Infections with Multi-Drug Resistant Gram-Negative Pathogens in Patients Receiving Treatment for Hematological Malignancies: Risk Factors and Outcomes.

Background: Bacterial infection, the most common complication of chemotherapy-induced neutropenia, is associated with substantial morbidity and mortality. Gram-negative pathogens are prominent causes and account for 30% of microbiologically documented infections in neutropenic patients. The recent years have seen a steady increase in isolation of multi-drug resistant (MDR) pathogens, resistant to antibiotics commonly used as first-line therapy for febrile neutropenia. This trend of increasing resistance to a wide range of antibiotics poses a great therapeutic challenge in the treatment of bacterial infections in neutropenic hosts. This may have adverse impact on treatment outcomes due to delay in initiation of adequate antibacterial therapy.

Aims: This study aimed to identify risk factors associated with infections caused by MDR gram-negative pathogens, and determine the impact of such infections on treatment outcomes and mortality in patients receiving treatment for hematological malignancies.

Methods: A case-control study was conducted in patients treated for hematological malignancies in Singapore General Hospital with positive clinical culture for gram-negative pathogens from January 2005 to May 2008. Multi-drug resistance was defined as complete resistance to penicillins, beta-lactam/beta-lactamase inhibitor combinations, cephalosporins, monobactams, co-trimoxazole, and fluoroquinolones. Patients infected with MDR gram-negative pathogens were designated as case patients. Controls were selected from patients with gram-negative pathogens that did not meet criteria for MDR, matched for date of isolation of pathogen and time at risk.

Results: Sixty-eight cases of gram-negative infection caused by MDR pathogens were identified, and were compared to 68 controls. Majority of the patients had primary diagnosis of acute leukemia (81.2% of cases, and 75.4% of controls). Most of these patients received chemotherapy for treatment (91.3% of cases, and 95.7% of controls) while the rest underwent hematopoietic stem cell transplantation. Multivariate analysis revealed the following independent risk factors associated with MDR gram-negative pathogens:

1. the use of ciprofloxacin as antibacterial prophylaxis (OR, 29.41; 95% CI, 1.32 – 500.0; p = 0.014);

2. presence of central venous catheter (OR, 4.381; 95% CI, 1.128 – 17.022; p = 0.033); and

3. severe neutropenia with absolute neutrophil count less than 100/uL at time of infection (OR, 4.922; 95% CI, 1.448 – 16.735; p = 0.011).

Clinical and microbiological outcomes were comparable between the 2 groups. Overall mortality rates were similar with 8 deaths (11.6%) in patients with MDR gram-negative pathogens and 13 deaths (18.8%) in the control group (p = 0.343). More patients with MDR gram-negative pathogens died from infection-related causes, with 7 out of 8 deaths among cases and 6 out of 13 deaths among controls. However, this difference did not reach statistical significance. Patients infected with MDR gram-negative pathogens received significantly longer duration of antibiotic treatment (p = 0.03). In addition, the proportion of patients infected with MDR pathogens requiring admission to intensive care unit after infection was significantly higher as compared to that of the controls (33.3% vs 10.1% respectively, p = 0.009).

Conclusion: The increasing prevalence of documented infection caused by MDR pathogens has important implications on future therapy and outcomes. With the identification of these risk factors, effective strategies to curb the rise of MDR pathogens can be developed, such as reviewing use of antibacterial prophylaxis. Patient care can be further optimized with better risk-stratification of patients, together with modification of institution treatment guidelines for patients at higher risk for acquiring MDR pathogens.