increased. Solid tumors are frequently treated with combinations of surgery, radiotherapy, and chemotherapy. In contrast, in patients with hematologic malignancies, chemotherapy is the cornerstone of treatment [1]. New therapeutic options, such as immunotherapy and gene therapy, are being developed. However, a significant proportion of patients still do not achieve complete remission, and infection remains a frequent cause of treatment failure, particularly in patients with hematologic malignancies. Ocular and orbital infections are particularly important, not only because of their frequency but also because of the associated local and systemic morbidity.

Many factors increase the risk of infection in cancer patients: poor clinical and nutritional status, mechanical obstruction of natural passages, damage to anatomic barriers (as a result of surgery or use of prosthetic and intravascular devices), and defects of humoral and cell-mediated immunity that are either associated with disease or secondary to radiotherapy or chemotherapy [1–4]. Cytotoxic agents exert their effects on both malignant cells and normally replicating progenitor cells and thus also cause major damage to normal tissues with high cell turnover (i.e., bone marrow and mucous membranes), resulting in myelosuppression and alteration of physiological barriers [1, 5]. Historically, hemorrhage and infections have been major complications of chemotherapy and leading causes of chemotherapy-related mortality [1]. In the 1960s, both the severity and duration of granulocytopenia were identified as major determinants of infectious complications [1, 2, 5]. In the early 1970s, prompt empirical antibiotic treatment became the cornerstone of management of febrile neutropenia, resulting in drastic reduction of the mortality of bacterial infections [1, 2, 5]. Since then, major progress has been made in the understanding of the pathogenesis and treatment of infectious complications in cancer patients.

28.2 Epidemiology

The majority of infections in immunocompromised cancer patients are caused by microorganisms of the host’s endogenous flora [1, 6]. However, exogenous airborne and foodborne pathogens can also cause infection.

28.2.1 Bacterial

Gram-positive and gram-negative bacteria are the predominant pathogens in immunocompromised cancer patients. Over the past four decades, most cancer centers have experienced major changes in the etiology of bacterial infections in neutropenic patients [2, 4]. From the late 1960s to the early 1980s, aerobic gramnegative bacilli (Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa) were the predominant causative agents, and P. aeruginosa was the most common isolate in all centers [3, 4]. Empirical antibiotic regimens were developed that took account of this pattern [7–10]. In the mid-1980s, there was a steady increase in

gram-positive infections, and eventually 60–70% of cases of single-organism bacteremia were caused by gram-positive cocci (predominantly coagulase-negative staphylococci, viridans streptococci, and Staphylococcus aureus) [4, 5]. Although several factors have been proposed as contributors to this change in the pattern of causative agents—including more severe mucositis due to very aggressive chemotherapeutic regimens, longer duration of neutropenia, widespread use of long-dwelling right-atrial catheters, use of H2-receptor antagonists, and fluoroquinolone prophylaxis against gram-negative organisms—the underlying reasons are not absolutely clear. In recent years, however, the number of cases of gramnegative bacteremia has risen again, perhaps because of more parsimonious use of fluoroquinolones [1, 2, 5].

Gram-positive bacteria isolated from immunocompromised cancer patients today include S. aureus, coagulase-negative staphylococci, Enterococcus species, and viridans streptococci [1–5]. Viridans streptococci are part of the normal microbial flora and prevail in the oral cavity but also reside in the upper respiratory tract, the female genital tract, all regions of the gastrointestinal tract, and occasionally the skin [1, 3–5].

28.2.2 Viral

The herpesviruses are the most important viral pathogens in patients with cancer. This group includes herpes simplex virus 1 (HSV 1) and HSV 2, cytomegalovirus (CMV), varicella zoster virus, Epstein–Barr virus, and human herpesvirus 6 [1, 2, 11]. These DNA viruses establish a latent phase after primary infection, during which the viral genome resides in target cells for life with the potential to reactivate. Host defense against these viruses is dependent on viral-specific helpers and cytotoxic T lymphocytes, and thus both the likelihood of reactivation and the severity of disease are augmented during immunosuppression [2, 11].

HSV predominantly affects patients during profound neutropenia. Over 90% of the general adult population demonstrates seropositivity for HSV antibodies, indicating previous exposure [11]. The incidence of HSV reactivation in patients with previous exposure is approximately 70% after chemotherapy for leukemia or conditioning for hematopoietic stem cell transplantation [2].

CMV is very prevalent worldwide. It is the most serious of the viral pathogens in hematopoietic stem cell transplant recipients, and seropositive recipients are at greatest risk for developing CMV disease. Before the widespread adoption of prophylaxis against CMV, approximately 30% of seropositive transplant recipients developed CMV disease [2].

Reactivation of latent varicella zoster virus infection is common in patients with hematologic malignancies, especially after chemotherapy or treatment with corticosteroids, and typically occurs 3 months to 1 year after transplantation [2, 11].

Highly immunosuppressive regimens used for treatment of cancer patients have also created a population at higher risk for a variety of other viral infections, such as

those due to adenoviruses, polyomavirus, and community respiratory viruses [11]. The three most recently discovered human herpesviruses (human herpesviruses 6, 7, and 8), like other members of the family, may cause a primary infection, establish latent infection in a specific set of cells in the host, and then reactivate if conditions of altered immunity develop [2, 11].

28.2.3 Fungal

Fungal infections in cancer patients can be divided into three major categories: infections caused by the common opportunistic fungi (Candida species and Aspergillus species); infections caused by pathogenic fungi (Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis, which commonly cause self-limiting infections in the normal host); and infections caused by relatively uncommon more recently discovered fungal pathogens (e.g., phaeohyphomycetes, hyalohyphomycetes, and zygomycetes) [11–14].

Fungal infections are a major threat to immunocompromised patients. The incidence of invasive fungal infections has increased substantially during the past 30 years, to the extent that fungal infections are now a common cause of morbidity and mortality in patients with leukemia [11, 12]. Disseminated mycoses have been demonstrated at autopsy in 10–40% of patients with hematologic malignancies and are especially common in patients who have been treated with broad-spectrum antibiotics and corticosteroids [11, 15, 16]. Neutropenia has long been known to be a risk factor for fungal infections in patients with hematologic malignancies. Other risk factors include previous fungal infections; environmental exposure; long-term use of broad-spectrum antibiotics, steroids, or chemotherapeutic agents; and use of indwelling venous catheters.

Eighty to ninety percent of fungal infections are caused by Candida species. The remaining 10–20% are caused by Aspergillus species and other emerging fungi, including Fusarium, Pseudallescheria, Scedosporium, Rhizopus, and Mucor species [2, 5, 11]. Azole-resistant non-albicans Candida species have emerged in some cancer centers, usually in conjunction with several predisposing factors, including fluconazole prophylaxis [11].

Invasive candidiasis is generally preceded by colonization of mucosal surfaces [11, 12]. It can be classified as acute disseminated or chronic disseminated (hepatosplenic). Patients with proven bacterial or viral infections have a particularly high risk of infection by Candida species, perhaps because bacteremia with low-virulence bacteria is an indicator of mucosal lesions that allow Candida species to reach deep tissues and blood [11]. A high degree of colonization by Candida species in the gastrointestinal tract and oral cavity also increases the risk of systemic candidal infection [2].

Aspergillosis in neutropenic patients is usually caused by Aspergillus fumigatus or A. flavus. In contrast to candidiasis, aspergillosis is invariably acquired