ESBL-PE infections have increased in recent years and are a major cause of hospital and community-acquired infections (1,3,4,12,25,26). The carrier status in the healthy population is estimated at 14% worldwide, but in some regions, it can be as high as 46% (2), which implies a high risk of infection by resistant germs in patients admitting from the community to the healthcare centers. Colonization status increases in populations at higher risk such as patients with solid or hematological malignancies, with a prevalence of 19% (25). In Colombia, community-acquired urinary tract infections produced by Enterobacteriaceae with resistance to third-generation cephalosporins range from 3.4 to 17.2% (4).
Colonization by ESBL-PE is a very important risk factor for the subsequent development of infections or bacteremia by these microorganisms (12,17,27). Other clinical characteristics of the patients, the epidemiological environment and the healthcare-related procedures are recognized as risk factors for ESBL-PE infection (9).
The present study evaluated risk factors for isolation of ESBL-PE in cancer patients, derived and validated a scoring system to quickly identify these patients. The present study identified risk factors in cancer patients for ESBL-PE isolation, derived and validated a scoring system to identify these patients. The multivariable analysis identified eight variables associated with the presence of microbiological isolation of ESBL-PE, these included hospitalization in the last year, prolonged hospitalization greater than 7 days, immunosuppressive therapy by steroids or calcineurin inhibitors, presence of neutropenia, use of devices invasive, exposure to beta-lactam drugs in the last month, remission neoplasia and no use of chemotherapy in the last 3 months. These factors confirm some already identified in previous studies (9). The developed score includes simple variables to be evaluated clinically in the first contact with the patient and his previous medical history.
The crude scoring system achieved an acceptable ability to discriminate patients with ESBL-PE isolation. Operational performance was better for the Derivation Phase; however, it fell in the Validation Phase (ROC-AUC 0.68 and 0.60). The cut-off point selected by the Liu method (24) that maximizes sensitivity and specificity showed generally low values in both phases (sensitivity 68% and 32%, specificity 61% and 83% respectively), also, the accuracy was low, with misclassification of 30%.
The scoring systems can not only be measured with the capacity of maximum discrimination with the ROC-AUC because the objective of their implementation must also be taken into account. If the goal is to screen hospitalized patients to determine their risk of ESBL-PE infection, a cut-off point with maximum sensitivity should be sought to capture the majority of patients at risk, with the price of lowering specificity; in this way, patients would receive treatment with carbapenems and contact isolation. The limitation of this approach is that many patients without risk would end up receiving broad-spectrum antibiotics and contact isolation without needing. On the other hand, if the objective is to guide antibiotic therapy, specifically to avoid the indiscriminate use of carbapenems, a cut-off point with low sensitivity and high specificity should be sought (28,29).
In Tumbarello study (23), the cut-off point of at least 3 points had high sensitivity (93%) and NPV (97%), but low specificity (62%) and PPV (45%); when the cut-off point rose to 6 points, sensitivity and NPV decreased to 63% and 88%, but specificity and PPV increased to 95% and 80%. In the Duke model (30), with a cut-off point of 8 points, good specificity and PPV (95% and 79%, respectively) were obtained, but low sensitivity (58%). In the Kengkla study (31) the 9-point cut-off obtained moderate sensitivity (74%) and NPV (68%) with inadequate specificity (66%). The most recent model proposed by Lee (32) obtained high sensitivity (84%) and specificity (92%) using a cut-off greater than 2 points.
In the present study, set the highest sensitivity (cut-off point ≥ 1) in the Derivation and Validation phases, it is remarkable that majority of patients had at least 1 risk factor (sensitivity of 100% and 99% respectively), but with a high percentage of false positives (100% and 97%). This makes the scale impractical to exclude patients without risk of ESBL-PE infection and would overestimate the empirical use of carbapenems and the need for contact isolation. Maximizing specificity (cut-off point ≥ 7) allows to identify patients without ESBL-PE (100% specificity), but only 1% of patients with ESBL-PE are captured, with low capacity to select patients at high risk of ESBL-PE. This way, a large number of patients who may require carbapenem treatment would not receive it and therefore the risk of mortality could increase. It is considered that with this scoring system there is no good cut-off point to predict a high risk of ESBL-PE infection nor to make decisions about the prescription of empirical antibiotics.
Previous described scoring systems may have better discriminatory performance because of the inclusion of more selected populations like the inclusion of patients within the first 48 hours of admission, only with E. coli infection or presence of bacteremia (18). This study included patients of all age ranges, patients with infection or colonization, all Enterobacteria species, community, and hospital-acquired infections, as well as infection of any organ. These characteristics reflect better the behavior of infections in the real life of an institution to make the results more generalizable.
The included population had a higher prevalence of ESBL-PE than the ambulatory population in Colombia, especially E.coli (20% vs. 6.4%) (4). The Validation cohort shows that the population attending the National Institute of Cancer of Colombia has high morbidity, approximately 70% had a hospitalization in the last year, 40% received chemotherapy in the last 3 months, 45% had an invasive device and 25% was exposed to antibiotics in the last month. This represents a high prevalence of risk factors in the entire cancer population.
In the context of patients with cancer and immunosuppression, the current therapeutic behavior is oriented to establishing the patient's risk group and beginning empirical treatment with broad-spectrum antibiotics until microbiological isolation is achieved. This approach has been proposed recently based on observational studies where patients are classified according to immune status, the source of infection and the severity of disease presentation (7,8). For immunosuppressed patients (neutropenia, leukemia, lymphoma, HIV, solid organ or hematopoietic cell transplantation, cytotoxic chemotherapy or steroid use) and severely ill patients (high Pitt score or APACHE II, need for ICU or presence of septic shock) the beginning of empirical treatment with carbapenems has been recommended (8).
The results of this study allow us to conclude that in patients at high risk for ESBL-PE infections such as cancer patients, the risk score fails to adequately discriminate the patients and therefore other methods should be sought to early identify patients with ESBL-PE infections and to guide antibiotic therapy (33,34).
The limitations of the study include its retrospective nature, historic medical records as source of information; the lack of inclusion of some specific variables of cancer patients (type of neoplasia, type of chemotherapy, ECOG and Karnofsky scores) which could have provided more information or allowed a better classification of patients; the absence of distinction between infection vs colonization, variables that are retrospectively difficult to discriminate and are proposed to be validated prospectively; non-discrimination between infection from the community or healthcare-associated, nor discrimination between bacteremia or specific organ infections, which could be related to better specificity of risk factors. Finally, it is a study conducted in a single specialized cancer institution in Colombia and therefore the results are not generalizable to other institutions with different characteristics.