Microbiologically documented infections also account for 25–30 % of febrile episodes in neutropenic patients (Fig. 1.1). The majority of these are monomicrobial (i.e., caused by a single pathogen), but polymicrobial infections are being documented with increasing frequency. Recent data show that ~15–25 % of bacteremias in neutropenic patients, including catheter-related infections, are polymicrobial [11–13]. Infections involving deep tissue sites are predominantly polymicrobial [14]. These include neutropenic enterocolitis, perirectal infections, complicated skin/skin structure infections, and pneumonia. The majority of polymicrobial infections are caused by multiple bacterial pathogens (gram-positive, gram-negative, and occasionally anaerobic organisms) although bacterial and fungal or bacterial and viral infections can also co-exist.

The most common and important sites of infection in patients with acute leukemia are listed in Table 1.1. Overall, the respiratory tract is the most common site of infection. Approximately 25 % of patients with acute leukemia will develop a pulmonary infiltrate during an episode of neutropenia lasting 10 days or longer. Other parts of the respiratory tract including the oropharynx, upper airways, and the paranasal sinuses are also frequent sites of infection. Most pulmonary infiltrates are secondary to an infectious process (bacterial and fungal organisms predominate) although it is often quite difficult to establish a specific microbiologic diagnosis. Noninfectious causes of pulmonary infiltrates such as alveolar hemorrhage and drug toxicity are much less common. Consequently, empiric therapy directed against anticipated pathogens is generally administered in such patients and can be modified if confirmatory microbiologic data become available. The management of patients with pulmonary infections/complications is discussed in detail else where. Approximately 15–20 % of patients with acute leukemia and neutropenia will develop a bloodstream infection. These include primary bacteremias and central line-associated infections. Gram-positive bacteria are isolated most often (~75–80 % of the time) with organisms colonizing the skin (e.g., Staphylococcus species, Bacillus species, Corynebacterium species) being predominant [13–16]. In patients with oral or intestinal mucositis, viridans group streptococci (VGS), enterococci (including VRE), and enteric gram-negative organisms are common pathogens [17, 18]. The frequency of gram-negative bacteremia is lower in patients receiving antibacterial prophylaxis with agents such as the fluoroquinolones, than in patients not receiving prophylaxis [19, 20]. Fungemias occur ~4–6 % of the time, are caused most often by Candida species, and are often associated with indwelling central venous catheters [21–24]. With the exception of Fusarium species, invasive mold infections seldom cause fungemia [25, 26]. A small proportion of bacteremic infections are caused by nontuberculous mycobacteria [27].

Urinary tract infections are documented in 10–15 % of patients with acute leukemia, especially in patients requiring the placement of short-term or long-term urinary drainage catheters. Gram-negative bacterial pathogens such as Escherichia coli predominate although Candida species are not uncommon in patients with urinary catheters, stents, or other devices and in those that have received multiple courses of broad-spectrum antibacterial therapy for previous episode of neutropenic fever.

Common skin and skin structure infections include cellulitis, infections at phlebotomy or other puncture wounds, and surgical site infections in patients who have undergone recent surgery. Uncommon, but more serious infections include pyomyositis (occasionally caused by E. coli) and necrotizing fasciitis [28]. These conditions usually require surgical intervention in addition to antimicrobial therapy. Even less common are primary cutaneous mold infections [29, 30].

Infections along the gastrointestinal tract are not uncommon. Prior to the frequent use of antifungal prophylaxis, thrush and esophagitis caused mainly by Candida species (occasionally by herpes viruses) were commonplace. Azole and echinocandin prophylaxis has rendered these infections largely of historical interest. Neutropenic enterocolitis (typhlitis) occurs primarily in patients with acute leukemia who receive therapy with agents (e.g., cytosine arabinoside, in combination with idarubicin or another anthracycline) that cause high-grade intestinal mucositis although it is being described with increasing frequency in patients receiving other mucotoxic antineoplastic agents such as the taxanes and vinorelbine [31–33]. Perirectal infections occur more often in patients with preexisting local lesions such as fissures and hemorrhoids [34]. True abscess formation is uncommon in patients with severe and prolonged neutropenia, but surgical drainage is almost always beneficial [35, 36].

Recent epidemiologic data document a predominance of gram-positive pathogens from microbiologically documented infections [13–16]. Unfortunately, these data focus on monomicrobial bacteremic infections, and do not provide details from most other sites of infection, or from polymicrobial infections. This gives an incomplete and skewed view about the microbiology of these infections since bacteremias are caused most often by gram-positive organisms that colonize the skin, whereas infections at most other sites (lung, intestinal tract, urinary tract) have a predominance of gram-negative pathogens [14]. Additionally ~80 % of polymicrobial infections have a gram-negative component, and ~33 % are caused by multiple gram-negative species [11]. When all sites of infection and polymicrobial infections are taken into consideration, a substantially different picture emerges, with gram-negative pathogens being almost as frequent as gram-positive pathogens [14]. Indeed, some institutions are now reporting a predominance of gram-negative pathogens [37]. Knowledge of local epidemiologic patterns is critical as empiric regimens need to be designed with this information in mind.

Whereas bacterial infections predominate during the first 7–10 days of severe neutropenia, invasive fungal infections start to develop as neutropenia persists. Prior to the availability of agents like fluconazole, invasive candidiasis with or without hematogenous dissemination was common, with Candida albicans being the predominant species isolated. The frequency of invasive candidiasis has been substantially reduced with the routine usage of antifungal prophylaxis (azoles, echinocandins) in high-risk patients, with manifestations like Candida esophagitis, and chronic disseminated (hepatosplenic) candidiasis becoming increasingly of historical interest [97]. The use of some of these agents also led to the emergence of Candida spp. other than Candida albicans as frequent pathogens in this setting, although C. albicans continues to be the single most common species isolated [98, 99]. Regional differences have been documented with a preponderance of different Candida species at different centers [21, 22, 100–102]. These differences may represent divergent use of antifungal prophylaxis and/or geographic diversity. Consequently, local epidemiologic and susceptibility data should be used to guide empiric and targeted therapy. Other yeasts that are encountered in this setting include Trichosporon beigelii, Malassezia furfur, Saccharomyces cerevisiae, and occasionally Hansenula anomala [103, 104].

The risk of hematogenous dissemination with various yeasts is greater in patients who have indwelling vascular catheters and chemotherapy-induced mucositis or graft versus host disease [99, 105]. Currently, catheter removal in addition to appropriate antifungal therapy is recommended, although this strategy is by no means universally accepted [106–108]. Most C. albicans isolates maintain susceptibility to fluconazole and itraconazole. The newer triazole agents such as voriconazole also have potent activity against most pathogenic yeasts. The echinocandins appear to be effective for the treatment of candidiasis caused by most Candida species [106]. Treatment of candidiasis with polyenes is seldom necessary. Despite appropriate therapy, the overall mortality in cancer patients with candidemia (which is mainly due to the severity of the underlying disease) approaches 40 % [98]. Disseminated T. beigelii infections respond less frequently than disseminated candidiasis [104].

Invasive mold infections, due primarily to Aspergillus species, are the most frequent cause of serious, often life-threatening infections in patients with neutropenia that persists for more than 2 weeks [109]. Other risk factors include impaired cellular immunity, prolonged corticosteroid administration, allogeneic stem cell transplantation, and advanced age [103]. A. fumigatus is the predominant species isolated but non-fumigatus species of Aspergillus are emerging as significant pathogens [110–113]. The most common site of involvement is the lungs leading to invasive pulmonary aspergillosis (IPA). Other common sites of involvement include the paranasal sinuses, the central nervous system, the heart and pericardium, the liver, the kidneys, and occasionally, bones and joints. Cough, dyspnea, and hemoptysis are the classic manifestations of IPA but may be absent or muted in many patients due to severe immunosuppression leading to a blunted inflammatory response. Persistent fever in patients with prolonged neutropenia, despite appropriate antibiotic therapy, should raise the suspicion of invasive fungal infection including IPA. Most infections are diagnosed by computerized tomography (CT) imaging. Classic findings include nodular or wedge-shaped densities, the halo sign, and cavitary lesions [114, 115]. These findings change and evolve over time, and in response to therapy, consequently the performance of serial CT imaging has been found to be useful in monitoring patients with IPA. Aspergillus hyphae are angioinvasive in nature and result in release of fungal antigens into the bloodstream. Serologic testing to detect galactomannan or beta-D-glucan has been evaluated for the early diagnosis of invasive aspergillosis. The former appears to be more useful than the latter and may also be a predictor of outcome [116–120]. The use of these tests in conjunction with CT imaging has been discussed in various guidelines for the diagnosis and management of invasive fungal infections in neutropenic patients and HSCT recipients [121–123].

Several mold-active agents are now available for the prevention and treatment of invasive aspergillosis. These include amphotericin B and its lipid formulations, itraconazole, voriconazole, posaconazole, and the echinocandins. A detailed discussion of antifungal prophylaxis and therapy is beyond the scope of this chapter, but recent guidelines addressing these issues are available [121–125]. Although still uncommon, zygomycosis (mucormycosis) has emerged as an increasingly important infection in the past 15–20 years especially in patients with hematologic malignancies and HSCT recipients [99, 126, 127]. The increasing frequency of zygomycosis has at least in part been attributed to the use of voriconazole for various indications such as antifungal prophylaxis and empiric, pre-emptive or targeted therapy of invasive fungal infection [128–132]. The most common organisms isolated include Rhizopus species, Mucor species, and Cunninghamella species. Common sites of infection include the paranasal sinuses and orbit, the lungs, skin, and the central nervous system, with pulmonary manifestations being predominant in neutropenic cancer patients. Generalized dissemination occurs in up to 5 % of patients. Clinical features are often indistinguishable from other common mold infections. Early diagnosis of zygomycosis is important for timely therapeutic intervention, and ultimately, reduced mortality and improved survival. Conventional methods for laboratory assessment for zygomycosis include direct examination, cytopathologic examination, and histopathologic examination of respiratory and other relevant specimens. The use of immunohistochemical stains, fluorescent and in situ hybridization, or in situ polymerase chain reaction (PCR) may also be useful. Cultures from various specimens are often negative. There is increased reliance on diagnostic imaging such as CT of the paranasal sinuses and chest, which may reveal early findings even before the development of localizing symptoms [133, 134]. Unlike invasive aspergillosis where recent diagnostic and therapeutic advances have improved overall survival, the outcome of patients with hematologic malignancies who develop zygomycosis has not improved significantly [126, 127, 135]. Only two systemic antifungals have reliable activity against these organisms – amphotericin B and its lipid formulations and the new triazole, posaconazole. Recent guidelines advocate the lipid preparations of amphotericin B as first-line therapy, with posaconazole and combinations of caspofungin with lipid preparations of amphotericin B as second-line therapy [136, 137]. Surgery is recommended for rhinocerebral and soft tissue infections. Reversal of underlying risk factors is important. The duration of therapy remains unclear and should be guided by resolution of all associated symptoms and findings. Maintenance therapy and/or secondary prophylaxis should be considered in patients who remain severely immunosuppressed. Other uncommon but important molds that cause invasive infections in patients with hematologic malignancies include Fusarium species and Scedosporium species [138]. Unlike most other molds, fungemia is common in patients with fusariosis and may occur in ~40 % of patients [139]. Involvement of the paranasal sinuses, lungs, skin, and disseminated infection is also relatively common. Optimum therapy remains to be defined, and the overall outcome is poor. The incidence of Scedosporium infection appears to be increasing, with cases of S. prolificans generally occurring after 2000 [140]. As with fusariosis, optimum therapy remains to be defined, and the overall prognosis is poor.