Multi-body-site colonization screening cultures for predicting multi-drug resistant Gram-negative and Gram-positive bacteremia in hematological patients

Bloodstream infections (BSI) caused by multidrug-resistant bacteria (MDRB), particularly those involving extended-spectrum beta-lactamase (ESBL)- or carbapenemase-producing Enterobacterales, MDR Pseudomonas aeruginosa, and vancomycin-resistant enterococci (VRE), pose a major threat for patients with hematological malignancies undergoing chemotherapy or transplantation due to their inherent associated morbidity and mortality [1‐8]. Hematological patients are at increased risk of MRDB BSI as a result of extensive broad-spectrum antibiotics use, prolonged hospitalizations, and disruption of mucosal surfaces and neutropenia due to cytotoxic chemotherapy [1‐3]. Identifying MDRB-colonized patients through active surveillance could facilitate appropriate or early adjustment of empirical therapy for BSI, yet data supporting this assumption have been inconsistent [9‐17].

Nose and rectum are the preferred sites for surveillance of methicillin-resistant Staphylococcus aureus (MRSA) and VRE/MDR Gram-negative bacteria, respectively [18‐23]; nonetheless, there is no consensus regarding anatomical sites to be sampled for MDR Gram-negative bacteria screening, microbiological methods for the purpose, or the benefit of performing screening cultures targeting certain MDR bacteria (i.e. MDR-Stenotrophomonas maltophilia) [18, 24]. This was highlighted in a recent study revealing striking differences across Spanish centers in sampling protocols, body sites chosen for screening and microbiological testing procedures [25]. The purpose of the current study was twofold. First, we investigated the MDRB colonization rate in a series of hematological patients hospitalized for any cause using a multi-body-site surveillance approach and identified risk factors for this event. Second, we ascertained the incidence of MDRB BSI in patients with or without previous detection of MDRB colonization and determined whether the above screening strategy permitted anticipation of its occurrence.

We next investigated whether MDRB colonization was associated with any demographic or clinical characteristic of patients during hospital admission (Table 6). Frequency comparison analyses revealed statistically significant differences between colonized and non-colonized cases when comparing sex (p = 0.005), underlying hematological malignancy (p = 0.002), with increased MDRB colonization rate among patients with acute myeloid leukemia, and whether the patient had undergone hematopoietic stem cell transplantation (p = 0.025). A trend towards a higher MDRB colonization rate was seen in older patients (p = 0.06) and those who had been treated with antibiotics within the month prior to admission (p = 0.07). None of these factors except for sex and acute myeloid leukemia as the underlying disease were independently associated with MDRB colonization (Table 7).

Several factors mainly including broad-spectrum antibiotics use and prolonged hospital stays pose hematological patients at increased risk of MRDB colonization [1‐3]. In turn, disruption of mucosal surfaces and neutropenia due to cytotoxic chemotherapy or transplantation favor the occurrence of MDRB BSI, which are associated with high morbidity and mortality [1‐8]. In this study, we used a multi-body site screening strategy to investigate the rate of MDRB colonization in hematological patients admitted to the hospital for any cause (most frequently receipt of allogeneic or autologous stem cell transplantation, treatment of underlying disease or neutropenic fever) and to what extent this approach allowed us to predict MDRB BSI. Detection of genotypic determinants of antimicrobial resistance in MDRB was performed using a DNA-based microarray, which displays results that fully agree with genome sequencing data [26]. In line with previous studies [30, 31], to increase the rate of detection of MDRB we performed a combination of upper respiratory tract, gastrointestinal tract and axillar sampling. We documented colonization by one or more MDRB, mostly ESBL-producing Enterobacterales and MDR P. aeruginosa (including VIM-type carbapenemase producers) and S. maltophilia, in 33.7% of admissions, corresponding to 34.4% of patients in this series. Although MDRB colonization was more frequently documented during hospital stay, at either hematology ward or ICU, a non-negligible percentage of patients (14% of admissions) were identified as being colonized at baseline. Of note, colonization by carbapenemase-producing Enterobacterales and VRE was anecdotal, as expected considering the very low prevalence of these MDRB in our setting (not shown). Direct comparison of the current study with others addressing this same issue [9‐17] is simply unfeasible for a number of reasons, including differences across studies in patients characteristics, local epidemiology particularities and notably targeted MDRBs, screening strategy and methodology used for MDRB detection, all of which may impact dramatically on results. Regarding the latter, for example, we sampled the upper respiratory tract (pharyngeal and nasal specimens), axillary and rectal sites and combined rectal and axillary specimens, while others used only rectal specimens for surveillance. Although MDRB recovery was more likely from axillary-rectal specimens than from upper respiratory tract samples (in this context, nasal swabs were the most unrewarding specimen for detecting colonization with MDR Gram-negative bacteria) specially MDR Enterobacterales, surveillance of pharyngeal and nasal sites enabled us to document MDRB colonization, mostly by non-fermenting Gram-negative rods, that went undetected in axillary-rectal cultures in 25.4% of admissions.

Sex (male), underlying hematological malignancy (acute myeloid leukemia) and transplantation were associated with increased risk of MDRB colonization in univariate analysis, while a trend towards significance was observed in classically associated factors such as age and antibiotics treatment within the month prior to admission [1‐3]. The impact of sex and acute myeloid leukemia on increasing the risk of colonization by MDRB has been previously reported in particular for carbapenemase-producing Enterobacterales [10, 14, 32‐35].

In our view, the key observation of the current study was that overall, the MDRB-based BSI rate was significantly higher in MDRB-colonized patients than those who were not (p = 0.04). Moreover, among the 16 MDRB BSI episodes developing in MDRB-colonized patients, 13 were deemed to be caused by the colonizing isolate, principally ESBL-producing Enterobacterales and MDR P. aeruginosa. Indeed, MDRB colonization was independently associated with increased risk of MDRB BSI. Of these 13 isolates, 12 could be recovered from axillary-rectal cultures, while one (MDR-P. aeruginosa) was cultured from a pharyngeal specimen, but missed in axillary-rectal screening cultures. MDRB surveillance cultures, notably those from axillary-rectal sites, therefore offered valuable information to predict the antimicrobial susceptibility profile of BSI-causing MDRB in 81% of episodes. Our data concur to some extent with findings of several studies. Cattaneo and colleagues [12] conducted a multicenter prospective observational study involving 18 hematologic centers during a 6-month period; overall, 37 MDRB-colonized patients (25.7%) developed at least one BSI, of which 23 (16% of the whole series) developed BSI from the same MDRB pathogen with a rate of 15.6% for ESBL-producing Enterobacterales and 14.1% for carbapenemase-producing Gram-negative bacteria. The study concluded that empiric antibiotic treatment selection should be guided by known colonization in hematologic patients. Likewise, data from a study by Jaiswal et al. [10] demonstrated that hematologic patients colonized with carbapenemase-producing Enterobacterales have the highest risk of MDRB-BSI and mortality, particularly those with acute myeloid leukemia. In turn, Ballo et al. [11] highlighted the importance of exhaustive MDRB screening in acute myeloid patients with febrile neutropenia, as they require special surveillance due to their high risk of invasive infection and mortality. Liss et al. [13] found that colonization with ESBL-producing Enterobacterales was associated with increased risk ratios towards BSI development due to ESBL-producing Enterobacterales. Finally, Sadowska-Klasa et al. [17] retrospectively analyzed the data of 120 patients who underwent HCT for hematologic disorders and found that prior colonization was significantly correlated with MDRB infections (p < 0.001), especially bacteremia (p = 0.038).

The main limitation of the study is the relatively low number of registered MDRB BSI episodes. Nonetheless, the multi-body-site surveillance approach and MDRB pre-enrichment using selective broths, both of which may increase sensitivity for MDRB detection, can be considered strengths.

In summary, our data indicated that MDRB colonization in a highly heterogeneous cohort of hematological patients is a frequent event associated with increased risk of MDRB BSI. Thus, MDRB colonization screening cultures may be useful for predicting MDRB BSI and tailoring empirical antibiotic treatments on an individual basis. The data also suggested that upper respiratory tract sampling for surveillance cultures adds little to axillary-rectal swabbing only in terms of predicting MDR Gram-negative BSI development.