Clinically relevant infections in hematology and oncology: bacterial infections and the role of novel antibiotics in times of multidrug resistance

Patients with hematologic neoplasias and solid tumors are at increased risk for different kinds of infections due to both common and opportunistic pathogens. The most acute and clinically relevant problem is bacterial infections, which significantly contribute to morbidity and mortality in hemato-oncological patients. In addition, infections lead to delays and/or dose reductions of chemotherapeutics.

For febrile neutropenia, several guidelines have been published that cover all different aspects and provide good advice for the clinical management of this topic [1]. However, the epidemiology of pathogens responsible for bacterial infections is constantly evolving, with multidrug resistance being an increasingly common problem. Much less is known about the best possible treatment of multidrug resistant (MDR) bacteria in cancer patients. While a variety of novel antibiotics and/or combinations of antibiotics with new betalactamase inhibitors have been introduced, these new treatment options are not necessarily better and can even be less effective for the treatment of “standard pathogens”. Thus, the aim of this article is to focus on the impact of multidrug resistance on the management of cancer patients with bacterial infections and discuss possible indications for the most important new antibiotic compounds as well as the putative downsides of novel therapeutics.

In approximately half of patients with febrile neutropenia, the causative pathogen cannot be identified, so initial antibiotic treatment will often continue to be empirical. In high-risk patients, guidelines usually suggest the use of broad-spectrum betalactams with coverage of enterobacteriaceae, P. aerugiosa, S. aureus and Streptococci as first line agents. Thus, usually piperacillin/tazobactam, group 1 carbapenems (imipenem, meropenem) or pseudomonas-cephalosporins (cefepim, ceftazidim) are chosen as first-line antibiotics [1].

With the emergence of MDR pathogens, there is an increased risk of choosing the wrong initial empirical antibiotic therapy. While historically grampositive cocci have been the most prevalent pathogens in cancer patients, in recent years there has been a shift towards gramnegative bacteria [2]. The most common gramnegative bacteria isolated from bacteremia in patients with cancer are E. coli, P. aeruginosa, K. pneumoniae, Enterobacter spp. and, even more problematic to treat, Acinetobacter spp. and S. maltophilia. Staphylococci are most prevalent among grampositive bacteria, followed by Enterococci [3, 4]. These changes in epidemiology also have implications for treatment options. While there is a rather wide range of antibiotics available for the treatment of resistant grampositive bacteria, the treatment options for certain gramnegative pathogens are much more limited.

In fact, when MDR gramnegative bacilli could be identified as the causative pathogen, a study by Martinez-Nadal found that approximately 40% of neutropenic patients with bacteremia were treated with inappropriate empirical antibiotics, despite choosing treatment regimens suggested by international guidelines. This led to significantly higher mortality, especially in patients that initially presented with pneumonia, shock and with infections due to P. aeruginosa [3].

The World Health Organization has defined a list of priority pathogens that are a major threat to human health due to their resistance profile and the limited availability of effective antibiotics. Many of these bacteria of critical or high priority are typically found as pathogens in patients with febrile neutropenia, i.e. extended spectrum betalactamase (ESBL)-producing or carbapenem-resistant enterobacteriaceae (CRE), carbapenem-resistant P. aeruginosa or Acinetobacter baumannii, as well as grampositive bacteria like methicillin-resistant or vancomycin-resistant S. aureus and vancomycin-resistant E. faecium. Knowledge of local epidemiology is important for the empirical choice of initial antibiotic therapy and whether to try to cover MDR bacteria before getting results from microbiological cultures. Furthermore, some clinical conditions are also correlated with increased incidence of MDR pathogens in neutropenic patients, i.e. duration of neutropenia, presence of indwelling central venous catheters and patient age [5]. To identify patients at risk for infections with MDR pathogens is even more relevant in critically ill patients, since inadequate empirical therapy results in higher mortality [6]. In clinical practice, the highest risk for the wrong choice of empirical therapy in neutropenic patients is given in bacteremia due to S. maltophilia, E. faecium, MDR‑P. aeruginosa, coagulase-negative staphylococci and, to a less extent, ESBL E. coli [3].

In the past few years, a number of new antibiotics have become available; some are combinations of old substances with novel betalactamase inhibitors, others are new members of existing antibiotic classes. The most relevant new additions to the antibiotic armamentarium are listed in Table 1.