Patients with onco-haematological diseases combine multiple infection risk factors: immunodeficiency, modification of the endogenous flora, and alteration of the skin and intestinal barriers by catheters and chemotherapy. As the latter phenomenon can lead to life threatening bacteremia, SDD can be carried out in patients with grade 4 neutropenia. This SDD is prescribed during aplasias following allogeneic and autologous BMT and induction chemotherapy for acute leukaemias, in order to reduce the digestive bacterial concentration of GNB species . The investigation of cases of fever in neutropenic patients will include carrying out a stool culture, an ECBU, a chest X-ray and blood cultures taken at the same time (if needed) from central and peripheral catheters, to elucidate the involvement of the central catheter in the sepsis . Nevertheless, from the microbiological point of view, nearly 70% of febrile neutropenia cases remain undocumented [10, 11]. The increasing use of highly active cytotoxic treatments and allografts has led to an increase in the number of neutropenic patients treated in onco-haematology. Over a period of 8 years, the neutropenic population represented almost 60% of patients hospitalized in our department. These patients are at risk of infection: during the period 2003–2010, 46% of patients had one or more bacteraemias during a grade 3 neutropenic episode.
The main feature of these trends is the constant increase in GNB, in particular NF-GNB, in absolute numbers and incidence rate. Table 2 shows the variation in absolute terms of the various bacterial families or species between 1996–2002 and 2003–2010. With essentially equal numbers of blood cultures included in the two study periods, 2 times as many E. coli, 2.5 times as many NF-GNB and 3 times more KES, were isolated in the second period than in the first. The NF-GNB have followed the evolution of GNB; 15 years ago they already represented half of all isolated GNB. The first isolated species in our study is E. coli. This result is in line with various studies dealing with large series of immunocompetent and immunosuppressed patients [12-15]. Other studies performed in patients with well-established cancer showed the opposite trend (i.e. a predominance of GPC, in particular negative coagulase staphylococcus). However, very few studies of the microbiology of bacteraemia in onco-haematology patients have been published. A study performed in India has shown that in hospitalized patients with acute myeloid leukaemia and presenting with bacteraemia, the most commonly encountered species was P. aeruginosa, followed by enterobacteriaceae such as Klebsiella pneumoniae and E. coli . In 2008, Cattaneo et al.  revealed a change in the epidemiology of bacteraemia in patients with haematological malignancies and an increase of E. coli, but also of P. aeruginosa. Finally, in a recent study of haematology patients by the same authors between June 2004 and January 2010, from 441 positive blood cultures nearly 60% were identified as GNB, of which 66 were P. aeruginosa (15%) . Another study, carried out over a 1-year period, showed that in neutropenic patients coagulase-negative staphylococci represented more than 50% of blood culture isolates . Similar results were reported in 2009 by a Moroccan team .
Table 2. Epidemiology between 1996–2002 and 2003–2010
|Study 1996–2002||690||432 (62.6%)||216 (31.3%)||60||38||14||104||9||10||23|
|Study 2003–2010||723||135 (18.7%)||512 (70.8%)||134||106||19||253||4||13||59|
| || ||p 0.001||p 0.001|| || || || || || || |
This re-emergence of GNB can be partially explained by a decrease in the prophylactic use of fluoroquinolones and the treatment of cases of febrile neutropenia . It can also be explained by the lack of active antibacterial agents for naturally multi-resistant species (Acinetobacter, P. aeruginosa and S. maltophilia). In our department, fluoroquinolones are only used as a prophylaxis for allogeneic BMT, and on a case-by-case basis, when the patient's renal function contraindicates the use of aminoglycosides and for the induction of acute leukaemia.
The influence of SDD is more difficult to evaluate: theoretically, it targets the Gram-negative digestive reservoir, in particular emerging P. aeruginosa. Although they are naturally resistant to colistin, Proteus, Serratia and Providencia do not emerge. SSD thus remains controversial as a daily practice, and if using SDD might reduce bacteraemia rates, infection-related fatality rates are not reduced . Selective pressure related to empirical first-line treatment of febrile neutropenia could also partially explain the growing incidence of P. aeruginosa. Among the various GNBs, S. maltophilia occupies a central position. This trend was also observed by another team . This increase in incidence rate raises difficulties, especially in terms of treatment, as a consequence of the natural resistance of this species, in particular to carbapenems. The respiratory and gastrointestinal tracts are reservoirs for S. maltophilia. The increase in S. maltophilia bacteraemia, which reveals antibiotic selective pressure, needs to be carefully monitored as a consequence of the risk of a therapeutic impasse. For the forty-five patients with S. maltophilia bacteraemia, it would be interesting to know the number of treatments including imipenem prior to the bacteraemia; unfortunately these data are difficult to record in a retrospective study.
In parallel with this phenomenon, the incidence of GPC has decreased. This decline has multifactorial origins: a decrease through improved control of the implementation and monitoring of central venous lines, the controlled prescription of fluoroquinolones  and the appropriate use of glycopeptides. The rate at which anaerobic bacteria are isolated remains low, and similar to the rates found in the literature . The proportion of candidaemia also remains low, with no change with respect to the last decade. The 2012 data from the ‘Interscience Conference on Antimicrobial Agents and Chemotherapy’ reveals a 2% incidence in grafted patients . In the present study, only three cases of candidaemia (i.e. an incidence rate of 0.4%), all of which occurred in grafted patients, were observed. The study of patients’ stool flora in onco-haematology, allowing on one hand the SDD to be confirmed, and on the other hand a probabilistic antibiotherapy to be adapted in the case of febrile episodes, reveals discrepancies in the data . Indeed, in the same 2003–2010 study period, quantitative stool cultures revealed a clear predominance of GPC, enterococci in particular. GNBs were rarely isolated from quantitative stool cultures. Nevertheless, the study of this stool flora does not allow digestive translocations to be predicted or an antibiotherapy to be adapted. These data partially explain why the systematic monitoring of digestive flora in neutropenic patients remains controversial  and is no longer performed in many hospitals.
The main purpose of a surveillance of a specific disease such as bacteraemia is to detect shifts in antimicrobial susceptibility of the involved bacteria and should guide the choice of an empirical therapy. The rate of penicillinase was 60%, as opposed to 51% to 60% reported in various studies . Furthermore, the 1998–2009 ONERBA study of the monitoring of bacteraemia reveals a 12% fall in the sensitivity of enterobacteria to fluoroquinolones, with a sensitivity of 80% to 85%. In our department, the rate of ciprofloxacin resistance is higher (25%), despite the absence of fluoroquinolones in the treatment protocols. This significant increase of ciprofloxacin resistance was described by European Centre for Disease Prevention and Control (ECDC) in invasive French E. coli between 2001 (9%) and 2010 (between 10% and 25%) . In the literature, 5% of bacteraemia are related to ESBL . In our work, a slight (4%) but not significant increase of ESBL was identified. In NF-GNB, the study of P. aeruginosa resistance to ‘anti-pseudomonas’ molecules reported similar or even lower resistance rates than those reported by the ONERBA and ECDC: 60% to 65% sensitivity to ticarcillin vs. 75% in our study, and 75% to 85% of strains sensitive to ceftazidime vs. 87%. The resistance of P. aeruginosa to imipenem is mainly related to the loss of D2 porin: the resistance rates found by ONERBA and in our study are close to 10% , whereas ECDC found a resistance rate of 17.8% . Fluoroquinolones and aminoglycosides remain highly efficient and these must be used in combination. According to the studies, the resistances to ciprofloxacin and amikacin vary respectively from 60% to 80% and from 80% to 90% [28-31]. Furthermore, no carbapenemase or methylase producing bacteria were isolated. In our work, a small proportion (6.5%) of oxacillin-resistant S. aureus was identified. This feature is discordant with ECDC, which reported a rate of oxacillin resistance among S. aureus of 21.6% . This feature may be explained in part by the low number of strains in our work. No vancomycin-resistant Enterococcus sp. was detected, despite the use of this glycopeptide as a second-line treatment for febrile neutropenia. Table 3 shows the change in resistance of the main bacterial species, between 1996–2002 and 2003–2010.
Table 3. Antibiotic resistance between 1996–2002 and 2003–2010
| || || || ||NS||p 0.001|| || || ||NS|