Unwelcome guests: Risk factors for multidrug-resistant bacterial infections in adults with acute lymphoblastic leukemia

Abstract

Abstract Introduction: Despite significant improvements in survival among adult patients with acute lymphoblastic leukemia (ALL), severe infections remain the leading cause of non–disease-related mortality. These patients are especially vulnerable to bacterial infections during treatment. Infections are associated with poorer clinical outcomes; in particular, the 30-day survival rate drops to 37.5% when multidrug-resistant (MDR) bacterial infections are present. Although empirical antibiotic therapy has contributed to improved survival, the risk factors for the development of MDR infections in this population remain unclear. Methods: We conducted a single-center, retrospective, observational, nested case-control study within a cohort at a tertiary-care hospital in Mexico. The study included patients aged over 18 years who were hospitalized for a bacterial infectious episode with a diagnosis of ALL while receiving active treatment between January 2015 and December 2024. MDR was defined as resistance to at least one antibiotic in three or more distinct antibiotic classes according to antibiogram results. The primary objective was to identify risk factors for MDR bacterial infections in adults with ALL undergoing treatment. Secondary objectives were to evaluate the prevalence of MDR bacterial infections and MDR infection-related mortality in patients with ALL receiving treatment. Results: The study included 113 patients who met the inclusion criteria, with a total of 378 infectious episodes analyzed. The median age was 37 years (range 17–72), 57.3% were women, and treatment regimens included CALGB10403 in 36% (n=136), Hyper-CVAD in 48.1% (n=182), and other regimens in 15.9% (n=60). A bacterial isolate was obtained in 60.6% of episodes (n=229), of which 36% were MDR (n=136), 23.3% were extended-spectrum β-lactamase (ESBL)-producing organisms (n=88), and 6.3% were carbapenem-resistant organisms (CRO) (n=24). In multivariate analysis, risk factors associated with MDR infection compared to non-MDR or culture-negative episodes were: hospitalization within the previous 12 months (for MDR: OR 5.136, 95% CI 2.362–11.170, p<0.001; for ESBL: OR 4.069, 95% CI 1.563–10.597, p=0.004); antibiotic use within the last 90 days (for MDR: OR 5.406, 95% CI 2.859–10.222, p<0.001; for ESBL: OR 3.913, 95% CI 1.868–8.199, p<0.001); hypoalbuminemia (for MDR: OR 3.913, 95% CI 1.868–8.199, p=0.05; for ESBL: OR 2.007, 95% CI 1.128–3.570, p=0.018; for CRO: OR 4.927, 95% CI 1.331–18.241, p=0.017); and ICU admission in the previous 90 days (for MDR: OR 8.219, 95% CI 3.212–21.033, p<0.001; for ESBL: OR 3.625, 95% CI 1.827–7.192, p<0.001; for CRO: OR 10.106, 95% CI 3.242–31.498, p<0.001). The probability of isolating an MDR microorganism was evaluated based on the presence or absence of risk factors. The observed probability was 23% with two risk factors, 62% with three risk factors, and 93% with all four risk factors. For carbapenem-resistant organisms (CRO), a probability of 35% was observed when two risk factors were present. Among the 367 infectious episodes, first-line empirical therapy consisted of a carbapenem in 52.1% (n=197), piperacillin/tazobactam in 36.2% (n=137), and other antibiotics in 8.8%. Adequate initial antibiotic therapy was administered in 83% of episodes, while 16.7% received inappropriate initial treatment. There was a statistically significant difference in 30-day survival between patients receiving adequate versus inadequate initial therapy (95.1% vs. 77.1%; HR 5.48, 95% CI 2.96–10.16, p<0.001). Overall, mortality per infectious episode was 10.8%. There was a statistically significant difference in 30-day survival between patients with MDR versus non-MDR infections (95.8% vs. 85.7%; HR 2.92, 95% CI 1.72–4.95, p=0.001), ESBL versus non-ESBL infections (94.7% vs. 83.4%; HR 2.90, 95% CI 1.56–5.39, p=0.001), and CRO versus non-CRO infections (94.2% vs. 62.5%; HR 5.28, 95% CI 3.06–12.87, p<0.001). Conclusions: The prevalence of multidrug-resistant (MDR) infections in adults with acute lymphoblastic leukemia (ALL) is high (36%). The main risk factors are previous hospitalization, recent antibiotic use, hypoalbuminemia, and ICU admission. MDR infections are associated with increased mortality. Appropriate selection of empirical antibiotic therapy is crucial for improving prognosis and survival.