The strategy of antibiotic use in critically ill neutropenic patients

Matthieu Legrand 1 2 Adeline Max 1 Benot Schlemmer 1 Elie Azoulay 1 Bertrand Gachot 0 0 Department of Intensive Care and Infectious Diseases, Institut Gustave Roussy , 39, rue Camille Desmoulins, 94805 Villejuif cedex, France 1 Medical Intensive Care Unit , AP-HP, Saint-Louis Hospital , 1 rue Claude Vellefaux, Assistance Publique - Hopitaux de Paris, University of Paris 7 Denis Diderot , 75010, Paris, France 2 Department of Anesthesiology and Critical Care, Lariboisire Hospital , Assistance Publique - Hopitaux de Paris, University of Paris 7 Denis Diderot , 2 rue Ambroise-Par, 75475 Paris , Cedex 10, France Suspicion of sepsis in neutropenic patients requires immediate antimicrobial treatment. The initial regimen in critically ill patients should cover both Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa. However, the risk of selecting multidrug-resistant pathogens should be considered when using broadspectrum antibiotics for a prolonged period of time. The choice of the first-line empirical drugs should take into account the underlying malignancy, local bacterial ecology, clinical presentation and severity of acute illness. This review provides an up-to-date guide that will assist physicians in choosing the best strategy regarding the use of antibiotics in neutropenic patients, with a special focus on critically ill patients, based on the above-mentioned considerations and on the most recent international guidelines and literature. - Introduction Neutropenia is defined as a neutrophil count 500/ mm3 or 1000/mm3 with a predicted decrease to 500/mm3 [1,2]. Infection remains a major complication of neutropenia, and severe sepsis and septic shock are associated with high hospital mortality [3,4]. Fever, defined as a single oral temperature 38.3C or 38.0C for at least 1 hour, develops in 10-50% of patients after chemotherapy for solid tumors and in more than 80% of patients with hematological malignancies [5]. Urgent and appropriate antibiotic administration is mandatory to prevent further clinical deterioration, especially in critically ill patients with signs of respiratory distress or severe sepsis. Therefore, the first-line antibiotics should cover the pathogens deemed to be most likely based on the patients characteristics, neutropenia, and local epidemiology. However, the changing epidemiology of infections, global increase in resistant strains, and need to contain healthcare costs require careful selection of antibiotics. Only 10-40% of episodes of febrile neutropenia are microbiologically documented in neutropenic patients, which hampers appropriate antibiotic spectrum adjustment in most cases [5]. This review provides an up-to-date guide to assist physicians in choosing the optimal antibiotic regimen in neutropenic patients, based on the above-mentioned considerations and on the most recent international guidelines and literature. Bacterial epidemiology in neutropenic patients During the 1990s, Gram-positive bacteria emerged as the leading agents responsible for infections in neutropenic patients worldwide. In adults with bloodstream infections and malignancies in the United States, the proportion of Gram-positive organisms increased from 62% in 1995 to 76% in 2000, whereas the proportion of Gram-negative infections decreased from 22% to 15% [6]. Factors that may increase the risk of Gram-positive sepsis in neutropenic patients include the widespread use of central venous catheters, introduction of prophylactic quinolone therapy, increased use of proton pump inhibitors, and rising prevalence of chemotherapy-induced mucositis [7]. Importantly, Gram-negative bacteria seem to be causing an increasing number of infections in neutropenic patients since the early 2000s (Table 1). The selection of empirical antimicrobials depends in part on an assessment of which pathogens are most likely to be involved. Table 2 shows a nonexhaustive list of pathogens with their possible sites of development in neutropenic patients. Although Gram-negative bacteria are usually associated with severe infections that have high mortality rates, coagulase-negative staphylococci (CNS), which are recognized as the most common causes of nosocomial bacteremia, often are associated with more indolent forms of infections and have been more prevalent among Table 1 Bloodstream bacterial isolates in clinical trials enrolling neutropenic adults between 1998 and 2009 Feld et al. Regazzoni et J Clin al. Intensive Oncol Care Med 2000 [26] 2003 [48] Enterobacteriaceae 6 (14) Table 2 Nonexhaustive list of bacteria that cause disease in febrile neutropenic patients, with their usual sites of development Coagulase-negative staphylococci Bloodstream infections, catheter-associated sepsis Viridans group streptococci Enterococcus faecium Enterococcus faecalis Stomatococcus mucilaginosus Stenotrophomonas maltophilia Alcaligenes xylosoxidans and Burkholderia cepacia Mycobacterium chelonae Mycobacterium fortuit (...truncated)