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Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis

Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative... ORIGINAL RESEARCH ARTICLE published: 12 February 2015 CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.2015.00011 Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis 1 1 2 3 4 5 Rima Moghnieh *, Nour Estaitieh , Anas Mugharbil , Tamima Jisr , Dania I. Abdallah , Fouad Ziade , 6 2 Loubna Sinno and Ahmad Ibrahim Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon Division of Hematology-Oncology, Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon Department of Laboratory Medicine, Makassed General Hospital, Beirut, Lebanon Pharmacy Department, Makassed General Hospital, Beirut, Lebanon Faculty of Public Health, Lebanese University, Beirut, Lebanon Research Coordinator, Makassed General Hospital, Beirut, Lebanon Edited by: Introduction: Bacteremia remains a major cause of life-threatening complications in Ghassan M. Matar, American patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of University of Beirut, Lebanon causative microorganisms differ with time and place. Data from Lebanon are scarce. We Reviewed by: aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital Charles Martin Dozois, Institut in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant National de la Recherche Scientifique, Canada organism (MDRO)-associated bacteremia. Max Maurin, Université Materials and Methods: This is a retrospective study of 75 episodes of bacteremia Aix-Marseille II, France occurring in febrile neutropenic patients admitted to the hematology-oncology unit at *Correspondence: Makassed General Hospital, Lebanon, from October 2009-January 2012.It corresponds Rima Moghnieh, Department of Internal Medicine, Makassed to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients General Hospital, PO Box 11-6301 including antimicrobial resistance and identification of risk factors associated with third Riad El-Solh, Beirut 1107 2210, generation cephalosporin resistance (3GCR) and MDRO-associated bacteremia. Lebanon e-mail: amlakkis@yahoo.com Results: Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/ tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05). Conclusion: Our findings have major implications for the management of febrile neutropenia, especially in breakthrough bacteremia and fever when patients are already on broadspectrum antibiotics. Emergence of resistance to 3GCs and, to a lesser extent, to carbapenems in GN isolates has to be considered seriously in our local guidelines for empiric treatment of febrile neutropenia, especially given that their occurrence was proven to be associated with poorer outcomes. Keywords: febrile neutropenia, bacteremia, 3GCR gram-negative bacteria, MDR gram-negative bacteria, Lebanon Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 1 Moghnieh et al. Bacteremias in neutropenia in Lebanon INTRODUCTION caused by third generation cephalosporin-resistant (3GCR) and carbapenem-resistant bacteria. The progress of anticancer therapy with aggressive supportive care for patients with malignancies and patients undergoing MATERIALS AND METHODS hematopoietic stem cell transplantation (HSCT) have recently SETTING, PATIENTS AND STUDY DESIGN improved patient prognosis (Trecarichi and Tumbarello, 2014). This is retrospective study performed at Makassed General However, these advances, resulting in a prolonged and profound level of immunosuppression, neutropenia in particular, along Hospital, a 200-bed university hospital in Beirut, Lebanon. The hospital’s Institutional Review Board approved the study, and an with the extensive use of implantable medical devices, have also increased the risk of severe infections (Trecarichi and Tumbarello, informed consent was waived since it was observation. Medical records of patients admitted between October 2009 and January 2014). Different types of infections may occur in cancer patients, 2012 were reviewed. Seventy-five episodes of bacteremia occur- but bloodstream infections (BSIs) are the most common severe ring in 70 hospitalized neutropenic adult patients were recorded. infectious complications; the reported prevalence of BSIs ranges Adult cancer patients with fever and neutropenia, includ- from 11 to 38%, and the crude mortality rate reaches up to 40% ing those undergoing Hematopoietic Stem Cell Transplantation (Wisplinghoff et al., 2003a,b; Tumbarello et al., 2012; Montassier (HSCT), with positive blood cultures were selected. All posi- et al., 2013). tive results of blood cultures with the corresponding antibiogram The type of microorganisms isolated on blood culture from were checked and recorded from the Microbiology Laboratory febrile neutropenic patients varies with time and place (Jones, 1999; Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; Irfan log books and computerized laboratory records. Information regarding these episodes were collected and recorded in a specific et al., 2008; Freifeld et al., 2011). Data from the Middle East and North Africa (MENA) region is scarce. database from patients’ medical records. Patient characteristics were identified, including age, gender, At the beginning of the use of cytotoxic chemotherapy in type of cancer, risk level, recurrence of admissions, duration the 1960s and 1970s in cancer patients, gram-negative bacteria of neutropenia prior to bacteremia, hospital stay prior to bac- (GNB) were the most common organisms causing bacteremia teremia, presence of a focus of infection, presence of a central in febrile neutropenic patients (Jones, 1999; Irfan et al., 2008); line or an implantable venous access, outcome, sepsis, intu- however, at the turn of the century, the most common bacterial bation, HSCT, antibiotic and antifungal intake in the hospital pathogens isolated from blood cultures were coagulase-negative setting. Univariate analysis of these characteristics was used to staphylococci (Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; identify risk factors for3GCR and multi-drug resistant (MDR) Freifeld et al., 2011). organism-associated bacteremia. However, in recent years several studies have demonstrated a clear trend in the epidemiology of BSIs, showing a shift DEFINITIONS AND INCLUSION CRITERIA of prevalence from gram-positive to gram-negative bacteria Patients were included if they met all three of the following (Wisplinghoff et al., 2003b; Pagano et al., 2012; Montassier et al., inclusion criteria: 2013). There is an emergence of drug-resistant GNB such as mul- tidrug resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, extended-spectrum (1) Fever, defined as a single oral temperature of 38.3 Coran oral temperature of 38 Clasting 1h or more. beta-lactamase (ESBL)-producing GNB, and carbapenemase- producing GNB (Zinner, 1999; Wisplinghoff et al., 2003b; (2) Neutropenia, defined as a neutrophil count of <500 3 3 cells/mm ,oracountof <1000 cells/mm with a docu- Ramphal, 2004; Freifeld et al., 2011; Pagano et al., 2012; Wu et al., 2012; Montassier et al., 2013). The issue of antimicrobial mented decrease to <500 cells/mm within the following 48–72 h. resistance has become a significant problem worldwide, where (3) Receipt of chemotherapy prior to the episode of treatment of infections due to MDR bacteria represents a clinical challenge because the therapeutic options are often very limited. febrileneutropenia. Risk factors of bacteremia due to MDR GNB in febrile neu- tropenic cancer patients vary depending on the type of organism, Patients who had fever and neutropenia as a result of their duration of hospitalization, and antibiotic therapy (Gudiol and underlying disease without having received chemotherapy were Carratala, 2014). excluded. So, the fact that the epidemiology of pathogens is dynamic In Lebanon, anaerobic cultures are performed only in ref- makes contemporary local data extremely important, and iden- erence laboratories. Hospital-based laboratories perform only tification of pathogens locally recovered from blood cultures of aerobic cultures. According to hospital policy, one set of blood febrile neutropenic patients and the patterns of their antibi- cultures consists of two bottles of aerobic cultures taken from two otic susceptibilities are essential in making therapeutic decisions different draws at the same time, with no bottles for anaerobic (Sigurdardottir et al., 2005). culture. Bacteremia is defined as isolation of the same bacterial The purpose of this study is to evaluate the epidemi- or pathogen from at least one set of blood cultures (2 bottles ology of bacteremia occurring during neutropenia in adult taken at the same time). Bacteremia is considered polymicro- cancer chemotherapy patients in a university hospital in bial if at least two organisms from the same blood culture on Lebanon, with a special emphasis on the prevalence, sus- two occasions are isolated or more than one organism each in ceptibility profile and risk factors associated with bacteremia at least two separate blood cultureswithin 48 h (Reuben et al., Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 2 Moghnieh et al. Bacteremias in neutropenia in Lebanon 1989). Bacteremia occurring more than 14 days after a previous patients, antibiotic treatment, and patient outcomes are shown episode and separated by repeatedly negative blood cultures was in Table 1. considered a separate episode. Each separate hospital admission Of the 75 bacteremias, 42.7% were due to gram-positive for febrile neutropenia was defined as one episode. Subsequent organisms, and the remaining 57.3% were gram-negative. hospital admissions for febrile neutropenia in the same patient were included as separate cases. Bacteremia caused by a potential skin contaminant (such as Table 1 | Epidemiological and clinical characteristics of all episodes of coagulase-negative staphylococci, Bacillus,or Corynebacterium bacteremia. species) was considered significant only if it met the following Characteristic Total [n = 75(%)] criteria: AGE (YEARS) (1) Growth of the same bacterial strainin two blood cultures 0–18 5 (6.67) taken from two different sites at the same time. 18–65 62 (82.67) (2) Growth of the same bacterial strain in one blood culture and >65 8 (10.67) in one other sterile site (urine, cerebrospinal fluid, ascetic GENDER fluid, pleural fluid, joint fluid). Male 36 (48) (3) Growth of the same bacterial strain in one peripheral blood Female 39 (52) culture and one blood culture taken from an intravenous TUMOR TYPE catheter where both cultures were taken at the same time. Leukemia 56 (74.67) Lymphoma 15 (20) Interpretive criteria (breakpoints) for susceptible, intermedi- Solid 4 (5.33) ate, and resistant bacterial isolates were those included in the MASCC score Clinical and Laboratory Standards Institute guidelines (Clinical >21 5 (6.67) and Laboratory Standards Institute, 2010). <21 70 (93.33) The 3GCR Enterobacteriaceae phenotypes included all isolates NEUTROPENIA DURATION PRIOR TO BACTEREMIA not susceptible to one or more of five agents including aztreonam, <7 days 26 (34.67) cefotaxime, ceftizoxime, ceftazidime, and ceftriaxone (Clinical >7 days 26 (34.67) and Laboratory Standards Institute, 2010). These isolates were, Unknown 23 (30.67) however, susceptible to imipenem. HOSPITAL STAY PRIOR TO BACTEREMIA Many different definitions for multidrug resistance are used in <2 days 21 (28) the medical literature to characterize different patterns of resis- Between 2and7days 4(5.33) tance in healthcare-associated, antimicrobial-resistant bacteria >7 days 48 (64) (Magiorakos et al., 2012).However, generally speaking, MDR- Unknown 2 (2.67) Gram negative bacteria are resistant to key antimicrobial agents RECURRENT ADMISSION (Siegel et al., 2007; Hidron et al., 2008). Third and fourth Yes 67 (89.33) generation cephalosporins, along with fluoroquinolones, amino- No 8 (10.67) glycosides, and carbapenems, constitute the major therapeutic FOCUS OF INFECTION options in treatment guidelines of febrile neutropenia in adult No/Unknown 17 (22.67) cancer patients (Freifeld et al., 2011; Averbuch et al., 2013). In Pneumonia 3 (4) this study, gram-negative bacteria were considered MDR when Gastroenteritis 13 (17.33) resistant to third and fourth generation cephalosporins, fluoro- Urinary tract infection 7 (9.33) quinolones, aminoglycosides and carbapenems, including S. mal- Skin and soft tissue infection 3 (4) tophilia, carbapenem-resistant P. aeruginosa and Acinetobacter Central line associated 30 (40) baumannii, or carbapenem-resistant 3GCR Enterobacteriaceae. Portal catheter associated 2 (2.67) PLACEMENT OF CENTRAL VENOUS CATHETER STATISTICAL ANALYSIS Yes 52 (69.33) Data were reported as the mean standard deviation (SD) or num- <10 days 18 (24) ber of patients (percentage). T-tests (two-tailed), Fisher’s exact >10 days 34 (45.33) tests and Chi-square tests were used to assess any significant dif- No 23 (30.67) ferencesamong the groups. P < 0.05 were considered statistically OUTCOME significant. Death 7 (9.33) Recovery 68 (90.67) RESULTS Sepsis 8 (10.67) During the study period, 75 episodes of bacteremia occurring Intubation 7 (9.33) in 70 hospitalized neutropenic adult patients with hemato- Hematopoietic stem cell transplantation 41 (54.67) logical malignancies, including those undergoing HSCT, were recorded. Epidemiological and clinical characteristics of the N.B. MASCC, Multinational Association of Supportive Care in Cancer. Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 3 Moghnieh et al. Bacteremias in neutropenia in Lebanon Gram-positive bacteremias were mostly due to methicillin- prior to bacteremia, recurrent admissions, neutropenia prior to resistant coagulase negative staphylococci, which represented bacteremia, presence of CVC, and focus of infection, did not show 66% of gram-positive bacteremias and 28% of total bacteremias. any statistical significance, suggesting that the former factors were No methicillin-resistant Staphylococcus aureus-related bacteremia not risk factors. However, history and duration of antibiotic was detected and only one episode of methicillin-sensitive intake before the episode of bacteremia was majorly implicated in Staphylococcus aureus-related bacteremia was observed. (Refer to the occurrence of 3GCR bacteremia. The type of broad spectrum Tables 2, 3). antibiotic use did not affect the results; butduration of intake did Among the gram-negative bacteremias, Escherichia coli (22.7% affect results. The use of carbapenems, piperacillin/tazobactam, of total, 39.5% of gram-negative) and Klebsiella pneumonia or 3rd or 4th GC ± aminoglycosides for more than 4 days prior (13.3% of total, 23.3% of gram-negative)were the most important to the bacteremic episode was significantly associated with 3GCR causative agents. Out of the 17 bacteremias caused by E. coli,eight bacteremia compared with all other types of bacteremias. (P < were due to 3GCR resistant strains (10.7% of total bacteremias 0.01) A worse outcome, defined by need for intubation and the and 47% of E. coli strains). From those caused by K. pneumoniae occurrence of sepsis in bacteremic patients, was also statistically (10 bacteremias), five cases were due to 3GCR strains (6.7% of significant in the 3GCR group compared with the other groups. total bacteremia and 50% of K. pneumoniae). In general, 28% of (P < 0.03) (Refer to Tables 5, 6). the total bacteremias were due to 3GC sensitive gram-negative Similarly, infection with an MDR strain was associated with bacteria and 29.3% of the total bacteremias were caused by significantly higher rates of subsequent intubation, sepsis, and 3GC resistant gram-negative bacteria. Concerning carbapenem mortality. (P < 0.03)The history and duration of antibiotic susceptibility in the 3GC resistant category, seven cases were intake before the episode of bacteremia was significantly asso- carbapenem-resistant, representing 9.3% of total bacteremias. ciated with the occurrence of MDR bacteremia as well. The (Refer to Tables 2, 4). use of cephalosporins ± aminoglycosides was not significantly Results of the univariate analysis of factors potentially asso- associated with MDR bacteremia, while the use of carbapen- ciated with 3GCR bacteremia, including baseline and demo- ems or piperacillin/tazobactam for more than 4 days prior to graphic characteristics, major disease and risk, hospitalization MDR-bacteremia was significantly associated with its occurrence. (P < 0.04) (Refer to Tables 5, 6). Table 2 | Causative organisms of all episodes of bacteremia. DISCUSSION Data from Lebanon in neutropenic patients is scarce, and the Causative organisms Number of episodes available literature reveals the dynamic nature of the etiology [n = 75(%)] of bacteremias with time. Previous studies from Lebanon have shown gram-negative organisms to be the predominant agents in gram-positive Bacteria 32 (42.67) febrile neutropenic patients (Hamzeh et al., 2000; Kanafani et al., Staphylococcus aureus 1(1.33) 2007). In addition to the subdivision between gram-positive and Coagulase-negative staphylococci (CNS) 28 (37.33) gram-negative organisms, we investigated antibiotic susceptibility Methicillin resistant CNS 21 (28) patterns and the risk factors associated with bacteremia caused by Streptococcus pneumoniae 1(1.33) antibiotic-resistant gram-negative organisms. Enterococcus faecium 1(1.33) In this study, the distribution of the 75 cases was almost equal Aerococcus viridans 1(1.33) between gram-positive and gram-negative organisms (42.7 vs. gram-negative Bacteria (GNB) 43 (57.33) 57.3%). Yet, a study by Kanafani et al. (2007) in 2007 from Escherichia coli 17 (22.67) Lebanon showed gram-negative predominance in febrile neu- 3GCR -Escherichia coli 8(10.67) tropenia bacteremic episodes. Gram-negative organisms were Pseudomonas aeruginosa 3(4) responsible for 78.8% of bloodstream infections compared with Pseudomonas putida 1(1.33) 33.3% gram-positive organisms (Kanafani et al., 2007). Pseudomonas stutzeri 1(1.33) In fact, the shift from a preponderance of gram-negative bacte- Klebsiella pneumoniae 10 (13.33) ria causing bloodstream infections in febrile neutropenic patients 3GCR- Klebsiella pneumoniae 5(6.67) to gram-positive bacteria has been observed worldwide. The Klebsiella oxytoca 1(1.33) widespread use of indwelling catheters, early-generation fluoro- Proteus mirabilis 3(4) quinolone prophylaxis, and broad spectrum empirical anti-gram- Enterobacter cloacae 2(2.67) negative antibacterial therapy led to an increase in the incidence Acinetobacter baumannii 2(2.67) of gram-positive pathogens in the 1980s and 1990s (Zinner, 1999; Stenotrophomonas maltophilia 2(2.67) Ramphal, 2004; Freifeld et al., 2011). Thereafter, the most com- Salmonella species 1(1.33) mon bacterial etiologic agent isolated from blood cultures in 3GC sensitive GNB 21 (28) most centers was reported to be coagulase-negative staphylococci 3GCR GNB 22 (29.33) (Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; Freifeld et al., 3GCR carbapenem-sensitive GNB 15 (20) 2011). In our study, coagulase-negative staphylococci were the 3GCR carbapenem-resistant GNB 7 (9.33) most common among gram-positive organisms (37.3% of total N.B. 3GCR, third generation cephalosporin-resistant. cases, 87.5% of gram-positive cases), where methicillin-resistant Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 4 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 3 | Antibiotic susceptibility profile of isolated gram-positive bacteria. Antibiotic No of susceptible gram-positive isolates (%) CNS S. aureus S. pneumoniae E. faecium A. viridans Total [n = 28(%)] [n = 1(%)] [n = 1(%)] [n = 1(%)] [n = 1(%)] [n = 32(%)] Oxacillin 7 (25) 1 (100) 1 (100) 0 (0) 0 (0) 9 (28.1) Ampicillin – 1 (100) 1 (100) 0 (0) 0 (0) 10 (31.3) Rifampin 24 (85.7) 1 (100) 1 (100) 0 (0) 0 (0) 26 (81.3) Clindamycin 16 (57.1) 1 (100) 1 (100) 0 (0) 1 (100) 19 (59.4) Teicoplanin 28 (100) 1 (100) 1 (100) 1 (100) 1 (100) 32 (100) Vancomycin 28 (100) 1 (100) 1 (100) 1 (100) 1 (100) 32 (100) N.B. A.viridans, Aerococcus viridans; CNS, Coagulase Negative Staphylococci; E. faecium, Enterococcus faecium; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumonia. Table 4 | Antibiotic susceptibility profile of isolated gram-negative bacteria. No. of susceptible gram-negative isolates (%) Antibiotic E. coli Klebsiella Pseudomonas P.mirabilis Enterobacter S. maltophilia A. baumannii Salmonella Total [n = 17(%)] spp. spp. [n = 3(%)] spp. [n = 2(%)] [n = 2(%)] spp. [n = 43(%)] [n = 11(%)] [n = 5(%)] [n = 2(%)] [n = 1(%)] Amox/Clav 5 (29.4) 5 (45.5) 0 (0) 3 (100) 0 (0) 0 (0) 0 (0) 1 (100) 11 (25.6) Amikacin 15 (88.2) 10 (90.9) 5 (100) 3 (100) 2 (100) 0 (0) 1 (50) 1 (100) 37 (86) Cefepime 5 (29.4) 6 (54.5) 3 (60) 3 (100) 1 (50) 0 (0) 0 (0) 1 (100) 19 (44.2) Ceftazidime 8 (57.1) 5 (45.5) 4 (80) 3 (100) 0 (0) 1 (50) 1 (50) 1 (100) 23 (53.5) Ceftriaxone 8 (57.1) 6 (54.5) 2 (40) 3 (100) 0 (0) 0 (0) 0 (0) 1 (100) 19 (44.2) Imipenem 14 (82.4) 11 (100) 4 (80) 3 (100) 2 (100) 0 (0) 1 (50) 1 (100) 36 (83.7) Pip/Tazo 13 (76.5) 7 (63.6) 5 (100) 3 (100) 0 (0) 0 (0) 1 (50) 1 (100) 30 (69.8) Tigecycline 17 (100) 10 (90.9) 1 (20) 3 (100) 2 (100) 2 (100) 2 (100) 1 (100) 40 (93) Colistin 17 (100) 11 (100) 4 (80) 3 (100) 2 (100) 0 (0) 2 (100) 1 (100) 40 (93) Quinolones 7 (41.2) 7 (63.6) 4 (80) 1 (33.3) 0 (0) 2 (100) 1 (50) 0 (0) 22 (51.2) N.B. A.baumannii, Acinetobacter baumannii; Amox/Clav, Amoxicillin/Clavulanate; E. coli, Escherichia coli; Pip/Tazo, Piperacillin/Tazobactam; P.mirabilis, Proteus mirabilis; S. maltophilia, Stenotrophomonas maltophilia; spp, species. coagulase-negative staphylococciisolatesrepresented 28% of the E. coli isolates have been reported with a frequency ranging total cases and 65.6% of gram-positive cases. from 12 to 75% (mean 35%) in cancer patients. 3GCR K. pneu- Our results showed that E. coli and K. pneumoniae were the moniae isolates causing BSIs in neutropenic patients have been most prevalent gram-negative organisms, representing 22.7 and reported with a frequency ranging from 3 to 66.6% (mean 37.8%) 13.3%, respectively, of total cases. A systematic literature review (Trecarichi and Tumbarello, 2014). conducted by Trecarichi and Tumbarello (2014) from January We found that 9.3% of episodes of bacteremia in cancer 2007 to August 2013 examined the recent trends in epidemiology patients were caused by MDR gram-negative bacteria. This and antimicrobial resistance in gram-negative bacteria recovered finding is in line with recent studies, which report an increase in from cancer patients, with a particular emphasis on the impact of antibiotic resistance among gram-negative bacteria in immuno- antimicrobial resistance on the clinical outcome of severe infec- compromised hosts. One study performed in Italy by Gudiol et al. tions caused by such microorganisms. The gram-negative bacte- (2011) reported an incidence of 13.7% of MDR gram-negative rial species most frequently isolated were E. coli, whose frequency associated bacteremia, andin another study performed in Pakistan ranged from 10.1 to 53.6% (mean 32.1%), and K. pneumoniae, by Irfan et al. (2008), the emergence of carbapenem resistance which was isolated with a frequency ranging from 4.1 to 44.6% was reported in Pseudomonas species (20.7% of the isolates) (mean 19.5%) (Trecarichi and Tumbarello, 2014). and in Acinetobacter species (65.4% of the isolates). In another In ourstudy,3GCRstrains of E. coli and K. pneumoniae study by Trecarichi et al. (2011) from Italy, among 38 patients caused 10.7 and 6.7% of total bacteremias, respectively. 3GCR- diagnosed with P. aeruginosa bacteremia, 27 were MDR species Enterobacteriaceae colonization or infection of patients with (71.1%). The percentages of in vitro resistance to major antimi- febrile neutropenia has been reported with increased frequency crobial classes were the following: carbapenems (imipenem during the last decade. Bloodstream infections due to 3GCR and meropenem) 60%, antipseudomonal cephalosporins Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 5 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 5 | Baseline and demographic characteristics, clinical features, and outcome of patients with 3GCR-bacteremia compared with non-3GCR-bacteremia and MDR-bacteremia compared with non-MDR-bacteremia. Characteristic 3GCR-Bacteremia Non-3GCR-Bacteremia P-value MDR Bacteremia Non-MDR Bacteremia P-value [n = 22(%)] [n = 53(%)] [n = 7(%)] [n = 68(%)] AGE (YEARS) 0–18 1 (4.5) 4 (7.5) 0 (0) 5 (7.4) 18–65 19 (86.4) 43 (81.1) 6 (85.7) 56 (82.4) >65 2 (9.1) 6 (11.3) 0.846 1 (14.3) 7 (10.3) 0.734 GENDER Male 9 (40.9) 27 (50.9) 3 (42.9) 33 (48.5) Female 13 (59.1) 26 (49.1) 0.428 4 (57.1) 35 (51.5) 0.775 TUMOR TYPE Leukemia 17 (77.3) 39 (73.6) 6 (85.7) 50 (73.5) Lymphoma 4 (18.2) 11 (20.8) 0 (0) 15 (22.1) Solid 1 (4.5) 3 (5.7) 0.944 1 (14.3) 3 (4.4) 0.243 MASCC SCORE >21 0 (0) 5 (9.4) 0 (0) 5 (7.4) <21 22 (100) 48 (90.6) 0.136 7 (100) 63 (92.6) 0.458 NEUTROPENIA DURATION PRIOR TO BACTEREMIA <7days 8(36.4) 15 (28.3) 3 (42.9) 20 (29.4) >7days 7(31.8) 19 (35.8) 1 (14.3) 25 (36.8) Unknown 7 (31.8) 19 (35.8) 0.789 3 (42.9) 23 (33.8) 0.485 HOSPITAL STAY PRIOR TO BACTEREMIA <2days 7(31.8) 14 (26.4) 2 (28.6) 19 (27.9) Between 2and7days 2(9.1) 2 (3.8) 1 (14.3) 3 (4.4) >7 days 13 (59.1) 35 (66) 4 (57.1) 44 (64.7) Unknown 0 (0) 2 (3.8) 0.586 0 (0) 2 (2.9) 0.700 RECURRENT ADMISSION Yes 2 (9.1) 6 (11.3) 0 (0) 8 (11.8) No 20 (90.9) 47 (88.7) 0.776 7 (100) 60 (88.2) 0.337 FOCUS OF INFECTION No/Unknown 3 (13.6) 14 (26.4) 1 (14.3) 16 (23.5) Pneumonia 1 (4.5) 2 (3.8) 1 (14.3) 2 (2.9) Gastroenteritis 0 (0) 3 (5.7) 0 (0) 3 (4.4) UTI 6 (27.3) 7 (13.2) 2 (28.6) 11 (16.2) SStI 8 (36.4) 22 (41.5) 2 (28.6) 28 (41.2) Central line associated 1 (4.5) 1 (1.9) 0 (0) 2 (2.9) Portal catheter associated 3 (13.6) 4 (7.5) 0.507 1 (14.3) 6 (8.8) 0.702 PLACEMENT OF CVC Yes 7 (31.8) 16 (30.2) 2 (28.6) 21 (30.9) <10 days 6 (27.3) 12 (22.6) 3 (42.9) 15 (22.1) >10 days 9 (40.9) 25 (47.2) 2 (28.6) 32 (47.1) No 7 (31.8) 16 (30.2) 0.866 2 (28.6) 21 (30.9) 0.442 OUTCOME Death 5 (22.7) 2 (3.8) 4 (57.1) 3 (4.4) Recovery 17 (77.3) 51 (96.2) 0.010 3 (42.9) 65 (95.6) <0.0001 Sepsis 5 (22.7) 3 (5.7) 0.029 4 (57.1) 4 (5.9) <0.0001 Intubation 5 (22.7) 2 (3.8) 0.010 4 (57.1) 3 (4.4) <0.0001 HSCT 13 (59.1) 29 (54.7) 0.728 4 (57.1) 38 (55.9) 0.949 N.B. MASCC, Multinational Association of Supportive Care in Cancer, UTI, Urinary tract infection; SStI, Skin and soft tissue Infection; CVC, Central Venous Catheter; HSCT, Hematopoietic stem cell transplantation. (ceftazidime and cefepime) 42%, and piperacillin 24% Third and fourth generation cephalosporins remain the first line (Trecarichi et al., 2011). option for primary therapy in febrile neutropenia (Freifeld et al., The emergence of 3GCR Enterobacteriaceae and MDR gram- 2011; Averbuch et al., 2013). In this group of patients, appro- negative organisms causing bacteremia in cancer patients is very priate initial empirical antibiotic therapy is essential, (Gudiol critical in terms of empiric therapy for febrile neutropenia. and Carratala, 2014) and empiric antibiotic therapy in febrile Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 6 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 6 | Antimicrobial history and duration prior to bacteremia in all cases, in patients with 3GCR- bacteremia compared with non-3GCR-bacteremia and in MDR-bacteremiacompared with non-MDR-bacteremia. Antimicrobial duration Total 3GCR- Non-3GCR- P-value MDR- Non-MDR- P-value before bacteremia n = 75 (%) Bacteremia Bacteremia Bacteremia Bacteremia [n = 22(%)] [n = 53(%)] [n = 7(%)] [n = 68(%)] Carbapenem (Group1) <4 8(10.67) 1 (4.5) 7 (13.2) 0.269 1 (14.3) 7 (10.3) 0.745 days Carbapenem>4 days 14 (18.67) 8 (36.4) 6 (11.3) 0.011 4 (57.1) 10 (14.7) 0.006 No Carbapenem 55 (73.33) 1 (4.5) 4 (7.5) 0.635 1 (14.3) 4 (5.9) 0.396 PIP/TAZ (Group2) <4days 5(6.67) 5 (22.7) 2 (3.8) 0.010 2 (28.6) 5 (7.4) 0.066 PIP/TAZ >4days 7(9.33) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12 (17.6) 0.112 No PIP/TAZ 65 (86.67) 6 (27.3) 5 (9.4) 0.047 2 (28.6) 9 (13.2) 0.275 3rd or 4th GC ± Amikacin 15 (20) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12(17.6) 0.112 (Group3) <4 days 3rd or 4th GC ± Amikacin>4 11 (14.67) 8 (36.4) 6 (11.3) 0.011 3 (42.9) 11 (16.2) 0.085 days No 3rd or 4th GC ± Amikacin 51 (68) 2 (9.1) 11 (20.8) 0.224 2 (28.6) 11 (16.2) 0.409 Group 1 or 2 or 3 <4 days 15 (20) 7 (31.8) 5 (9.4) 0.016 3 (42.9) 9 (13.2) 0.042 Group 1 or 2 or 3 >4 days 14 (18.67) 2 (9.1) 5 (9.4) 0.963 2 (28.6) 5 (7.4) 0.066 No group 2 or 3 or 4 49 (65.33) 4 (18.2) 5 (9.4) 0.288 2 (28.6) 7 (10.3) 0.156 Carbapenem or PIP/TAZ <4 13 (17.33) 1 (4.5) 7 (13.2) 0.269 1 (14.3) 7 (10.3) 0.745 days Carbapenem or PIP/TAZ >4 12 (16) 8 (36.4) 6 (11.3) 0.011 4 (57.1) 10 (14.7) 0.006 days No Carbapenem or PIP/TAZ 52 (69.33) 1 (4.5) 4 (7.5) 0.635 1 (14.3) 4 (5.9) 0.396 Antifungal other than 7(9.33) 5 (22.7) 2 (3.8) 0.010 2 (28.6) 5 (7.4) 0.066 Fluconazole <4 days Antifungal other than 9(12) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12 (17.6) 0.112 Fluconazole >4 days No Antifungal other than 62 (82.67) 6 (27.3) 5 (9.4) 0.047 2 (28.6) 9 (13.2) 0.275 Fluconazole N.B. PIP/TAZ, Piperacillin/Tazobactam; 3rd or 4th GC, Third or Fourth Generation Cephalosporin. neutropenic patients has reduced mortality rates from approxi- were MDR-gram-negative in origin. Previous exposure to third mately 21% (Viscoli et al., 2005) to 2–10%, (Vidal et al., 2004; generation cephalosporins either as prophylaxis or empirical ther- Toussaint et al., 2006) depending upon the underlying diagnosis, apy and belonging to one of the HSCT centers were associated degree of cancer control, duration of severe neutropenia and type with an increased risk for ESBL-producing Enterobacteriaceae of infection. Inappropriate empiric therapy is defined, in con- (Oliveira et al., 2007).Another retrospective case-control study text, as not including at least one antibiotic active in vitro against involving HSCT recipients (Garnica et al., 2009)showedby the infecting microorganism(s) (Freifeld et al., 2011; Averbuch univariate analysis that previous use of a third or fourth- et al., 2013), and the emergence of 3GCR and MDR organisms in generation cephalosporin (P = 0.005 and 0.02, respectively) and febrile neutropenia renders 3rd or 4th GCs inappropriate choices duration of antibiotic use (P < 0.001) were among the factors in certain situations. associated with bacteremia due to MDR-gram-negative isolates Our results showed that the use of broad spectrum antibiotics, including K. pneumonia and P. aeruginosa. In another study including carbapenems, piperacillin/tazobactam, and 3rd or 4th performed in the United States by Rangaraj et al. (2010),the GC ± aminoglycosides, for more than 4 days prior to bacteremia use of multiple broad spectrum antibiotics compared with no was significantly associated with 3GCR bacteremia. (P < 0.01) antimicrobial agents was significantly associated with isolation However, in the case of carbapenem-resistant 3GCR bacteremia of MDR P. aeruginosa (8.2 vs. 0.7%, p < 0.005).This finding (MDR), the use of carbapenems or piperacillin/tazobactam, is consistent with a more recent study in 2013 by Satlin et al. but not cephalosporins, for more than 4 days prior to MDR- (2013), where exposure to any broadspectrum antibacterial agent bacteremia was significantly associated with its occurrence. (P < may be sufficient to increase the risk of carbapenem-resistant 0.04) (Refer to Table 6) Previous antibiotic therapy has been rec- Enterobacteriaceae acquisition and cause bloodstream infections ognized as a major risk factor for the development of bacterial in patients with hematologic malignancies. resistance. In prospective study involving13 Brazilian HSCT cen- Our results showed that patient outcome was influenced sig- ters (Oliveira et al., 2007), 22% of 91 episodes of bacteremia nificantly by antimicrobial resistance, and the risk ofsubsequent Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 7 Moghnieh et al. Bacteremias in neutropenia in Lebanon intubation, sepsis and mortality were high in the 3GC-resistant ESGICH/ESCMID and ELN. European guidelines for empirical antibacte- rial therapy for febrile neutropenic patients in the era of growing resistance: bacteremia group and in the MDR-bacteremia group com- summary of the 2011 4th European Conference on Infections in Leukemia. pared with patients having other bacteremias(P < 0.03).(Refer to Haematologica 98, 1826–1835. doi: 10.3324/haematol.2013.091025 Table 5) Other studies indicated that a dramatic increase in the Caselli, D., Cesaro, S., Ziino, O., Zanazzo, G., Manicone, R., Livadiotti, S., detection rate of MDR gram-negative bacteremia compared with et al. (2010). Multidrug resistant Pseudomonas aeruginosa infection in previous periods was associated with increased morbidity, mor- children undergoing chemotherapy and hematopoietic stem cell trans- plantation. Haematologica 95, 1612–1615. doi: 10.3324/haematol.2009. tality, and cost, especially in patients with hematological diseases (Lodise et al., 2007). Moreover, mortality was independently asso- Clinical and Laboratory Standards Institute (CLSI) (2010). Performance Standards ciated with inadequate initial antimicrobial treatment in the case for Antimicrobial Susceptibility Testing: 20th Informational Supplement. Wayne, of antibiotic-resistant bacteremia (Giske et al., 2008). Thus, local PA: CLSI. Dettenkofer, M., Ebner, W., Bertz, H., Babikir, R., Finke, J., Frank, U., et al. monitoring of bacterial isolates is recommended to adapt initial (2003). Surveillance of nosocomial infections in adult recipients of allogeneic empiric antibiotic therapy based on the local prevalence of MDR and autologous bone marrow and peripheral blood stem-cell transplantation. strains (Caselli et al., 2010). Bone Marrow Transplant. 31, 795–801. doi: 10.1038/sj.bmt.1703920 Our study has at least two major limitations. The first is that Freifeld, A. G., Bow, E. J.,Sepkowitz, K. A.,Boeckh, M. J.,Ito,J.I., Mullen,C.A., the samples were collected from a single medical center; there- et al. (2011). Infectious diseases society of america clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update fore, results could not be generalized to other medical centers in by the infectious diseases society of america. Clin. Infect. Dis. 52, 427–431. doi: Lebanon because the microbial ecology differs from one center to 10.1093/cid/ciq147 another. The second limitation is that the small sample size did Garnica, M., Maiolino, A., and Nucci, M. (2009). Factors associated with bac- not allow us to perform a multivariate analysis and limited our teremia due to multidrug-resistant Gram-negative bacilli in hematopoietic stem statistical analysis to a univariate model. cell transplant recipients. Braz.J.Med.Biol. Res. 42, 89–93. doi: 10.1590/S0100- 879X2009000300010 Giske, C. G., Monnet, D. L., Cars, O., and Carmeli, Y. (2008). ReAct-action on CONCLUSION antibiotic resistance clinical and economic impact of common multidrug- In conclusion, our data showed equal occurrence of gram- resistant gram-negative bacilli. Antimicrob. Agents Chemother. 52, 813–821. doi: 10.1128/AAC.01169-07 negative and gram-positive organisms causing bacteremia in Gudiol, C., and Carratala, J. (2014). Antibiotic resistance in cancer patients. Expert febrile neutropenic cancer patients in our center. We found Rev. Anti. Infect. Ther. 12, 1003–1016. doi: 10.1586/14787210.2014.920253 that bacteremia caused by gram-negative antimicrobial resistant Gudiol, C., Tubau, F., Calatayud, L., Garcia-Vidal, C., Cisnal, M., Sánchez-Ortega, strains is common among cancer patients, especially in those I., et al. (2011). Bacteraemia due to multidrug-resistant Gram-negative bacilli exposed to antibiotic pressure. Emergence of resistance to third in cancer patients: risk factors, antibiotic therapy and outcomes. J. Antimicrob. 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A multi-centre prospective study of febrile neutropenia in Norway: construed as a potential conflict of interest. microbiological findings and antimicrobial susceptibility. Scand. J. Infect. Dis. 37, 455–464. doi: 10.1080/00365540510038497 Received: 13 November 2014; accepted: 17 January 2015; published online: 12 Toussaint, E., Bahel-Ball, E., Vekemans, M., Georgala, A., Al-Hakak, L., Paesmans, February 2015. M., et al. (2006). Causes of fever in cancer patients (prospective study over 477 Citation: Moghnieh R, Estaitieh N, Mugharbil A, Jisr T, Abdallah DI, Ziade F, Sinno L episodes). Support Care Cancer 14, 763–769. doi: 10.1007/s00520-005-0898-0 and Ibrahim A (2015) Third generation cephalosporin resistant Enterobacteriaceae Trecarichi, E. M., and Tumbarello, M. (2014). Antimicrobial-resistant Gram- and multidrug resistant gram-negative bacteria causing bacteremia in febrile neu- negative bacteria in febrile neutropenic patients with cancer: current epi- tropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major demiology and clinical impact. Curr. Opin. Infect. Dis. 27, 200–210. doi: risk factor, and correlation with poor prognosis. Front. Cell. Infect. Microbiol. 5:11. 10.1097/QCO.0000000000000038 doi: 10.3389/fcimb.2015.00011 Trecarichi, E. M., Tumbarello, M., Caira, M., Candoni, A., Cattaneo, C., Pastore, D., This article was submitted to the journal Frontiers in Cellular and Infection et al. (2011). Multidrug resistant Pseudomonas aeruginosa bloodstream infection Microbiology. in adult patients with hematologic malignancies. Haematologica 96, e1–e3 doi: Copyright © 2015 Moghnieh, Estaitieh, Mugharbil, Jisr, Abdallah, Ziade, Sinno and 10.3324/haematol.2010.036640 Ibrahim. This is an open-access article distributed under the terms of the Creative Tumbarello, M., Trecarichi, E. M., Caira, M., Candoni, A., Pastore, D., Cattaneo, C., Commons Attribution License (CC BY). The use, distribution or reproduction in other et al. (2012). He.M.A.B.I.S. (Hematological Malignancies Associated Bacterial forums is permitted, provided the original author(s) or licensor are credited and that Infections Surveillance) Italy. Derivation and validation of a scoring system to the original publication in this journal is cited, in accordance with accepted academic identify patients with bacteremia and hematological malignancies at higher risk practice. No use, distribution or reproduction is permitted which does not comply with for mortality. PLoS ONE 7:e51612. doi: 10.1371/journal.pone.0051612 these terms. 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Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis

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Abstract

ORIGINAL RESEARCH ARTICLE published: 12 February 2015 CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.2015.00011 Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis 1 1 2 3 4 5 Rima Moghnieh *, Nour Estaitieh , Anas Mugharbil , Tamima Jisr , Dania I. Abdallah , Fouad Ziade , 6 2 Loubna Sinno and Ahmad Ibrahim Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon Division of Hematology-Oncology, Department of Internal Medicine, Makassed General Hospital, Beirut, Lebanon Department of Laboratory Medicine, Makassed General Hospital, Beirut, Lebanon Pharmacy Department, Makassed General Hospital, Beirut, Lebanon Faculty of Public Health, Lebanese University, Beirut, Lebanon Research Coordinator, Makassed General Hospital, Beirut, Lebanon Edited by: Introduction: Bacteremia remains a major cause of life-threatening complications in Ghassan M. Matar, American patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of University of Beirut, Lebanon causative microorganisms differ with time and place. Data from Lebanon are scarce. We Reviewed by: aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital Charles Martin Dozois, Institut in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant National de la Recherche Scientifique, Canada organism (MDRO)-associated bacteremia. Max Maurin, Université Materials and Methods: This is a retrospective study of 75 episodes of bacteremia Aix-Marseille II, France occurring in febrile neutropenic patients admitted to the hematology-oncology unit at *Correspondence: Makassed General Hospital, Lebanon, from October 2009-January 2012.It corresponds Rima Moghnieh, Department of Internal Medicine, Makassed to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients General Hospital, PO Box 11-6301 including antimicrobial resistance and identification of risk factors associated with third Riad El-Solh, Beirut 1107 2210, generation cephalosporin resistance (3GCR) and MDRO-associated bacteremia. Lebanon e-mail: amlakkis@yahoo.com Results: Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/ tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05). Conclusion: Our findings have major implications for the management of febrile neutropenia, especially in breakthrough bacteremia and fever when patients are already on broadspectrum antibiotics. Emergence of resistance to 3GCs and, to a lesser extent, to carbapenems in GN isolates has to be considered seriously in our local guidelines for empiric treatment of febrile neutropenia, especially given that their occurrence was proven to be associated with poorer outcomes. Keywords: febrile neutropenia, bacteremia, 3GCR gram-negative bacteria, MDR gram-negative bacteria, Lebanon Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 1 Moghnieh et al. Bacteremias in neutropenia in Lebanon INTRODUCTION caused by third generation cephalosporin-resistant (3GCR) and carbapenem-resistant bacteria. The progress of anticancer therapy with aggressive supportive care for patients with malignancies and patients undergoing MATERIALS AND METHODS hematopoietic stem cell transplantation (HSCT) have recently SETTING, PATIENTS AND STUDY DESIGN improved patient prognosis (Trecarichi and Tumbarello, 2014). This is retrospective study performed at Makassed General However, these advances, resulting in a prolonged and profound level of immunosuppression, neutropenia in particular, along Hospital, a 200-bed university hospital in Beirut, Lebanon. The hospital’s Institutional Review Board approved the study, and an with the extensive use of implantable medical devices, have also increased the risk of severe infections (Trecarichi and Tumbarello, informed consent was waived since it was observation. Medical records of patients admitted between October 2009 and January 2014). Different types of infections may occur in cancer patients, 2012 were reviewed. Seventy-five episodes of bacteremia occur- but bloodstream infections (BSIs) are the most common severe ring in 70 hospitalized neutropenic adult patients were recorded. infectious complications; the reported prevalence of BSIs ranges Adult cancer patients with fever and neutropenia, includ- from 11 to 38%, and the crude mortality rate reaches up to 40% ing those undergoing Hematopoietic Stem Cell Transplantation (Wisplinghoff et al., 2003a,b; Tumbarello et al., 2012; Montassier (HSCT), with positive blood cultures were selected. All posi- et al., 2013). tive results of blood cultures with the corresponding antibiogram The type of microorganisms isolated on blood culture from were checked and recorded from the Microbiology Laboratory febrile neutropenic patients varies with time and place (Jones, 1999; Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; Irfan log books and computerized laboratory records. Information regarding these episodes were collected and recorded in a specific et al., 2008; Freifeld et al., 2011). Data from the Middle East and North Africa (MENA) region is scarce. database from patients’ medical records. Patient characteristics were identified, including age, gender, At the beginning of the use of cytotoxic chemotherapy in type of cancer, risk level, recurrence of admissions, duration the 1960s and 1970s in cancer patients, gram-negative bacteria of neutropenia prior to bacteremia, hospital stay prior to bac- (GNB) were the most common organisms causing bacteremia teremia, presence of a focus of infection, presence of a central in febrile neutropenic patients (Jones, 1999; Irfan et al., 2008); line or an implantable venous access, outcome, sepsis, intu- however, at the turn of the century, the most common bacterial bation, HSCT, antibiotic and antifungal intake in the hospital pathogens isolated from blood cultures were coagulase-negative setting. Univariate analysis of these characteristics was used to staphylococci (Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; identify risk factors for3GCR and multi-drug resistant (MDR) Freifeld et al., 2011). organism-associated bacteremia. However, in recent years several studies have demonstrated a clear trend in the epidemiology of BSIs, showing a shift DEFINITIONS AND INCLUSION CRITERIA of prevalence from gram-positive to gram-negative bacteria Patients were included if they met all three of the following (Wisplinghoff et al., 2003b; Pagano et al., 2012; Montassier et al., inclusion criteria: 2013). There is an emergence of drug-resistant GNB such as mul- tidrug resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, extended-spectrum (1) Fever, defined as a single oral temperature of 38.3 Coran oral temperature of 38 Clasting 1h or more. beta-lactamase (ESBL)-producing GNB, and carbapenemase- producing GNB (Zinner, 1999; Wisplinghoff et al., 2003b; (2) Neutropenia, defined as a neutrophil count of <500 3 3 cells/mm ,oracountof <1000 cells/mm with a docu- Ramphal, 2004; Freifeld et al., 2011; Pagano et al., 2012; Wu et al., 2012; Montassier et al., 2013). The issue of antimicrobial mented decrease to <500 cells/mm within the following 48–72 h. resistance has become a significant problem worldwide, where (3) Receipt of chemotherapy prior to the episode of treatment of infections due to MDR bacteria represents a clinical challenge because the therapeutic options are often very limited. febrileneutropenia. Risk factors of bacteremia due to MDR GNB in febrile neu- tropenic cancer patients vary depending on the type of organism, Patients who had fever and neutropenia as a result of their duration of hospitalization, and antibiotic therapy (Gudiol and underlying disease without having received chemotherapy were Carratala, 2014). excluded. So, the fact that the epidemiology of pathogens is dynamic In Lebanon, anaerobic cultures are performed only in ref- makes contemporary local data extremely important, and iden- erence laboratories. Hospital-based laboratories perform only tification of pathogens locally recovered from blood cultures of aerobic cultures. According to hospital policy, one set of blood febrile neutropenic patients and the patterns of their antibi- cultures consists of two bottles of aerobic cultures taken from two otic susceptibilities are essential in making therapeutic decisions different draws at the same time, with no bottles for anaerobic (Sigurdardottir et al., 2005). culture. Bacteremia is defined as isolation of the same bacterial The purpose of this study is to evaluate the epidemi- or pathogen from at least one set of blood cultures (2 bottles ology of bacteremia occurring during neutropenia in adult taken at the same time). Bacteremia is considered polymicro- cancer chemotherapy patients in a university hospital in bial if at least two organisms from the same blood culture on Lebanon, with a special emphasis on the prevalence, sus- two occasions are isolated or more than one organism each in ceptibility profile and risk factors associated with bacteremia at least two separate blood cultureswithin 48 h (Reuben et al., Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 2 Moghnieh et al. Bacteremias in neutropenia in Lebanon 1989). Bacteremia occurring more than 14 days after a previous patients, antibiotic treatment, and patient outcomes are shown episode and separated by repeatedly negative blood cultures was in Table 1. considered a separate episode. Each separate hospital admission Of the 75 bacteremias, 42.7% were due to gram-positive for febrile neutropenia was defined as one episode. Subsequent organisms, and the remaining 57.3% were gram-negative. hospital admissions for febrile neutropenia in the same patient were included as separate cases. Bacteremia caused by a potential skin contaminant (such as Table 1 | Epidemiological and clinical characteristics of all episodes of coagulase-negative staphylococci, Bacillus,or Corynebacterium bacteremia. species) was considered significant only if it met the following Characteristic Total [n = 75(%)] criteria: AGE (YEARS) (1) Growth of the same bacterial strainin two blood cultures 0–18 5 (6.67) taken from two different sites at the same time. 18–65 62 (82.67) (2) Growth of the same bacterial strain in one blood culture and >65 8 (10.67) in one other sterile site (urine, cerebrospinal fluid, ascetic GENDER fluid, pleural fluid, joint fluid). Male 36 (48) (3) Growth of the same bacterial strain in one peripheral blood Female 39 (52) culture and one blood culture taken from an intravenous TUMOR TYPE catheter where both cultures were taken at the same time. Leukemia 56 (74.67) Lymphoma 15 (20) Interpretive criteria (breakpoints) for susceptible, intermedi- Solid 4 (5.33) ate, and resistant bacterial isolates were those included in the MASCC score Clinical and Laboratory Standards Institute guidelines (Clinical >21 5 (6.67) and Laboratory Standards Institute, 2010). <21 70 (93.33) The 3GCR Enterobacteriaceae phenotypes included all isolates NEUTROPENIA DURATION PRIOR TO BACTEREMIA not susceptible to one or more of five agents including aztreonam, <7 days 26 (34.67) cefotaxime, ceftizoxime, ceftazidime, and ceftriaxone (Clinical >7 days 26 (34.67) and Laboratory Standards Institute, 2010). These isolates were, Unknown 23 (30.67) however, susceptible to imipenem. HOSPITAL STAY PRIOR TO BACTEREMIA Many different definitions for multidrug resistance are used in <2 days 21 (28) the medical literature to characterize different patterns of resis- Between 2and7days 4(5.33) tance in healthcare-associated, antimicrobial-resistant bacteria >7 days 48 (64) (Magiorakos et al., 2012).However, generally speaking, MDR- Unknown 2 (2.67) Gram negative bacteria are resistant to key antimicrobial agents RECURRENT ADMISSION (Siegel et al., 2007; Hidron et al., 2008). Third and fourth Yes 67 (89.33) generation cephalosporins, along with fluoroquinolones, amino- No 8 (10.67) glycosides, and carbapenems, constitute the major therapeutic FOCUS OF INFECTION options in treatment guidelines of febrile neutropenia in adult No/Unknown 17 (22.67) cancer patients (Freifeld et al., 2011; Averbuch et al., 2013). In Pneumonia 3 (4) this study, gram-negative bacteria were considered MDR when Gastroenteritis 13 (17.33) resistant to third and fourth generation cephalosporins, fluoro- Urinary tract infection 7 (9.33) quinolones, aminoglycosides and carbapenems, including S. mal- Skin and soft tissue infection 3 (4) tophilia, carbapenem-resistant P. aeruginosa and Acinetobacter Central line associated 30 (40) baumannii, or carbapenem-resistant 3GCR Enterobacteriaceae. Portal catheter associated 2 (2.67) PLACEMENT OF CENTRAL VENOUS CATHETER STATISTICAL ANALYSIS Yes 52 (69.33) Data were reported as the mean standard deviation (SD) or num- <10 days 18 (24) ber of patients (percentage). T-tests (two-tailed), Fisher’s exact >10 days 34 (45.33) tests and Chi-square tests were used to assess any significant dif- No 23 (30.67) ferencesamong the groups. P < 0.05 were considered statistically OUTCOME significant. Death 7 (9.33) Recovery 68 (90.67) RESULTS Sepsis 8 (10.67) During the study period, 75 episodes of bacteremia occurring Intubation 7 (9.33) in 70 hospitalized neutropenic adult patients with hemato- Hematopoietic stem cell transplantation 41 (54.67) logical malignancies, including those undergoing HSCT, were recorded. Epidemiological and clinical characteristics of the N.B. MASCC, Multinational Association of Supportive Care in Cancer. Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 3 Moghnieh et al. Bacteremias in neutropenia in Lebanon Gram-positive bacteremias were mostly due to methicillin- prior to bacteremia, recurrent admissions, neutropenia prior to resistant coagulase negative staphylococci, which represented bacteremia, presence of CVC, and focus of infection, did not show 66% of gram-positive bacteremias and 28% of total bacteremias. any statistical significance, suggesting that the former factors were No methicillin-resistant Staphylococcus aureus-related bacteremia not risk factors. However, history and duration of antibiotic was detected and only one episode of methicillin-sensitive intake before the episode of bacteremia was majorly implicated in Staphylococcus aureus-related bacteremia was observed. (Refer to the occurrence of 3GCR bacteremia. The type of broad spectrum Tables 2, 3). antibiotic use did not affect the results; butduration of intake did Among the gram-negative bacteremias, Escherichia coli (22.7% affect results. The use of carbapenems, piperacillin/tazobactam, of total, 39.5% of gram-negative) and Klebsiella pneumonia or 3rd or 4th GC ± aminoglycosides for more than 4 days prior (13.3% of total, 23.3% of gram-negative)were the most important to the bacteremic episode was significantly associated with 3GCR causative agents. Out of the 17 bacteremias caused by E. coli,eight bacteremia compared with all other types of bacteremias. (P < were due to 3GCR resistant strains (10.7% of total bacteremias 0.01) A worse outcome, defined by need for intubation and the and 47% of E. coli strains). From those caused by K. pneumoniae occurrence of sepsis in bacteremic patients, was also statistically (10 bacteremias), five cases were due to 3GCR strains (6.7% of significant in the 3GCR group compared with the other groups. total bacteremia and 50% of K. pneumoniae). In general, 28% of (P < 0.03) (Refer to Tables 5, 6). the total bacteremias were due to 3GC sensitive gram-negative Similarly, infection with an MDR strain was associated with bacteria and 29.3% of the total bacteremias were caused by significantly higher rates of subsequent intubation, sepsis, and 3GC resistant gram-negative bacteria. Concerning carbapenem mortality. (P < 0.03)The history and duration of antibiotic susceptibility in the 3GC resistant category, seven cases were intake before the episode of bacteremia was significantly asso- carbapenem-resistant, representing 9.3% of total bacteremias. ciated with the occurrence of MDR bacteremia as well. The (Refer to Tables 2, 4). use of cephalosporins ± aminoglycosides was not significantly Results of the univariate analysis of factors potentially asso- associated with MDR bacteremia, while the use of carbapen- ciated with 3GCR bacteremia, including baseline and demo- ems or piperacillin/tazobactam for more than 4 days prior to graphic characteristics, major disease and risk, hospitalization MDR-bacteremia was significantly associated with its occurrence. (P < 0.04) (Refer to Tables 5, 6). Table 2 | Causative organisms of all episodes of bacteremia. DISCUSSION Data from Lebanon in neutropenic patients is scarce, and the Causative organisms Number of episodes available literature reveals the dynamic nature of the etiology [n = 75(%)] of bacteremias with time. Previous studies from Lebanon have shown gram-negative organisms to be the predominant agents in gram-positive Bacteria 32 (42.67) febrile neutropenic patients (Hamzeh et al., 2000; Kanafani et al., Staphylococcus aureus 1(1.33) 2007). In addition to the subdivision between gram-positive and Coagulase-negative staphylococci (CNS) 28 (37.33) gram-negative organisms, we investigated antibiotic susceptibility Methicillin resistant CNS 21 (28) patterns and the risk factors associated with bacteremia caused by Streptococcus pneumoniae 1(1.33) antibiotic-resistant gram-negative organisms. Enterococcus faecium 1(1.33) In this study, the distribution of the 75 cases was almost equal Aerococcus viridans 1(1.33) between gram-positive and gram-negative organisms (42.7 vs. gram-negative Bacteria (GNB) 43 (57.33) 57.3%). Yet, a study by Kanafani et al. (2007) in 2007 from Escherichia coli 17 (22.67) Lebanon showed gram-negative predominance in febrile neu- 3GCR -Escherichia coli 8(10.67) tropenia bacteremic episodes. Gram-negative organisms were Pseudomonas aeruginosa 3(4) responsible for 78.8% of bloodstream infections compared with Pseudomonas putida 1(1.33) 33.3% gram-positive organisms (Kanafani et al., 2007). Pseudomonas stutzeri 1(1.33) In fact, the shift from a preponderance of gram-negative bacte- Klebsiella pneumoniae 10 (13.33) ria causing bloodstream infections in febrile neutropenic patients 3GCR- Klebsiella pneumoniae 5(6.67) to gram-positive bacteria has been observed worldwide. The Klebsiella oxytoca 1(1.33) widespread use of indwelling catheters, early-generation fluoro- Proteus mirabilis 3(4) quinolone prophylaxis, and broad spectrum empirical anti-gram- Enterobacter cloacae 2(2.67) negative antibacterial therapy led to an increase in the incidence Acinetobacter baumannii 2(2.67) of gram-positive pathogens in the 1980s and 1990s (Zinner, 1999; Stenotrophomonas maltophilia 2(2.67) Ramphal, 2004; Freifeld et al., 2011). Thereafter, the most com- Salmonella species 1(1.33) mon bacterial etiologic agent isolated from blood cultures in 3GC sensitive GNB 21 (28) most centers was reported to be coagulase-negative staphylococci 3GCR GNB 22 (29.33) (Dettenkofer et al., 2003; Wisplinghoff et al., 2003b; Freifeld et al., 3GCR carbapenem-sensitive GNB 15 (20) 2011). In our study, coagulase-negative staphylococci were the 3GCR carbapenem-resistant GNB 7 (9.33) most common among gram-positive organisms (37.3% of total N.B. 3GCR, third generation cephalosporin-resistant. cases, 87.5% of gram-positive cases), where methicillin-resistant Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 4 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 3 | Antibiotic susceptibility profile of isolated gram-positive bacteria. Antibiotic No of susceptible gram-positive isolates (%) CNS S. aureus S. pneumoniae E. faecium A. viridans Total [n = 28(%)] [n = 1(%)] [n = 1(%)] [n = 1(%)] [n = 1(%)] [n = 32(%)] Oxacillin 7 (25) 1 (100) 1 (100) 0 (0) 0 (0) 9 (28.1) Ampicillin – 1 (100) 1 (100) 0 (0) 0 (0) 10 (31.3) Rifampin 24 (85.7) 1 (100) 1 (100) 0 (0) 0 (0) 26 (81.3) Clindamycin 16 (57.1) 1 (100) 1 (100) 0 (0) 1 (100) 19 (59.4) Teicoplanin 28 (100) 1 (100) 1 (100) 1 (100) 1 (100) 32 (100) Vancomycin 28 (100) 1 (100) 1 (100) 1 (100) 1 (100) 32 (100) N.B. A.viridans, Aerococcus viridans; CNS, Coagulase Negative Staphylococci; E. faecium, Enterococcus faecium; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumonia. Table 4 | Antibiotic susceptibility profile of isolated gram-negative bacteria. No. of susceptible gram-negative isolates (%) Antibiotic E. coli Klebsiella Pseudomonas P.mirabilis Enterobacter S. maltophilia A. baumannii Salmonella Total [n = 17(%)] spp. spp. [n = 3(%)] spp. [n = 2(%)] [n = 2(%)] spp. [n = 43(%)] [n = 11(%)] [n = 5(%)] [n = 2(%)] [n = 1(%)] Amox/Clav 5 (29.4) 5 (45.5) 0 (0) 3 (100) 0 (0) 0 (0) 0 (0) 1 (100) 11 (25.6) Amikacin 15 (88.2) 10 (90.9) 5 (100) 3 (100) 2 (100) 0 (0) 1 (50) 1 (100) 37 (86) Cefepime 5 (29.4) 6 (54.5) 3 (60) 3 (100) 1 (50) 0 (0) 0 (0) 1 (100) 19 (44.2) Ceftazidime 8 (57.1) 5 (45.5) 4 (80) 3 (100) 0 (0) 1 (50) 1 (50) 1 (100) 23 (53.5) Ceftriaxone 8 (57.1) 6 (54.5) 2 (40) 3 (100) 0 (0) 0 (0) 0 (0) 1 (100) 19 (44.2) Imipenem 14 (82.4) 11 (100) 4 (80) 3 (100) 2 (100) 0 (0) 1 (50) 1 (100) 36 (83.7) Pip/Tazo 13 (76.5) 7 (63.6) 5 (100) 3 (100) 0 (0) 0 (0) 1 (50) 1 (100) 30 (69.8) Tigecycline 17 (100) 10 (90.9) 1 (20) 3 (100) 2 (100) 2 (100) 2 (100) 1 (100) 40 (93) Colistin 17 (100) 11 (100) 4 (80) 3 (100) 2 (100) 0 (0) 2 (100) 1 (100) 40 (93) Quinolones 7 (41.2) 7 (63.6) 4 (80) 1 (33.3) 0 (0) 2 (100) 1 (50) 0 (0) 22 (51.2) N.B. A.baumannii, Acinetobacter baumannii; Amox/Clav, Amoxicillin/Clavulanate; E. coli, Escherichia coli; Pip/Tazo, Piperacillin/Tazobactam; P.mirabilis, Proteus mirabilis; S. maltophilia, Stenotrophomonas maltophilia; spp, species. coagulase-negative staphylococciisolatesrepresented 28% of the E. coli isolates have been reported with a frequency ranging total cases and 65.6% of gram-positive cases. from 12 to 75% (mean 35%) in cancer patients. 3GCR K. pneu- Our results showed that E. coli and K. pneumoniae were the moniae isolates causing BSIs in neutropenic patients have been most prevalent gram-negative organisms, representing 22.7 and reported with a frequency ranging from 3 to 66.6% (mean 37.8%) 13.3%, respectively, of total cases. A systematic literature review (Trecarichi and Tumbarello, 2014). conducted by Trecarichi and Tumbarello (2014) from January We found that 9.3% of episodes of bacteremia in cancer 2007 to August 2013 examined the recent trends in epidemiology patients were caused by MDR gram-negative bacteria. This and antimicrobial resistance in gram-negative bacteria recovered finding is in line with recent studies, which report an increase in from cancer patients, with a particular emphasis on the impact of antibiotic resistance among gram-negative bacteria in immuno- antimicrobial resistance on the clinical outcome of severe infec- compromised hosts. One study performed in Italy by Gudiol et al. tions caused by such microorganisms. The gram-negative bacte- (2011) reported an incidence of 13.7% of MDR gram-negative rial species most frequently isolated were E. coli, whose frequency associated bacteremia, andin another study performed in Pakistan ranged from 10.1 to 53.6% (mean 32.1%), and K. pneumoniae, by Irfan et al. (2008), the emergence of carbapenem resistance which was isolated with a frequency ranging from 4.1 to 44.6% was reported in Pseudomonas species (20.7% of the isolates) (mean 19.5%) (Trecarichi and Tumbarello, 2014). and in Acinetobacter species (65.4% of the isolates). In another In ourstudy,3GCRstrains of E. coli and K. pneumoniae study by Trecarichi et al. (2011) from Italy, among 38 patients caused 10.7 and 6.7% of total bacteremias, respectively. 3GCR- diagnosed with P. aeruginosa bacteremia, 27 were MDR species Enterobacteriaceae colonization or infection of patients with (71.1%). The percentages of in vitro resistance to major antimi- febrile neutropenia has been reported with increased frequency crobial classes were the following: carbapenems (imipenem during the last decade. Bloodstream infections due to 3GCR and meropenem) 60%, antipseudomonal cephalosporins Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 5 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 5 | Baseline and demographic characteristics, clinical features, and outcome of patients with 3GCR-bacteremia compared with non-3GCR-bacteremia and MDR-bacteremia compared with non-MDR-bacteremia. Characteristic 3GCR-Bacteremia Non-3GCR-Bacteremia P-value MDR Bacteremia Non-MDR Bacteremia P-value [n = 22(%)] [n = 53(%)] [n = 7(%)] [n = 68(%)] AGE (YEARS) 0–18 1 (4.5) 4 (7.5) 0 (0) 5 (7.4) 18–65 19 (86.4) 43 (81.1) 6 (85.7) 56 (82.4) >65 2 (9.1) 6 (11.3) 0.846 1 (14.3) 7 (10.3) 0.734 GENDER Male 9 (40.9) 27 (50.9) 3 (42.9) 33 (48.5) Female 13 (59.1) 26 (49.1) 0.428 4 (57.1) 35 (51.5) 0.775 TUMOR TYPE Leukemia 17 (77.3) 39 (73.6) 6 (85.7) 50 (73.5) Lymphoma 4 (18.2) 11 (20.8) 0 (0) 15 (22.1) Solid 1 (4.5) 3 (5.7) 0.944 1 (14.3) 3 (4.4) 0.243 MASCC SCORE >21 0 (0) 5 (9.4) 0 (0) 5 (7.4) <21 22 (100) 48 (90.6) 0.136 7 (100) 63 (92.6) 0.458 NEUTROPENIA DURATION PRIOR TO BACTEREMIA <7days 8(36.4) 15 (28.3) 3 (42.9) 20 (29.4) >7days 7(31.8) 19 (35.8) 1 (14.3) 25 (36.8) Unknown 7 (31.8) 19 (35.8) 0.789 3 (42.9) 23 (33.8) 0.485 HOSPITAL STAY PRIOR TO BACTEREMIA <2days 7(31.8) 14 (26.4) 2 (28.6) 19 (27.9) Between 2and7days 2(9.1) 2 (3.8) 1 (14.3) 3 (4.4) >7 days 13 (59.1) 35 (66) 4 (57.1) 44 (64.7) Unknown 0 (0) 2 (3.8) 0.586 0 (0) 2 (2.9) 0.700 RECURRENT ADMISSION Yes 2 (9.1) 6 (11.3) 0 (0) 8 (11.8) No 20 (90.9) 47 (88.7) 0.776 7 (100) 60 (88.2) 0.337 FOCUS OF INFECTION No/Unknown 3 (13.6) 14 (26.4) 1 (14.3) 16 (23.5) Pneumonia 1 (4.5) 2 (3.8) 1 (14.3) 2 (2.9) Gastroenteritis 0 (0) 3 (5.7) 0 (0) 3 (4.4) UTI 6 (27.3) 7 (13.2) 2 (28.6) 11 (16.2) SStI 8 (36.4) 22 (41.5) 2 (28.6) 28 (41.2) Central line associated 1 (4.5) 1 (1.9) 0 (0) 2 (2.9) Portal catheter associated 3 (13.6) 4 (7.5) 0.507 1 (14.3) 6 (8.8) 0.702 PLACEMENT OF CVC Yes 7 (31.8) 16 (30.2) 2 (28.6) 21 (30.9) <10 days 6 (27.3) 12 (22.6) 3 (42.9) 15 (22.1) >10 days 9 (40.9) 25 (47.2) 2 (28.6) 32 (47.1) No 7 (31.8) 16 (30.2) 0.866 2 (28.6) 21 (30.9) 0.442 OUTCOME Death 5 (22.7) 2 (3.8) 4 (57.1) 3 (4.4) Recovery 17 (77.3) 51 (96.2) 0.010 3 (42.9) 65 (95.6) <0.0001 Sepsis 5 (22.7) 3 (5.7) 0.029 4 (57.1) 4 (5.9) <0.0001 Intubation 5 (22.7) 2 (3.8) 0.010 4 (57.1) 3 (4.4) <0.0001 HSCT 13 (59.1) 29 (54.7) 0.728 4 (57.1) 38 (55.9) 0.949 N.B. MASCC, Multinational Association of Supportive Care in Cancer, UTI, Urinary tract infection; SStI, Skin and soft tissue Infection; CVC, Central Venous Catheter; HSCT, Hematopoietic stem cell transplantation. (ceftazidime and cefepime) 42%, and piperacillin 24% Third and fourth generation cephalosporins remain the first line (Trecarichi et al., 2011). option for primary therapy in febrile neutropenia (Freifeld et al., The emergence of 3GCR Enterobacteriaceae and MDR gram- 2011; Averbuch et al., 2013). In this group of patients, appro- negative organisms causing bacteremia in cancer patients is very priate initial empirical antibiotic therapy is essential, (Gudiol critical in terms of empiric therapy for febrile neutropenia. and Carratala, 2014) and empiric antibiotic therapy in febrile Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 6 Moghnieh et al. Bacteremias in neutropenia in Lebanon Table 6 | Antimicrobial history and duration prior to bacteremia in all cases, in patients with 3GCR- bacteremia compared with non-3GCR-bacteremia and in MDR-bacteremiacompared with non-MDR-bacteremia. Antimicrobial duration Total 3GCR- Non-3GCR- P-value MDR- Non-MDR- P-value before bacteremia n = 75 (%) Bacteremia Bacteremia Bacteremia Bacteremia [n = 22(%)] [n = 53(%)] [n = 7(%)] [n = 68(%)] Carbapenem (Group1) <4 8(10.67) 1 (4.5) 7 (13.2) 0.269 1 (14.3) 7 (10.3) 0.745 days Carbapenem>4 days 14 (18.67) 8 (36.4) 6 (11.3) 0.011 4 (57.1) 10 (14.7) 0.006 No Carbapenem 55 (73.33) 1 (4.5) 4 (7.5) 0.635 1 (14.3) 4 (5.9) 0.396 PIP/TAZ (Group2) <4days 5(6.67) 5 (22.7) 2 (3.8) 0.010 2 (28.6) 5 (7.4) 0.066 PIP/TAZ >4days 7(9.33) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12 (17.6) 0.112 No PIP/TAZ 65 (86.67) 6 (27.3) 5 (9.4) 0.047 2 (28.6) 9 (13.2) 0.275 3rd or 4th GC ± Amikacin 15 (20) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12(17.6) 0.112 (Group3) <4 days 3rd or 4th GC ± Amikacin>4 11 (14.67) 8 (36.4) 6 (11.3) 0.011 3 (42.9) 11 (16.2) 0.085 days No 3rd or 4th GC ± Amikacin 51 (68) 2 (9.1) 11 (20.8) 0.224 2 (28.6) 11 (16.2) 0.409 Group 1 or 2 or 3 <4 days 15 (20) 7 (31.8) 5 (9.4) 0.016 3 (42.9) 9 (13.2) 0.042 Group 1 or 2 or 3 >4 days 14 (18.67) 2 (9.1) 5 (9.4) 0.963 2 (28.6) 5 (7.4) 0.066 No group 2 or 3 or 4 49 (65.33) 4 (18.2) 5 (9.4) 0.288 2 (28.6) 7 (10.3) 0.156 Carbapenem or PIP/TAZ <4 13 (17.33) 1 (4.5) 7 (13.2) 0.269 1 (14.3) 7 (10.3) 0.745 days Carbapenem or PIP/TAZ >4 12 (16) 8 (36.4) 6 (11.3) 0.011 4 (57.1) 10 (14.7) 0.006 days No Carbapenem or PIP/TAZ 52 (69.33) 1 (4.5) 4 (7.5) 0.635 1 (14.3) 4 (5.9) 0.396 Antifungal other than 7(9.33) 5 (22.7) 2 (3.8) 0.010 2 (28.6) 5 (7.4) 0.066 Fluconazole <4 days Antifungal other than 9(12) 3 (13.6) 12 (22.6) 0.375 3 (42.9) 12 (17.6) 0.112 Fluconazole >4 days No Antifungal other than 62 (82.67) 6 (27.3) 5 (9.4) 0.047 2 (28.6) 9 (13.2) 0.275 Fluconazole N.B. PIP/TAZ, Piperacillin/Tazobactam; 3rd or 4th GC, Third or Fourth Generation Cephalosporin. neutropenic patients has reduced mortality rates from approxi- were MDR-gram-negative in origin. Previous exposure to third mately 21% (Viscoli et al., 2005) to 2–10%, (Vidal et al., 2004; generation cephalosporins either as prophylaxis or empirical ther- Toussaint et al., 2006) depending upon the underlying diagnosis, apy and belonging to one of the HSCT centers were associated degree of cancer control, duration of severe neutropenia and type with an increased risk for ESBL-producing Enterobacteriaceae of infection. Inappropriate empiric therapy is defined, in con- (Oliveira et al., 2007).Another retrospective case-control study text, as not including at least one antibiotic active in vitro against involving HSCT recipients (Garnica et al., 2009)showedby the infecting microorganism(s) (Freifeld et al., 2011; Averbuch univariate analysis that previous use of a third or fourth- et al., 2013), and the emergence of 3GCR and MDR organisms in generation cephalosporin (P = 0.005 and 0.02, respectively) and febrile neutropenia renders 3rd or 4th GCs inappropriate choices duration of antibiotic use (P < 0.001) were among the factors in certain situations. associated with bacteremia due to MDR-gram-negative isolates Our results showed that the use of broad spectrum antibiotics, including K. pneumonia and P. aeruginosa. In another study including carbapenems, piperacillin/tazobactam, and 3rd or 4th performed in the United States by Rangaraj et al. (2010),the GC ± aminoglycosides, for more than 4 days prior to bacteremia use of multiple broad spectrum antibiotics compared with no was significantly associated with 3GCR bacteremia. (P < 0.01) antimicrobial agents was significantly associated with isolation However, in the case of carbapenem-resistant 3GCR bacteremia of MDR P. aeruginosa (8.2 vs. 0.7%, p < 0.005).This finding (MDR), the use of carbapenems or piperacillin/tazobactam, is consistent with a more recent study in 2013 by Satlin et al. but not cephalosporins, for more than 4 days prior to MDR- (2013), where exposure to any broadspectrum antibacterial agent bacteremia was significantly associated with its occurrence. (P < may be sufficient to increase the risk of carbapenem-resistant 0.04) (Refer to Table 6) Previous antibiotic therapy has been rec- Enterobacteriaceae acquisition and cause bloodstream infections ognized as a major risk factor for the development of bacterial in patients with hematologic malignancies. resistance. In prospective study involving13 Brazilian HSCT cen- Our results showed that patient outcome was influenced sig- ters (Oliveira et al., 2007), 22% of 91 episodes of bacteremia nificantly by antimicrobial resistance, and the risk ofsubsequent Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 7 Moghnieh et al. Bacteremias in neutropenia in Lebanon intubation, sepsis and mortality were high in the 3GC-resistant ESGICH/ESCMID and ELN. European guidelines for empirical antibacte- rial therapy for febrile neutropenic patients in the era of growing resistance: bacteremia group and in the MDR-bacteremia group com- summary of the 2011 4th European Conference on Infections in Leukemia. pared with patients having other bacteremias(P < 0.03).(Refer to Haematologica 98, 1826–1835. doi: 10.3324/haematol.2013.091025 Table 5) Other studies indicated that a dramatic increase in the Caselli, D., Cesaro, S., Ziino, O., Zanazzo, G., Manicone, R., Livadiotti, S., detection rate of MDR gram-negative bacteremia compared with et al. (2010). Multidrug resistant Pseudomonas aeruginosa infection in previous periods was associated with increased morbidity, mor- children undergoing chemotherapy and hematopoietic stem cell trans- plantation. Haematologica 95, 1612–1615. doi: 10.3324/haematol.2009. tality, and cost, especially in patients with hematological diseases (Lodise et al., 2007). Moreover, mortality was independently asso- Clinical and Laboratory Standards Institute (CLSI) (2010). Performance Standards ciated with inadequate initial antimicrobial treatment in the case for Antimicrobial Susceptibility Testing: 20th Informational Supplement. Wayne, of antibiotic-resistant bacteremia (Giske et al., 2008). Thus, local PA: CLSI. Dettenkofer, M., Ebner, W., Bertz, H., Babikir, R., Finke, J., Frank, U., et al. monitoring of bacterial isolates is recommended to adapt initial (2003). Surveillance of nosocomial infections in adult recipients of allogeneic empiric antibiotic therapy based on the local prevalence of MDR and autologous bone marrow and peripheral blood stem-cell transplantation. strains (Caselli et al., 2010). Bone Marrow Transplant. 31, 795–801. doi: 10.1038/sj.bmt.1703920 Our study has at least two major limitations. The first is that Freifeld, A. G., Bow, E. J.,Sepkowitz, K. A.,Boeckh, M. J.,Ito,J.I., Mullen,C.A., the samples were collected from a single medical center; there- et al. (2011). Infectious diseases society of america clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update fore, results could not be generalized to other medical centers in by the infectious diseases society of america. Clin. Infect. Dis. 52, 427–431. doi: Lebanon because the microbial ecology differs from one center to 10.1093/cid/ciq147 another. The second limitation is that the small sample size did Garnica, M., Maiolino, A., and Nucci, M. (2009). Factors associated with bac- not allow us to perform a multivariate analysis and limited our teremia due to multidrug-resistant Gram-negative bacilli in hematopoietic stem statistical analysis to a univariate model. cell transplant recipients. Braz.J.Med.Biol. Res. 42, 89–93. doi: 10.1590/S0100- 879X2009000300010 Giske, C. G., Monnet, D. L., Cars, O., and Carmeli, Y. (2008). ReAct-action on CONCLUSION antibiotic resistance clinical and economic impact of common multidrug- In conclusion, our data showed equal occurrence of gram- resistant gram-negative bacilli. Antimicrob. Agents Chemother. 52, 813–821. doi: 10.1128/AAC.01169-07 negative and gram-positive organisms causing bacteremia in Gudiol, C., and Carratala, J. (2014). Antibiotic resistance in cancer patients. Expert febrile neutropenic cancer patients in our center. We found Rev. Anti. Infect. Ther. 12, 1003–1016. doi: 10.1586/14787210.2014.920253 that bacteremia caused by gram-negative antimicrobial resistant Gudiol, C., Tubau, F., Calatayud, L., Garcia-Vidal, C., Cisnal, M., Sánchez-Ortega, strains is common among cancer patients, especially in those I., et al. (2011). Bacteraemia due to multidrug-resistant Gram-negative bacilli exposed to antibiotic pressure. Emergence of resistance to third in cancer patients: risk factors, antibiotic therapy and outcomes. J. Antimicrob. Chemother. 66, 657–663. doi: 10.1093/jac/dkq494 and fourth generation cephalosporins and, to a lesser extent, Hamzeh, F., Kanj, S. S., and Uwaydah, M. (2000). Febrile neutropenia in cancer to carbapenems, in gram-negative isolates has to be considered patients in a tertiary care medical center in Lebanon: microbial spectrum and seriously in our local guidelines for empiric treatment of febrile outcome. J. Med. Liban. 48, 136–142 neutropenia, especially given that their occurrence was associated Hidron, A. I., Edwards, J. R., Patel, J., Horan, T. C., Sievert, D. M., Pollock, D. A., with poorer clinical outcomes. et al. (2008). NHSN annual update: antimicrobial-resistant pathogens associ- ated with healthcare-associated infections: annual summary of data reported The empiric use of broad spectrum antibiotics in febrile neu- to the National Healthcare Safety Network at the Centers for Disease Control tropenia is very critical. On the one hand, it is crucial to decrease and Prevention, 2006–2007. Infect.Control Hosp.Epidemiol. 29, 996–1011. doi: mortality during the febrile episode; on the other hand, it is a risk 10.1086/591861 factor for emergence bacteremia with resistant organisms. In our Irfan, S., Idrees, F., Mehraj, V., Habib, F., Adil, S., and Hasan, R. (2008). Emergence therapeutic guidelines for the management of febrile neutrope- of carbapenem resistant gram negative and vancomycin resistant gram positive organisms in bacteremic isolates of febrile neutropenic patients: a descriptive nia, we should include coverage for MDR bacteria in patients who study. BMC Infect. Dis. 8:80. doi: 10.1186/1471-2334-8-80 have persistent or relapsing fever after 4 days of initial empiric Jones, R. N. (1999). Contemporary antimicrobial susceptibility pattern of bacterial therapy. pathogens commonly associated with febrile patients with neutropenia. Clin. Infect. Dis. 29, 495–502. doi: 10.1086/598621 Kanafani, Z. A. ,Dakdouki, G. K. , El-Chammas, K. I., Eid, S., Araj, G. F., and Kanj, AUTHOR CONTRIBUTIONS S. S. (2007). Bloodstreaminfections in febrile neutropenicpatients at a tertiary All authors have contributed equally to the analysis and interpre- care center in Lebanon: a view of the past decade. Int. J. Infect. Dis. 11, 450–453. tation of the study data as well as to the drafting of the article, but doi: 10.1016/j.ijid.2006.12.008 Rima Moghnieh made the primary contribution to the concep- Lodise, T. P. Jr., Patel, N., Kwa, A., Graves, J., Furuno, J. P., Graffunder, E., et al. (2007). Predictors of 30-day mortality among patients with tion and design of the study and revising the draft critically for Pseudomonasaeruginosa bloodstream infections: impact of delayed appropri- important intellectual contentand Nour Estaitieh to the acquisi- ate antibiotic selection. Antimicrob. Agents Chemother. 51, 3510–3515. doi: tion and collection of data. 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A multi-centre prospective study of febrile neutropenia in Norway: construed as a potential conflict of interest. microbiological findings and antimicrobial susceptibility. Scand. J. Infect. Dis. 37, 455–464. doi: 10.1080/00365540510038497 Received: 13 November 2014; accepted: 17 January 2015; published online: 12 Toussaint, E., Bahel-Ball, E., Vekemans, M., Georgala, A., Al-Hakak, L., Paesmans, February 2015. M., et al. (2006). Causes of fever in cancer patients (prospective study over 477 Citation: Moghnieh R, Estaitieh N, Mugharbil A, Jisr T, Abdallah DI, Ziade F, Sinno L episodes). Support Care Cancer 14, 763–769. doi: 10.1007/s00520-005-0898-0 and Ibrahim A (2015) Third generation cephalosporin resistant Enterobacteriaceae Trecarichi, E. M., and Tumbarello, M. (2014). Antimicrobial-resistant Gram- and multidrug resistant gram-negative bacteria causing bacteremia in febrile neu- negative bacteria in febrile neutropenic patients with cancer: current epi- tropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major demiology and clinical impact. Curr. Opin. Infect. Dis. 27, 200–210. doi: risk factor, and correlation with poor prognosis. Front. Cell. Infect. Microbiol. 5:11. 10.1097/QCO.0000000000000038 doi: 10.3389/fcimb.2015.00011 Trecarichi, E. M., Tumbarello, M., Caira, M., Candoni, A., Cattaneo, C., Pastore, D., This article was submitted to the journal Frontiers in Cellular and Infection et al. (2011). Multidrug resistant Pseudomonas aeruginosa bloodstream infection Microbiology. in adult patients with hematologic malignancies. Haematologica 96, e1–e3 doi: Copyright © 2015 Moghnieh, Estaitieh, Mugharbil, Jisr, Abdallah, Ziade, Sinno and 10.3324/haematol.2010.036640 Ibrahim. This is an open-access article distributed under the terms of the Creative Tumbarello, M., Trecarichi, E. M., Caira, M., Candoni, A., Pastore, D., Cattaneo, C., Commons Attribution License (CC BY). The use, distribution or reproduction in other et al. (2012). He.M.A.B.I.S. (Hematological Malignancies Associated Bacterial forums is permitted, provided the original author(s) or licensor are credited and that Infections Surveillance) Italy. Derivation and validation of a scoring system to the original publication in this journal is cited, in accordance with accepted academic identify patients with bacteremia and hematological malignancies at higher risk practice. No use, distribution or reproduction is permitted which does not comply with for mortality. PLoS ONE 7:e51612. doi: 10.1371/journal.pone.0051612 these terms. Frontiers in Cellular and Infection Microbiology www.frontiersin.org February 2015 | Volume 5 | Article 11 | 9

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