Sepsis is a leading cause of mortality in patients with hematologic malignancies or solid tumors undergoing intensive cytotoxic chemotherapy [1]. Particularly, failure to initiate appropriate empiric therapy in patients with sepsis and septic shock is associated with a substantial increase in morbidity and mortality [2]. Neutropenia, defined as an absolute neutrophil count (ANC) of < 500/mm³, remains the most frequently occurring unfavorable consequence of chemotherapeutic agents. Administration of prompt, empiric, broad-spectrum, hospital-based, and parenteral antimicrobial therapy has become the standard of care for most patients with febrile neutropenia. Patients with febrile neutropenia that developed after chemotherapy with clinical instability or Multinational Association of Supportive Care in Cancer score of < 21, require hospitalization for intravenous (IV) empiric antibiotic therapy. Monotherapy with an anti-pseudomonal ß-lactam agent, i.e., cefepime, carbapenem, or piperacillin-tazobactam, is recommended. In particular, clinically unstable patients with febrile neutropenia may require a combination of broad-spectrum ß-lactam antibiotics and aminoglycoside to extend the antibacterial spectrum and to obtain a synergistic effect against some gram-negative bacteria [3,4]. However, the susceptibility and resistance of anticipated pathogens to antimicrobials varied over time globally, with a recent shift toward gram-negative bacteria in the bacterial epidemiology of hematological patients [5-7]. Moreover, the production of extended-spectrum ß-lactamases (ESBLs) and subsequent resistant gram-positive pathogens have drawn attention due to the spread of antimicrobial resistance.

Sepsis and septic shock are life-threatening conditions caused by a dysregulated immune response to infection and often lead to tissue and organ injures and death [8-10]. Although a few studies have evaluated the microbial etiology of patients with neutropenic sepsis, none of them have focused on neutropenic septic shock [1,11].

Therefore, a cohort study to determine the microbial spectrum of infections and resistance patterns of their isolates in patients with chemotherapy-induced neutropenic septic shock was conducted.

This study demonstrated that the proportion of MDR bacteria (30.3%) found in patients with chemotherapy-induced neutropenic septic shock is high. Furthermore, MDR bacteria were also found to be resistant to monotherapy with an anti-pseudomonal ß-lactam agent such as cefepime (48.5%).

The Infectious Diseases Society of America guidelines suggested that high-risk patients should be hospitalized for IV empiric antibiotic therapy, and monotherapy with anti-pseudomonal ß-lactam agents, i.e., cefepime, carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended. Although some observational data have suggested that highdose cefepime (e.g., 2 g every 8 hours) can be effective against ESBL-producing pathogens [14,15], most of the available evidence does not encourage its use. In a randomized trial of patients with urinary tract infection with ESBL-producing pathogens, treatment failure with cefepime was found to be higher than that with ertapenem or piperacillin-tazobactam [16]. Similarly, a retrospective study that used an MIC of ≤ 8 µg/mL as the cut-off point for cefepime susceptibility reported that cefepime was inferior to carbapenems against bacteremia caused by ESBL-producing Enterobacteriaceae [17]. Therefore, this evidence, along with the high prevalence of MDR pathogens resistant to cefepime observed in the current study, suggests that monotherapy with cefepime may not be suitable for the treatment of septic shock in patients with neutropenia.

According to the guidelines of administering empiric therapy for the treatment of febrile neutropenia in Korea, gram-negative bacteria were more frequently observed in studies conducted until the early 2000s. Among the gram-negative bacteria, E. coli is the most common, followed by P. aeruginosa and Klebsiella spp. Similarly, in our study, which was conducted after 2012, gram-negative organisms were also the most common causative organism, with E. coli as the most common pathogen. However, data regarding the antimicrobial susceptibility to pathogens in febrile neutropenia have been limited in Korea, and the reported resistance rates vary. The rate of third-generation cephalosporin-resistant E. coli was reported to be 0% to 7.0% [4].

In a study published in 2013, approximately 26% of bacteremia due to E. coli or Klebsiella pneumoniae were caused by ESBL-producing organisms [18]. In the current study, the proportion of MDR pathogens was high (approximately 35%), and all of them were gram-negative bacteria. In particular, approximately 34% of E. coli and Klebsiella spp., the most common causative agents of febrile neutropenia with septic shock, were ESBL-producing organisms. The high proportion of MDR pathogens in our study may be due to the regional and study population differences, and patients with neutropenic septic shock might have higher MDR pathogens than those with febrile neutropenia only.

Previous studies have demonstrated that primary bacteremia was the most common cause of infection in patients with neutropenia, followed by urinary tract infection and pneumonia [19]. The typical pathogen was slightly different for each type of infection, with P. aeruginosa and S. pneumoniae being the most common causative agents in infections originating from the lungs. Additional pathogens to be considered in cancer patients with neutropenia include gram-negative enteric organisms such as P. aeruginosa, Klebsiella spp., and E. coli [20]. The most common pathogens in infections originating in the abdomen and urogenital regions were E. coli, whereas soft tissue and central venous catheter-related infections were mainly caused by gram-positive bacteria. Among the patients belonging to the “unknown origin” group, the most common causative agents were noted to be CoNS and E. coli [1].

This study identified numerous causative organisms, which greatly varied according to the infection site. However, in contrast to the previous evidence, E. coli was most frequently identified in blood cultures from skin and soft tissue infections in this study. Skin and soft tissue infections caused by gram-negative bacteria, such as E. coli, are uncommon and present as primary skin infections with a cutaneous portal of entry [21]. Secondary bloodstream infections that originated from the digestive tract may also occur. However, the number of cases that have been previously reported was limited, and all of them were found to have occurred in immunocompromised patients [22].

The identification rate of MDR bacteria also differed according to the infection site. This variation in the proportion of MDR bacteria based on the infection site is crucial during the use of early empiric antibiotics. Therefore, antibiotics used for the treatment of septic shock in patients with neutropenia should be carefully selected, taking into consideration the increased rates of ESBL-producing organisms and the suspected infection site. Although gram-positive bacteria were also identified as causative organisms, MDR gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus were not found in this study. Therefore, the use of vancomycin should be evaluated based on the patient’s condition and the risk factors present, such as previous infections, colonization with the organism, and treatment in a hospital with high endemic rates.

Our study had several limitations. First, this was an observational study using data from a prospective septic shock registry, and unmeasured confounding variables may exist. Second, although this study included a relatively large cohort of patients with neutropenic septic shock, the sample was too small to carry out specific analyses. Third, the data used in this study were collected from a single center; thus, the results should be cautiously interpreted in studies conducted in different populations and countries. Future studies should include controlled prospective trials that identify patients highly at risk of infection because of MDR pathogens.

In conclusion, MDR bacteria were prevalent (30.3%) in patients with chemotherapy-induced neutropenic septic shock, and 48.5% of them were resistant to cefepime. If MDR bacteria are suspected to be the causative agents, piperacillin-tazobactam or carbapenem may be considered as empiric antibiotics. Moreover, aminoglycoside may also be added to the initial regimen for the management of complications.