Bernards AT, Purmer I, Brimicombe R, Bergmans D, van Tiel F, Bosch FH, Mascini E, van Griethuysen A, Bindels A, Jansz A, van Steveninck FA, van der Zwet WC, Fijen JW, Thijsen S, de Jong R, Oudbier J, Raben A, van der Vorm E, Koeman M, Rothbarth P, Rijkeboer A, Gruteke P, Hart-Sweet H, Peerbooms P, Winsser LJ, van Elsacker-Niele AM, Demmendaal K, Brandenburg A, de Smet AM, Bonten MJ. Effects of decontamination of the oropharynx and intestinal tract on antibiotic resistance in ICUs: a randomized clinical trial. JAMA 2014; 312: 1429-37. https://doi.org/10.1001/jama.2014.7247 PMid:25271544      
  166. Tascini C, Sbrana F, Flammini S, Tagliaferri E, Arena F, Leonildi A, Ciullo I, Amadori F, Di Paolo A, Ripoli A, Lewis R, Rossolini GM, Menichetti F; GENGUT Study Group. Oral gentamicin gut decontamination for prevention of KPC-producing Klebsiella pneumoniae infections: relevance of concomitant systemic antibiotic therapy. Antimicrob Agents Chemother 2014; 58: 1972-6. https://doi.org/10.1128/AAC.02283-13 PMid:24419337 PMCid:PMC4023775    


Abstract views:


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

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

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


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