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Prophylaxis and Empirical Therapy of Infection in Cancer Patients
Cancer patients probably represent the best example of how both a disease and its treatment can impair the complex immunologic network aimed at maintaining the integrity of our body and defending it against infections from both the external and the internal environment. For decades we have known that a granulocyte count of less than 500 cells/mm 3 (and especially <100 cells/mm 3 ) is associated with an increased risk of severe bacterial and fungal infections. There is also evidence that patients with a granulocyte count between 500 and 1000 cells/mm 3 , especially if rapidly decreasing, are also at high risk of infectious complications, because neutropenia is not a static but a dynamic concept. Indeed, a survey on fever during neutropenia in children with cancer showed the presence of severe infectious complications (e.g., bacteremia or invasive mycosis) in patients with a granulocyte count that never dropped below 500 cells/mm 3 , suggesting the presence of a “gray zone” that should be carefully monitored. The other three main factors that impact the risk of infectious complications in these patients are the damage of anatomic barriers, such as skin or mucosal membranes; the alteration of the microbiota diversity; and the presence of indwelling devices. Indeed, mucositis itself might result in severe infections due to microbial translocation, even in the absence of neutropenia, and a central venous catheter (CVC) may facilitate the entrance of endogenous and exogenous bacteria and fungi in the bloodstream or in subcutaneous tissues. The alteration of the microbiota diversity has been recently shown to affect the risk of infection and other important outcomes in hematology, in a way that is still not properly understood. In patients with solid tumors, cancer-related obstructions and surgical procedures, together with prolonged hospital admission, are additional conditions able to increase the infection risk. Neutropenia and mucositis are usually related to the type and intensity of traditional chemotherapy, while the microbiome alteration is multifactorial in origin, although the improper and excessive use of antibiotics and other drugs (e.g., proton pump inhibitors) is pivotal in this sense. In addition to the appreciation of the role of a damaged microbiota in affecting the risk of infection, in recent years, the widespread use of the novel targeted and biological agents, which have become part of many chemotherapeutic regimens, is posing new challenges that might change substantially what we know about the pathogenesis of infections in cancer patients, as well as their type and incidence.
Finally, the most important issue now challenging physicians and health care workers, as well as the scientific and nonscientific community, is the phenomenon of the growing antibiotic bacterial resistance worldwide, which has the potential to change substantially prophylactic and treatment issues. Antibiotic-resistant pathogens such as Enterobacteriaceae resistant to third-generation cephalosporins (producers of extended-spectrum β-lactamases [ESBLs]) or even carbapenems, multidrug-resistant (MDR) Pseudomonas aeruginosa or Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, vancomycin-intermediate S. aureus, and vancomycin-resistant enterococci (VRE) are spreading in cancer patients, with increasing endemicity and sporadic cases or outbreaks occurring almost everywhere in the world. For example in Italy, where carbapenemase-producing Klebsiella pneumoniae is currently endemic, a study of bloodstream infections (BSIs) in hematologic cancer patients found that 35% of K. pneumoniae strains were resistant to carbapenems and 70% of P. aeruginosa strains were MDR. An increase in colonization and infection by carbapenem-resistant Enterobacteriaceae has been reported in the pediatric cancer population as well. Although there are important geographical differences in the prevalence of carbapenem-resistant Enterobacteriaceae, no country can be considered untouched by the global spread of MDR gram-negatives. National systems for surveillance, with obligation for notification and recommendations for containment and infection control measures, should be put in place. This increase in MDR strains is radically changing our ability to prevent and cure infections in immunocompromised patients. The feasibility of the more aggressive medical interventions in hematologic cancer patients might be put under discussion if the actual trend toward more resistance is not reversed, since the rate of untreatable infections might become unacceptable. In addition, very few new antibiotics active against gram-negative rods have been marketed or are on the horizon, and the challenge is to ensure that an increasing antimicrobial resistance does not reverse the gains that have been made in improving survival and quality of life in patients with cancer through novel therapies or better surgical techniques.
As shown in Table 306.1 , the clinical approach to a cancer patient with signs and symptoms of infection is multifactorial. Before planning a rational management strategy, physicians should answer several crucial questions about the type and stage of the underlying disease and the clinical presentation in order to provide an effective intervention. In addition, factors potentially associated with the presence of MDR bacteria, such as local epidemiology and the patient's colonization or previous infection with MDR strains, should currently be very carefully considered.
TABLE 306.1
What Should a Clinician Wonder About and Look for When Approaching a Cancer Patient With a Suspected Infection?
| QUESTIONS | RATIONALE FOR THE QUESTION |
|---|---|
The underlying disease:
|
The incidence of infectious complications is different according to the underlying disease and consequent intensity of chemotherapy. The stage of disease may influence type, risk, and outcome of infection. |
Recent treatments:
|
Different drugs may give different type of immunosuppression and favor different infectious complications. Previous transplantation might result in long-term immunodeficiency, particularly if immunosuppressive treatment is continued. Immune reconstitution depends on the type of donor and conditioning regimens used in allogeneic HSCT. |
White blood cell count:
|
The presence of neutropenia increases significantly the risk of infection. The knowledge of local epidemiologic data on antimicrobial susceptibility is mandatory for a correct choice of empirical therapy. |
Risk of infection caused by resistant bacteria:
|
In patients colonized by resistant bacteria, particularly if neutropenic, initial empirical therapy should cover these pathogens. If not colonized, but cared for in a setting where resistance is an issue, then consider the possibility of deescalation strategy. |
Central venous catheter:
|
The central venous access may be an important source of infection. |
| Past history of infections (both before and after the diagnosis of cancer) | It may suggest the etiology and drive the therapeutic choice (e.g., tuberculosis, toxoplasmosis, multidrug-resistant bacteria, or opportunistic fungal infections). |
| Country of origin | Specific endemic infections can reactivate (Chagas' disease, strongyloidiasis, tuberculosis, endemic mycoses). Epidemiology of antibacterial resistance varies worldwide; thus, patients coming from areas endemic for resistant bacteria should be treated accordingly. |
The clinical picture:
|
It may suggest the etiology and drive the therapeutic choice. The presence of mucositis is suggestive of infection with pathogens from oral flora or gastrointestinal tract. The pain may help to locate formation of abscesses or indicate presence of a locally invasive process, such as pulmonary aspergillosis. |
Administration of prophylaxis (no, yes, which drugs):
|
Breakthrough infections are possible, and fever during prophylaxis should be considered as failure of prophylaxis, unless proven otherwise. The occurrence of a bacterial/fungal/viral infection during specific prophylaxis may influence the choice of empirical therapy, depending on the drug used for prophylaxis. A resistant pathogen should be suspected in every case, unless the patient was clearly noncompliant or there is the possibility of low drug levels caused by poor absorption, increased metabolism, or drug interaction (e.g., azoles such as itraconazole, voriconazole, or posaconazole), or both. Knowledge of local epidemiology, including susceptibility pattern, is mandatory for correct diagnostic and therapeutic management. |
HSCT, Hematopoietic stem cell transplantation; PK/PD, pharmacokinetic/pharmacodynamic; PMNs, polymorphonuclear neutrophils.
In the following sections, the epidemiology and management principles of infections in cancer patients are described. Risk factors and clinical presentations of specific infections, along with their treatment, are not discussed here but are dealt with in chapters focused on individual infectious agents. Similarly, infections in recipients of allogeneic hematopoietic stem cell transplants (HSCTs) are discussed elsewhere (see Chapter 307 ), and we will only briefly address these patients, particularly in regard to what concerns early infections during the preengraftment, neutropenic phase.
Epidemiology and Risk Factors for Infections in Cancer Patients
The knowledge of the incidence of fever and documented infections in cancer patients according to the type of the underlying disease and related chemotherapy is mandatory for the implementation of effective management strategies, especially prophylaxis. However, the vast majority of epidemiologic data about these patients come from studies on empirical antibiotic therapy or prophylaxis, in which patients were selected according to inclusion and exclusion criteria. Thus this approach might be inadequate to describe the epidemiologic situation in real-life settings. In addition, little information is available about nonneutropenic patients.
Epidemiologic data on the incidence of infections are usually reported as percentages of events over a given number of patients or treatment courses, without adjusting for the duration of the period at risk. This is probably incorrect because the duration of exposure is crucial to understand the clinical impact of a given phenomenon. It is probably more appropriate to speak of incidence rates, that is, the number of events during a given risk period (usually 1000 days). For example, data on the rates of infectious complications that account for the number of days at risk allow for correct evaluation of the feasibility of antimicrobial prophylaxis and for comparing infectious risk among different cohorts or different treatment regimens. Unfortunately, such studies have rarely been done.
Pediatric studies reported rates of any infection or fever episode ranging from 12 to 31.1 per 1000 days at risk, being higher in case of aggressive treatment for acute leukemia and in neutropenic phases of autologous transplantations. The rate of bacteremia ranged, respectively, from 3.2 to 18.9 in adults and from 0.9 to 5.1 in children. The rate of invasive fungal disease in pediatric studies ranged from 0.1 to 0.84, and was 2.4 in a study that included both children and adults. Table 306.2 reports the epidemiology of febrile episodes, bacteremia, and invasive mycoses in cancer patients.
TABLE 306.2
Incidence of Main Infectious Complications in Cancer Patients
| PATIENT POPULATION | TYPE OF DISEASE | PERCENTAGES OF PATIENTS OR PERIODS WITH INFECTIOUS COMPLICATIONS a | REFERENCE | ||||
|---|---|---|---|---|---|---|---|
| ANY TYPE OF INFECTIOUS OR FEBRILE EPISODE | BACTEREMIA | INVASIVE FUNGAL DISEASE | |||||
| Any (Proven, Probable, and Possible) | Proven and Probable | ||||||
| Yeasts | Molds | ||||||
| Adults and children | Malignancies, not analyzed in detail | 62 | 35 | — | — | — | Gafter-Gvili et al., 2005 |
| Adults | Malignancy or autologous HSCT, not analyzed in detail | — | 18 | 0 | — | — | Dettenkofer et al., 2005 |
| Adults | High-risk acute leukemia | 78 | 30 | — | — | — | Bucaneve et al., 2005 |
| High-risk NHL or HSCT in solid tumors | 73 | 23 | — | — | — | ||
| Adults | Acute promyelocytic leukemia | 59 | 22 | 7.3 | 3 | 0.3 | Girmenia et al., 2003 |
| Other AnLL | — | 37 | 4.2 | 4 | 0.2 | ||
| Children | AnLL | 94 | 25 | 4.2 | 0.6 | 1.6 | Lehrnbecher et al., 2004 |
| Children | ALL, aggressive treatment | — | 30 | 10 | — | — | Castagnola et al., 2005 |
| ALL, less aggressive treatment | — | 17 | 3 | — | — | ||
| AnLL, aggressive treatment | — | 34 | 9 | — | — | ||
| Adults | Low-risk solid tumors, not analyzed in detail, including lymphomas | 12 | 0.4 | — | — | — | Cullen et al., 2005 |
| Adults | AnLL | — | — | — | 6 | 11 | Caira et al., 2008 |
| Adults | New-onset hematologic malignancies | 27 | 10 | 4 | 0.5 | 1.3 | Pagano et al., 2012 |
| Adults and children | Hematologic malignancies | — | 21 | 5 | — | — | Orasch et al., 2010 |
| Children | AnLL: Incidence per patient |
— | 51 | 16 | — | — | Castagnola et al., 2010 |
| Incidence per treatment course | 32 | 10 | |||||
| Children | Aggressive treatment for solid tumor, including autologous HSCT | — | 24 | 1.6 | 1 | 0.5 | Haupt et al., 2001 |
| Less aggressive treatment for solid tumors, not analyzed in detail | 3 | 0 | |||||
| Children | Neutropenic AL/NHL, aggressive treatment | 48 | 25 | 10 | 1.6 | 1.2 | Castagnola et al., 2007 |
| Neutropenic AL/NHL, not aggressive treatment | 21 | 8 | 1 | 0.8 | 0 | ||
| Neutropenic ST, aggressive treatment | 32 | 6 | 0.4 | 0.1 | 0.1 | ||
| Neutropenic ST, not aggressive treatment | 22 | 7 | 4 | 0.5 | 0.5 | ||
| Neutropenic postautologous HSCT | 58 | 14 | 2 | 0.6 | 0.6 | ||
| Children | Neutropenic with AML, receiving G-CSF | 61 | 14 | 2 | 1.8 | 0.6 | Lehrnbecher et al., 2007 |
| Neutropenic with AML, not receiving G-CSF | 56 | 11 | 0 | — | — | ||
—, Data not reported; AL, acute leukemia; ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; AnLL, acute nonlymphocytic leukemia; G-CSF, granulocyte colony-stimulating factor; NHL, non-Hodgkin lymphoma; HSCT, hematopoietic stem cell transplant; ST, solid tumor.
These data clearly show that the incidence rate and proportion of infectious complications are mainly related to the intensity of antineoplastic chemotherapy. Additional factors are represented by the phase of chemotherapy and the status of the neoplastic disease, with higher incidence of infectious complications in patients receiving remission-induction and rescue chemotherapy, compared with maintenance or consolidation treatments. The state of the underlying disease in terms of remission or relapse and progression is also an important factor for the occurrence and prognosis of infectious complications, as shown by studies in patients with invasive aspergillosis. Patients with acute myeloid leukemia, both adults and children, have the highest frequency of fevers, bacteremia, and invasive fungal diseases, especially during the first induction of remission and in relapsing leukemia, when the intensity of chemotherapy is higher. Lower frequencies have been observed in lymphoblastic leukemia, chronic lymphatic disorders, multiple myeloma, and non-Hodgkin lymphomas, whereas the lowest rates are observed in solid tumors clearly depending on the lower intensity of antineoplastic treatment strategies. A new and rapidly increasing problem is represented by patients (usually with chronic leukemia or multiple myeloma) who are treated with novel targeted or biologic therapies, such as imatinib, dasatinib, ibrutinib, rituximab, ruxolitinib, and others. These new drugs have the potential to modify the infection risk profiles, with an increasing risk of infections caused by previously rare pathogens, such as Pneumocystis jirovecii, Mycobacterium tuberculosis, fungal pathogens, or many viruses. On the other hand, their use instead of traditional chemotherapeutic agents might result in lower traditional toxicity, such as neutropenia.
Neutropenia
After the pivotal studies performed by Bodey and coworkers in 1966, many others confirmed the strict relationship between neutropenia and infection and some of them tried to estimate an infection rate correlated with neutropenia. For example, in 1993 Carlisle and colleagues showed that the rate of infections in neutropenic cancer patients was 46.3 episodes per 1000 days of neutropenia, with rates of 12.9 for bacteremia and 2.9 for invasive mycoses. More recent data from a prospective study in children with neutropenia showed a median incidence of infectious complications of 43% and a rate of 22.8 episodes per 1000 neutropenic days; bacteremia was diagnosed in 21% of the episodes and mold infections in 5%, with rates of 10.2 and 2.4 for 1000 neutropenic days, respectively. The rate of infections is higher after high-intensity chemotherapies and lower after maintenance treatment. The majority of primary febrile episodes usually occur soon (a few days) after the onset of neutropenia.
Mucositis and Microbiota Alterations
As already mentioned, in addition to neutropenia, the severity of mucosal barrier injury may have an impact on infection rates (for major details, see Chapter 305 ). Mucositis is one of the most important factors predisposing to fever and BSIs, caused both by bacteria and by Candida. The ulcerative phase induced by antineoplastic drugs with increased permeability and damage to the intestinal mucosal barrier promotes bacterial translocation, but the potential role of alterations in diversity of the intestinal microbiome in the development of mucositis and subsequent BSIs is increasingly recognized. Quantitative and qualitative alterations of the normal oral and intestinal microflora have been described in cancer patients and depend on many factors, such as underlying disease, chemotherapy (drugs and dosages) and radiotherapy, mucosal disruption, bowel motility disturbance, enteral/parenteral nutrition, and broad-spectrum antibiotic administration. Microbiologic analyses of fecal samples of children aggressively treated for acute leukemia showed a decreased amount of microbial flora, and in particular of bifidobacteria, Lactobacillus, and Escherichia coli, and a 100-fold reduction of the total number of bacteria, mainly for anaerobes, with a concomitant increase of potentially pathogenic enterococci. Moreover, in patients receiving HSCT, occupation of at least 30% of the microbiota by a single predominating bacterial taxon (intestinal domination) was associated with an increased risk for bacteremia due to specific pathogens. Finally, non-albicans Candida strains, mainly C. glabrata and C. krusei , also seem to be increased in stool from children receiving chemotherapy or HSCT, especially in the case of prolonged hospitalization.
Central Venous Catheters
The presence of a CVC is another well-known factor facilitating infections in cancer patients and influencing their etiology. A detailed description of problems related to infections associated with CVCs is beyond the scope of this chapter and can be found elsewhere in this text (see Chapter 300 ). Long-term vascular access devices adopted during antineoplastic chemotherapy or HSCT are represented by partially implanted silicone devices (Hickman or Broviac catheter), with or without valves, single or double lumen; peripherally or centrally totally implanted catheters (Port-A-Caths); and peripherally inserted central catheters. Patients with less frequent need of venous access are usually fitted with totally implanted catheters, while more intensive supportive care generally requires partially implanted single- or double-lumen devices, which allow rapid infusion of large amounts of liquids. Risk factors generally associated with the development of CVC-related infections are represented by the type of CVC, the number of lumens, and the number and characteristics of CVC manipulations, all mainly related to the intensity, duration, and schedule of antineoplastic chemotherapy, the type of supportive care, and the severity of clinical conditions. Bacteremia represents the most frequent infectious complication, whereas exit site, tunnel, and pocket CVC-related infections are less frequently reported. Partially implanted catheters have been associated with a three- to fourfold increase in the risk of infectious complications compared with totally implanted devices, and in a study in patients with a totally implanted device, younger age was the only identified risk factor. The risk of infection is generally higher in adults compared with children, and lower in the outpatient setting.
A recent review reported infection rates varying from a mean of 22.5 (95% confidence interval [CI], 21.2–23.7) per 100 devices for Hickman and Broviac catheters, 3.5 to 4 (95% CI, 2.4–5.6) for Port-A-Caths, and 3.1 (95% CI, 2.6–3.7) for peripherally inserted central catheters, with mean rates per 1000 catheter-days of 1.6 (95% CI, 1.5–1.7), 0.1 (95% CI, 0.01–0.2), and 1.1 (95% CI, 0.9–1.3), respectively. Patients with hematologic malignancies, and especially those with acute leukemia, have a higher incidence of catheter-related infections compared with patients with lymphoma, myeloma, or solid tumors, probably due to different type of catheters and frequency of catheter use. It is important to be very balanced when discussing the role of central catheters in predisposing to infection. Indeed, the role might be overestimated, because the catheter might just be the site of a secondary localization of pathogens actually coming from the intestinal flora. New definitions now suggest that 40% to 50% of BSIs in oncologic settings are actually endogenous and associated with mucosal barrier injury. This has an impact on the expectations regarding strategies that should prevent infections by improving catheter management.
Gram-positive bacteria represent the pathogens most frequently associated with CVC-related infections, but gram-negatives are reported with increasing frequency, especially in nonbacteremic episodes. Finally, some age-related differences in the proportions of pathogens causing CVC-related bacteremia have been reported, with gram-negatives being observed more frequently in adults and gram-positives and fungi in children.
Genetic Factors
The existence of genetic factors able to increase or decrease the susceptibility to infection in immunocompromised patients underlines an apparently trivial but important aspect: cancer patients are not the same, and every single patient might deserve an individualized approach. For example, in nonleukemic patients receiving less intensive chemotherapy, decreased levels of mannose-binding protein were associated with an increased risk of infection (49.9 vs. 29.6 per 1000 days at risk, P = .01). In a recent study of 269 children with cancer, mannose-binding lectin deficiency influenced both the incidence and the severity of febrile neutropenia. In breast cancer patients, genetic factors also were found to influence the risk of febrile neutropenia. Polymorphisms of Toll-like receptors and other components of innate immunity have been associated with an increased risk of invasive aspergillosis, both in cancer patients (including recipients of HSCT) and in other immunocompromised patients. The future will tell us whether genetic polymorphisms, alone or in combination, have a clinically significant impact on infection risk and might dictate prophylactic or therapeutic approaches.
New Therapies
Biologic Agents and Other New Drugs
As already mentioned, in recent years, monoclonal antibodies and other pharmaceutical compounds that are specifically engineered for targeting enzymes, cytokines, or receptors involved in the pathogenesis of specific types of cancer have been introduced into the armamentarium of antineoplastic chemotherapy. Main infectious complications associated with their use are reported in Table 306.3 .
TABLE 306.3
Selected Biologic Drugs for Treatment of Solid Tumors and Hematologic Malignancies and Possible Infectious Complications
| CLASS/SITE AND MECHANISM OF ACTION | DRUG | POSSIBLE INFECTIOUS COMPLICATIONS |
|---|---|---|
| Monoclonal Antibodies (mAbs) Targeting Surface Antigens on Lymphoid Cells | ||
| Bispecific T-Cell Engager (BiTE): anti-CD19 mAb conjugated to anti-CD3 mAb leading to T-mediated lysis of CD19+ cells | Blinatumomab | CVC-associated infections due to continuous prolonged intravenous infusion. Severe and prolonged hypogammaglobulinemia and possible neutropenia, with consequent infectious risk. VZV and HSV infections, pneumocystosis, and HBV reactivation. |
| Anti-CD20 mAbs | Rituximab | Possible hypogammaglobulinemia of variable duration, not associated with an increased risk of bacterial infections. HBV reactivation (both of chronic inactive and resolved infection); exacerbation of HCV infection. Possible neutropenia; severe viral respiratory tract infection. Cases of severe enteroviral infections, PML, VZV, CMV parvovirus infections. Vaccine response is almost absent in the first 6 months after rituximab administration. |
| Obinutuzumab | Similar to rituximab. Neutropenia and severe enteroviral infections have been reported. |
|
| Ofatumumab | Probably similar to rituximab. Reported neutropenia, HSV, viral respiratory infection, fatal case of HBV reactivation. |
|
| Ocrelizumab | Risk of infections associated with increasing doses, PML. Potentially increased risk of neutropenia and HBV reactivation. |
|
| Veltuzumab Ublituximab |
No data available for evaluation of the risk of severe infectious complications. Probably similar to rituximab. |
|
| Anti-CD20 mAbs conjugated with a radioactive isotope | 90 Y-Ibritumomab tiuxetan 131 I-tositumomab |
Higher rate of cytopenias, such as lymphopenia or neutropenia, due to combination with radioactive isotope. Cytopenia risk is higher if bone marrow is infiltrated by CD20+ hematologic malignancy. General safety profile probably similar to rituximab. |
| Anti-CD22 mAb | Epratuzumab | No significant increase in infections in placebo-controlled trials. Profile of infections similar to anti-CD20 mAbs: respiratory tract infections (viral and bacterial), pneumonia. |
| Anti-CD22 mAb conjugated with the DNA-damaging agent calicheamicin | Inotuzumab ozogamicin | |
| Anti-CD22 mAb conjugated with Pseudomonas exotoxin A | Moxetumomab pasudotox | |
| Anti-CD30 mAb conjugated with the microtubule disrupting agent monomethyl auristatin E | Brentuximab vedotin | Herpetic infections, including CMV; cases of PML and pneumocystosis. |
| Anti-CD33 mAb conjugated with a calicheamicin agent | Gemtuzumab ozogamicin | No significant increase in infections. |
| Anti-CD38 mAb | Daratumumab | Increased risk of VZV (prophylaxis warranted for 3 months after the end of treatment). Slightly higher risk of pneumonia and upper respiratory tract infections. |
| Anti-CD40 mAb | Dacetuzumab | Higher rate of neutropenia with dacetuzumab vs. placebo. Opportunistic infections similar to those observed in hyper-IgM syndrome (pneumocystosis, CMV reactivation, etc.) might be theoretically expected. |
| Anti-CD52 mAb | Alemtuzumab | Severe viral infections (particularly HSV, VZV and CMV, but also HHV6, BKV, parvovirus, adenovirus). Pneumocystosis and other fungal infections, toxoplasmosis, mycobacteriosis, reactivation or exacerbation of HBV infection, tuberculosis, listeriosis, infections due to acanthamoebae, Balamuthia mandrillaris, reactivation or worsening of chronic HBV infection have also been described. |
| Anti-CD139 (signaling lymphocytic activation molecule F7 [SLAMF7]) mAb | Elotuzumab | Lymphopenia and increased risk of opportunistic infections, particularly due to VZV. |
| Anti–C-C motif of chemokine receptor 4 (CCR4) mAb | Mogamulizumab | Infectious risk difficult to distinguish from the intrinsic effect of underlying diseases and concomitant lymphotoxic therapies. Pneumocystosis, HSV, VZV, HBV reactivation (risk of severe hepatitis in patients with high-level HBV DNA due to T-regulatory cell downregulation). |
| Tyrosine Kinase Inhibitors | ||
| Breakpoint Cluster Region–Abelson Murine Leukemia (BCR-ABL) Signaling Pathway | ||
| Inhibitor of tyrosine kinase BCR-ABL, c-KIT, and platelet-derived growth factor (PDGF)-receptor | Imatinib | Febrile neutropenia has been reported. Cases of pneumocystosis and viral diseases, including reactivation of hepatitis. |
| Inhibitor of tyrosine kinase BCR-ABL | Nilotinib | Cases of pneumocystosis and viral diseases, including reactivation of hepatitis. |
| Inhibitor of tyrosine kinase BCR-ABL, SRC family, c-KIT, and others | Dasatinib | Cases of pneumocystosis and viral diseases, including reactivation of HBV. Noninfectious pleural effusions, less often pneumonitis (in differential diagnosis with infections). |
| Bruton Tyrosine Kinase Signaling Pathway | ||
| Bruton tyrosine kinase inhibitor | Ibrutinib | Bacterial pneumonia, urinary tract infection and cellulitis, noninfectious pneumonitis, invasive fungal infections. |
| Janus Kinase–Signal Transducers and Activators of Transcription (JAK-STAT) Signaling Pathway | ||
| Inhibitor of the JAK pathway (kinases 1 and 2) | Ruxolitinib | VZV reactivation, cases of tuberculosis, PML, pneumocystosis, cryptococcosis, and other opportunistic infections associated with T-cell dysfunction. |
| Phosphatidylinositol 3-Kinase (PI3K) Delta Isoform Signaling Pathways | ||
| Inhibitor of PI3Kδ | Idelalisib | Pneumonia, sepsis (20%), opportunistic infections, along with noninfectious pulmonary and gastrointestinal inflammation. Prophylaxis of HBV reactivation and pneumocystosis and preemptive management strategy for CMV are warranted. |
| Others | ||
| Multikinase inhibitors | Lapatinib | Possible skin infections because of skin toxicity. |
| Pazopanib Regorafenib |
No significant data available for evaluation of the risk of severe infectious complications. | |
| Vascular Endothelial Growth Factor (VEGF) Signaling Pathway | ||
| Anti–human VEGF mAb | Bevacizumab | Infections in cases of chemotherapy-induced neutropenia: sepsis and pneumonia. Cases of intestinal perforation (with or without abscess formation), probably from the inhibition of endothelial cell proliferation and new blood vessel formation. Possible endophthalmitis due to intravitreal injections, but an increased risk of this type of infection has not been clearly demonstrated. |
| Recombinant protein circulating antagonist that prevents VEGF receptor binding | Aflibercept | Severe infections: incidence 7.3% (95% CI, 4.3–12.0%) with increased risk (RR, 1.87; 95% CI, 1.52–2.30). Mortality: 2.2% (95% CI, 1.5–3.1%), with increased risk (OR, 2.16; 95% CI, 1.14–4.11). The risk of infections with aflibercept substantially higher than with bevacizumab. |
| Inhibitor of tyrosine kinases on receptors for vascular endothelial growth factor (VEGFR), platelet-derived growth factor (PDGFR), and isoform B of tyrosine kinase (known as rapidly accelerated fibrosarcoma [B-RAF]) | Sorafenib | Infections, as well as gastrointestinal perforations, are reported in less than 1% of treated patients. |
| Inhibitors of tyrosine kinases on PDGFRs and VEGFRs | Sunitinib | Cases of necrotizing fasciitis, respiratory infections, and sepsis. |
| Inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and RET (rearranged during transfection) tyrosine kinase | Vandetanib | No significant increase in infections. |
| Tyrosine kinase inhibitor that inhibits angiogenesis blocking VEGFR-1– VEGFR-3, c-KIT, and PDGFR | Axitinib | No significant data available for evaluation of the risk of severe infectious complications. |
| Inhibitor of tyrosine kinases c-Met and VEGFR-2, and also AXL and RET | Cabozanitinib | No significant data available for evaluation of the risk of severe infectious complications. |
| Inhibitor of tyrosine kinases VEGFR-1–VEGFR-3 | Lenvatinib | No significant data available for evaluation of the risk of severe infectious complications. |
| Epidermal Growth Factor (EGF) Signaling Pathway | ||
| Anti–EGF receptor (ErbB1 or EGFR) mAb | Panitumumab (IgG2) Cetuximab (IgG1, chimeric) |
Cases of necrotizing fasciitis, abscesses sepsis caused by Staphylococcus aureus. Important dermatologic toxicity, such as rash, skin drying and fissuring, or paronychial inflammation, with infectious complications (abscess, bacteremia) in up to 30% of patients, including sepsis caused by S. aureus. More severe infections have been described when combined with neutropenia-inducing chemotherapy. |
| Nimotuzumab (humanized) | No significant data available for evaluation of the risk of severe infectious complications. | |
| mAb against human EGF receptor 2 (human ErbB-2 or HER2) | Trastuzumab | Infections are generally mild and reported as URTIs or UTIs. Increased risk of infections has been described in combination with chemotherapy. Exacerbation of chemotherapy-induced neutropenia. Infection ≥ grade 3: 8.5% of patients (95% CI, 4.5–15.4), RR vs. control, 1.21 (95% CI, 1.07–1.37). Febrile neutropenia in the neoadjuvant/adjuvant and combination therapies: 12.0% (95% CI, 8.1–17.4), RR vs. control, 1.28 (95% CI, 1.08–1.52) |
| Pertuzumab | >10% of febrile neutropenia, URTIs (associated with chemotherapy). | |
| Inhibitor of epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI), possibly also of mutated JAK2 | Erlotinib | Approximately 9% higher rate of infections compared to control arms for erlotinib. In a meta-analysis of over 6000 patients with NSCLC: any infection, 7% (95% CI, 4.7–10.3), severe infection, 2.1% (95% CI, 1.7–2.8), and fatal, 0.7% (95% CI, 0.4–1.0). There is a trend toward a higher risk with longer treatment. |
| Inhibitor of EGFR-TKI | Gefitinib | |
| Immune Checkpoints Inhibitors | ||
| mAbs inhibiting programmed cell death protein 1 (PD-1) | Nivolumab | No significant increase in infectious complications but immune-mediated complications are frequent and should be considered in differential diagnosis (pneumonitis, colitis, hepatitis). |
| Pembrolizumab | No significant data available for evaluation of the risk of severe infectious complications. | |
| mAbs inhibiting programmed cell death ligand 1 (PD-L1) | Atezolizumab | Cases of fever and UTIs. |
| Avelumab Durvalumab |
No significant data available for evaluation of the risk of severe infectious complications. | |
| mAb inhibiting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) | Ipilimumab | No significant data available for evaluation of the risk of severe infectious complications. |
| Tremelimumab | ||
| Immunomodulating Drugs | ||
| Angiogenesis inhibitor | Thalidomide | Neutropenia and lymphopenia described, reported increased risk of infections (RR, 1.64; 95% CI, 1.40–1.92). |
| Apoptosis inducer in vivo, with antiangiogenic and osteoclastogenic effects | Lenalidomide | Described a 14% (95% CI, 12.08–16.90) incidence of severe infections, with RR 2.23 (95% CI, 1-71–2.91), with possible fatal events. May increase risk and duration of cytopenia if combined with chemotherapy. |
| Immunomodulatory, like thalidomide and lenalidomide, based on its use in multiple myeloma | Pomalidomide | Severe infectious complications in 23%, frequently in the absence of neutropenia. Pneumonia is the most frequently reported localization. Antibacterial prophylaxis has been recommended for patients receiving this drug, but fluoroquinolones could be contraindicated for the risk of drug interactions. |
| Activator of monocytes and macrophages | Mifamurtide | Fever frequently described, but no specific data on severe infectious complications. |
| Proteasome inhibitors | Bortezomib | Increased risk of herpes zoster. |
| Carfilzomib | Low risk of febrile neutropenia. Pneumonia (13%) and URTIs (28%) observed in patients receiving single-drug therapy, but approximately 2%–6% had severe infections. Increased risk of herpes zoster. |
|
| Ixazomib | No significant data available for evaluation of the risk of severe infectious complications. | |
| Others | ||
| mAb against disialoganglioside (expressed on a variety of embryonal cancers (e.g., neuroblastoma, retinoblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma) | Dinutuximab (anti-GD2) | Fever is frequently observed, but there are data available for significant infectious complications. |
| Cyclopamine-competitive antagonist of the smoothened (a transmembrane protein) receptor that is a part of the hedgehog signaling pathway that is involved in proper cell differentiation | Vismodegib | No significant data available for evaluation of the risk of severe infectious complications. |
| Inhibitors of Histone Deacetylases | ||
| Histone deacetylase (HDAC) inhibitor, induces intracellular increase of transcription factors important for the expression of genes needed to induce cell differentiation | Vorinostat | Neutropenia reported, but no data available for significant infectious complications. |
| Nonselective HDAC (pan-HDAC inhibitor). | Panobinostat | Pneumonia described in 13% of treated patients. |
| Selective inhibitor of HDACs | Romidepsin | No significant data available for evaluation of the risk of severe infectious complications. |
| Mammalian target of rapamycin (mTOR) inhibitors | Everolimus Temsirolimus |
Infections attributable to mTOR inhibitors (mainly everolimus): any infection 9.3% (95% CI, 5.8–14.6%), severe infections 2.3% (95% CI, 1.2–4.4%). Important difference in the incidence depending on the type of cancer treated. |
BKV, BK virus; 95% CI, 95% confidence interval; CMV, cytomegalovirus; CVC, central venous catheter; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV6, human herpesvirus 6; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; NSCLC, non–small cell lung cancer; OR, odds ratio; PML, progressive multifocal leukoencephalopathy; RR, relative risk; URTI, upper respiratory tract infections; UTIs, urinary tract infections; VZV, varicella-zoster virus.
Several issues impair our ability to understand the exact role of these new compounds on the risk of infection in cancer patients. First, even in randomized, placebo-controlled trials and in large open-label studies, it is difficult to establish the rate of infectious complications, because these trials were powered to measure efficacy in relation to their primary objective, but not safety. If the risk of infection is low, it might go undetected. Second, there are many confounding factors because new drugs are usually used together or in sequence with old therapies, making it difficult, if not impossible, to evaluate their respective role. Third, very often, because of the lack of infectious disease expertise, registration studies did not use the same definitions of infectious complications or simply did not pay enough attention to them. Sadly, in some cases there was a tendency toward minimization and covering. There is at least one example showing that the infection risk might have been forecast. This is the case of eculizumab used for paroxysmal nocturnal hemoglobinuria, which targets the C5 complement component. As should be widely known, the inherited deficiency of the C5 complement component is associated with repeated episodes of invasive meningococcal disease. Thus this risk might have been forecast before starting large trials or before marketing this new drug, so appropriate preventive strategies could have been put in place.
There is hope that multicenter projects concentrating on infectious complications might help in determining their true risk and possible early preventive or diagnostic measures. For example, the Southern Network on Adverse Reactions (SONAR) project conducts safety initiatives focusing on monoclonal antibody–associated progressive multifocal leukoencephalopathy (PML). The field of biologic agents and anticancer molecules is rapidly changing, with a constant influx of new drugs and with new indications for the older ones. Therefore the data on their safety profile is also in constant evolution. As already mentioned, novel drugs are frequently administered in combination with “classic” antineoplastic agents and therefore it is not easy to disentangle their role in the development of infectious diseases. For example, a recent meta-analysis that investigated the impact of immunomodulatory drugs (e.g., thalidomide and derivatives) and proteasome inhibitors (e.g., bortezomib), variously associated with “classic” antineoplastic drugs in different phases of treatment for multiple myeloma, showed that the rate of severe infections in protocols including immunomodulatory drugs seemed generally lower than that observed with conventional therapy. Unfortunately, despite the great number of patients and clinical trials analyzed, the authors repeatedly commented on insufficient detail about methods for detecting and diagnosing infections and limited generalizability to broader nontrial populations.
For the compounds that have been in use for many years, we obviously have more information. For example, the monoclonal antibody anti-CD52 has been associated with a wide spectrum of infectious complications (mainly viral and fungal), and a low CD4 + T-lymphocyte count (with a possible cutoff of 200 CD4 + T-lymphocytes/mm 3 ) has been indicated as one of the most important factors related to the development of infections. Anti-CD20 compounds, the most widely studied being rituximab, cause a prolonged (2 to 6 months in median, but sometimes longer) suppression of immunoglobulin production. Reactivation of hepatitis B virus (HBV) has been observed in 85% of hepatitis B surface antigen (HBsAg)–positive and in 41.5% of HBsAg-negative/hepatitis B core antibody (HBcAb)–positive lymphoma patients treated with chemotherapy that included rituximab. More rarely, other severe viral infections (enteroviral infections, PML, parvovirus infections) have been reported. Brentuximab, another monoclonal antibody targeting lymphocytes through CD30, has also been associated with severe infections. In particular, PML after brentuximab was found to develop earlier than with rituximab or natalizumab (2–3 months vs. 63 weeks vs. 26 months, respectively). Therefore a low threshold for brain magnetic resonance imaging should be applied to patients treated with monoclonal antibodies who develop neurologic symptoms. Ruxolitinib was associated with varicella-zoster virus (VZV) reactivation and tuberculosis (TB), ibrutinib with invasive fungal diseases (IFDs), and idelalisib with herpes and cytomegalovirus (CMV) reactivations and with pneumocystosis. Last but not least, checkpoint inhibitors such as ipilimumab, which inhibits the cytotoxic T-lymphocyte–associated antigen 4 checkpoint, and nivolumab or pembrolizumab, which inhibit the programmed cell death protein 1 (PD1) checkpoint, are associated with severe immune-related adverse events, such as diarrhea, pneumonitis, or hepatitis. In these cases, differential diagnosis might be difficult and patients should always be tested for infectious etiologies, such as Clostridioides difficile (formerly Clostridium difficile ) colitis, pneumocystosis, or viral hepatitis. Tyrosine kinase inhibitors seem to be associated with infectious complications similar to those observed with other immunosuppressive drugs affecting mechanisms of cell-mediated immunity. For these drugs, among the most frequently reported infections are pneumocystosis and reactivation of HBV (observed also in HBsAg-negative/HBcAb-positive patients). Finally, high-dose retinoic acid has been used for treatment of acute promyelocytic leukemia and some pediatric solid tumors (neuroblastoma). The dosages adopted in acute leukemia can induce fever and hepatotoxicity (vitamin A “intoxication”), while in patients with solid tumors, cases of skin and soft tissue infections, especially due to S. aureus, can be observed. Intravesical administration of Calmette-Guérin bacillus, a live strain of Mycobacterium bovis, is adopted as a treatment of non–muscle-invasive bladder cancer. Disseminated genitourinary or osteomuscular infections have been reported.
Chimeric Antigen Receptor T-Lymphocyte Therapy
Originally designed to treat lymphocyte-derived malignancies, chimeric antigen receptor (CAR) T-cell therapy is now being used in a wide range of solid tumors. CAR T cells are derived from the patient's peripheral blood lymphocytes, which are transformed in vitro using a DNA construct that causes the lymphocyte to produce on its surface receptors that recognize a specific, selected tumor antigen. After CAR T cells are infused into the patient and encounter a cell with that antigen on its surface, the CAR T cells activate and become cytotoxic, thus killing the neoplastic cell. Potential adverse effects include killing of normal cells bearing the same antigen, as well as a cytokine release syndrome, which can cause high fever and multiorgan failure. Little is known about infectious complications associated with CAR T-cell therapy. In cases of therapy of leukemia or lymphoma with CAR T cells targeting CD19, the incidence of infections was comparable to observations from clinical trials of salvage chemoimmunotherapies in similar patients.
Update: Chimeric antigen receptor (CAR) T cell therapy: complications
Surgery
Bacteremia, usually associated with surgical site infection and deep organ abscess, is not uncommon in urologic, gynecologic, and abdominal surgery in cancer patients, but it is difficult to say with certainty if this happens significantly more often in oncologic versus nononcologic patients. Several studies reported the rates of postsurgery infections in different cancer populations. For example, among patients with peritoneal carcinomatosis undergoing peritonectomy and intraperitoneal hyperthermic chemotherapy, the proportion of infectious complications was rather high, varying from 24% to 36%, with more than two infectious episodes per patient. The rate of infectious complications is lower in other oncologic surgeries. In breast cancer, surgical site infection is a complication in 4% to 8% of cases, depending whether breast reconstruction is performed in one or two steps and whether surgery follows previous chemotherapy cycles. In case of malignant biliary obstruction, early infectious complications after percutaneous biliary stent insertion were present in 6.5% of patients. Similar incidence was reported in patients undergoing surgery for hepatocellular or metastatic carcinoma (3%–11%), and this incidence was apparently lower than in surgery for nonmalignant conditions such as hepatolithiasis (24%). The rate of infectious complications after hepatectomy for hepatocarcinoma was associated with surgical risk factors such as bile leakage and blood loss. A similar incidence of surgical site infections was reported after elective colon and rectal surgery (9% and 18%, respectively), and after orthopedic surgery (9.5%). Of interest, in the latter study the use of an implant or allograft did not represent a risk factor for infectious complications. Finally, postoperative respiratory infections have been reported in nearly 4% of patients undergoing surgery for lung cancer, and they occurred more frequently in the presence of advanced age, impaired respiratory function, advanced pathologic stage, and induction chemotherapy.
In conclusion, although not many data are available on infectious complications after surgery in solid tumors, it seems that surgical and intensive care unit–related factors are more important than previous antineoplastic chemotherapy in determining the risk of infection. Finally, in patients with solid tumors, surgery, together with long hospital stay and use of third-generation cephalosporins and glycopeptides, have been associated with an increased risk of infections caused by MDR pathogens.
Etiology
Surveillance studies on pathogens causing infections in cancer patients are of the utmost importance for the implementation of management strategies. Large-scale studies are obviously crucial because they can provide information about worldwide trends, but single-center surveillance reports may be even more important, because every geographic region, country, or single center may have peculiarities related to the type of patient, type of care, and local previous antibiotic policies. Most of the available information concerns bacterial and fungal pathogens isolated in the bloodstream, whereas the role of deep-seated infections, as well as the impact of viral infections, are less known.
Bacterial Infections
Over the last 30 years, gram-positive bacteria were the most frequent pathogens causing bloodstream infections in cancer patients. However, more recently, an increase in the frequency of bacteremias caused by gram-negative rods has been reported, with gram-negative pathogens becoming either predominant or at least as frequently isolated as the gram-positives. This trend has also been observed in a retrospective literature review and contemporary surveillance study performed in 2011 in 39 European hematology centers from 18 countries belonging to the network of the European Conference of Infections in Leukemia (ECIL). As shown in Fig. 306.1 , this study found that gram-negative pathogens were almost as frequently isolated as the gram-positives, with gram-positive/gram-negative ratios in bloodstream infections of 60%/40% and 55%/45%, in the literature review and the ECIL-4 surveillance, respectively. The detailed etiology was similar (see Fig. 306.1 ) in the literature review and the surveillance study, with a slightly higher rate of enterococci and Enterobacteriaceae and a decreased rate of P. aeruginosa in the surveillance study. These changes in etiology seemed to be associated with an important and alarming increase in the proportion of resistant pathogens, such as ESBL-producing Enterobacteriaceae, VRE, MDR P. aeruginosa, and the most worrisome, carbapenem-resistant gram-negative pathogens. Last but not least, in leukemic patients, most staphylococci are resistant to methicillin, whereas most gram-negative pathogens are resistant to fluoroquinolones.
Of note, the rates of resistance were generally higher in southern and eastern than in northern and western Europe, and this trend is also evident in the non–hematologic cancer population. A recent study in HSCT recipients has confirmed the alarming increase in resistance in this population as well, with increasing mortality rates. The increase in infections caused by resistant strains usually follows an increase in colonization with these pathogens, because cancer patients typically first get colonized and then develop endogenous infection. Indeed, colonization with resistant bacteria is one of the most important risk factors for infection with resistant bacteria. The association between colonization and subsequent infection has been reported for VRE, ESBL-producing Enterobacteriaceae, P. aeruginosa, Stenotrophomonas maltophilia, and carbapenem- or colistin-resistant K. pneumoniae. Obviously, the negative and positive predictive values of colonization are not 100% because not all the cases of MDR-BSI are preceded by documented colonization, whereas some colonized patients will not develop MDR-BSI. However, colonization may be the most easily identifiable risk factor, and screening protocols for drug-resistant bacteria should probably be implemented everywhere.
Anaerobic bacteria are isolated in less than 1% of positive blood cultures in cancer patients, but the proportion may increase to 3% among those undergoing abdominal surgery. Anaerobes are usually isolated in polymicrobial bacteremias, especially together with gram-negative rods, with a rate that seems to be higher than that observed in nononcology patients undergoing similar surgery (0.597 vs. 0.033 per 1000 hospital days, respectively). Differences in the etiology of bacterial infection between neutropenic and nonneutropenic cancer patients have been reported.
CVC-related bacteremias are generally caused by gram-positive cocci (especially coagulase-negative staphylococci), which are isolated in more than 50% of the episodes compared with the rate of 25% to 40% for gram-negative rods. As mentioned previously, the source of infection is likely to be partially different in cases of gram-positive and gram-negative CVC-related bacteremias. Infusate contamination is a rare but possible event, and in this case gram-negative rods, such as Klebsiella, Enterobacter, Citrobacter, Achromobacter, Serratia, Ralstonia, and Pseudomonas (other than P. aeruginosa ), are more likely involved. Polymicrobial infections are not rare with a predominance of gram-negative bacteria, whereas fungi (mainly Candida spp.) are usually monomicrobial and infrequent.
Bacterial gastroenteritis caused by classic enteric pathogens ( Salmonella and Shigella ) is a rare event in patients with acute leukemia, involving less than 1% of acute enteritis after chemotherapy. On the contrary, C. difficile is not unusual in cancer patients, with an incidence that is twofold higher than in the noncancer population. Helicobacter pylori has also been described as a possible cause of gastrointestinal disease in cancer patients.
Legionellosis and nocardiosis are rare but potentially life-threatening infections, with Legionella pneumonia sometimes presenting with unusual radiologic patterns. Mycoplasma pneumoniae and Chlamydia pneumoniae have been rarely described as a cause of pneumonia in cancer patients, but it is possible that their incidence is underreported. Similarly, TB is probably underestimated and underdiagnosed in cancer populations, although there are data showing that the rate approximates 90 cases per 100,000 persons (i.e., ninefold higher than in the general population in developed countries). Patients from high-endemicity countries account for most of the cases. Infections caused by nontuberculous mycobacteria are rare, outside of the already mentioned rare occurrence of local or even disseminated M. bovis infections in patients receiving Calmette-Guérin bacillus immunotherapy for bladder cancer.
Fungal Infections
Aspergillus spp. and Candida spp. are the most common fungal pathogens in cancer patients, with the former now seen more frequently than the latter. Other fungal pathogens include P. jirovecii, cryptococci, and molds such as Mucorales or Fusarium.
Among yeasts, Candida is the most frequently isolated organism, usually in BSIs, with an increasing proportion of non- albicans strains, probably due to the extensive use of prophylactic fluconazole. This phenomenon, known since 1999, was confirmed in a more recent European Organization for Research and Treatment of Cancer (EORTC) study, which reported that in cancer patients the overall incidence of fungemia was 2.3%, with C. albicans responsible for 72% of candidemia cases in the whole study population, but only 27% in patients with hematologic malignancies. Of note, in this study only 38% of fungemias occurred during neutropenia. In general, yeasts belonging to the Candida parapsilosis complex are usually associated with CVC contamination, whereas other Candida species are supposed to come from the gastrointestinal tract after selection and translocation. Candida glabrata is the species increasing in frequency and resistance, not only to fluconazole but also to echinocandins. Additionally, Candida auris is a recently identified species that caused outbreaks worldwide. It is characterized by resistance to numerous antifungals, mainly fluconazole, less frequently voriconazole and amphotericin B. Therefore echinocandins are the mainstay of treatment. Candida auris has a potential for clonal outbreaks, and is associated with 40% to 50% mortality due to patients’ poor general conditions, antifungal resistance, and its ability to form biofilm and cause persistent infection.
Among molds, Aspergillus represents the most frequently isolated or suspected organism. The majority of episodes are caused by Aspergillus fumigatus, although some centers report a predominance of infections caused by Aspergillus flavus and Aspergillus terreus. Aspergillus species are ubiquitous molds whose primary ecologic niche is represented by decomposing vegetable material, including potted plants, soil, flowers, and carpets. In healthy individuals, Aspergillus conidia are trapped in the upper respiratory tract, and only a small proportion of them enter the lower airways where Aspergillus may become an allergen. In immunocompromised patients, especially those with hematologic malignancies or after allogeneic HSCT, spores can germinate and cause an invasive disease. Thus invasive aspergillosis in patients with malignancy or receiving HSCT is an endemic disease, which is usually community acquired and endogenous, although epidemic outbreaks of exogenous infection associated with massive environmental exposures (in and outside the hospital) can occur. The incidence of invasive aspergillosis depends on the patient's age (lower in those younger than 10 years), the underlying malignancy, and its treatment, being the highest in patients with prolonged neutropenia, followed by those receiving high doses of steroid therapy. In a multicenter Italian study, the incidence of aspergillosis among hematologic cancer patients varied from 7.9% in acute nonlymphoblastic leukemia to 4.3% in acute lymphoblastic leukemia, 2.3% in chronic myelogenous leukemia, and less than 1% in chronic lymphocytic leukemia, Hodgkin and non-Hodgkin lymphoma, and multiple myeloma. A recently described risk group is represented by patients with chronic lymphoproliferative disorders, probably as a result of introducing more intensive treatment protocols. Additionally, the risk of aspergillosis in patients with acute lymphoblastic leukemia was reported as high as 11.7%. The incidence of invasive aspergillosis after autologous HSCT is low (0.3%–2%), and it occurs during preengraftment neutropenia.
The main challenge in the current management of invasive aspergillosis, which consists of voriconazole or isavuconazole as first-line therapy and prophylaxis with posaconazole in high-risk patients, is the increasing problem of primary resistance to azoles in A. fumigatus. Azole-resistant isolates harboring the TR34/L98H or the TR46/Y121F/T289A mutations have been found in the environment due to a widespread use of azoles in the agriculture industry in some countries. Patients may inhale spores of these strains and develop primary azole-resistant disease despite no previous antifungal therapy. The prevalence of resistant strains is only about 3% among 3788 isolates screened in Europe and differs highly between regions. Data on high prevalence of resistant strains in patients with hematologic malignancies in the Netherlands and Germany have been reported, but methodologic issues, including the choice of denominator to evaluate resistance rate, are crucial. Despite the fact that the phenomenon is so far relatively limited in most of the settings, knowledge of the frequency of azole resistance at the country and hospital level and within different patient groups is warranted. Secondary azole resistance, with different genetic patterns, has been reported in patients with chronic fungal infection after prolonged treatment, particularly in the case of suboptimal blood levels or high fungal burden.
Mucormycosis is being increasingly reported by some centers, especially in the US. It is unclear whether this represents a general trend, if it is influenced by local factors, or if these infections are simply diagnosed more often because of an increased clinical awareness or improved patient survival. Other fungi, such as Cryptococcus, Fusarium , Trichosporon, Saprochaete (Magnusiomyces/Blastoschizomyces), and Scedosporium, have been reported sporadically, but it is likely that previously uncommon organisms may appear more frequently because they are being selected by the widespread use of mold-active antifungal prophylaxis.
Pneumocystis jirovecii is a well-known cause of pneumonia in cancer patients not receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, especially if treated with high-dose and prolonged steroid therapy or certain antineoplastic drugs such as fludarabine or temozolomide. Attack rates vary from 6.5% to 43% in acute lymphoblastic leukemia, 4% to 25% in rhabdomyosarcomas, and nearly 1% in Hodgkin lymphoma and primary or metastatic central nervous system tumors.
Finally, infections or reactivations of dimorphic fungi, such as Histoplasma or Coccidioides, are possible in patients who live in or used to live in endemic areas.
Viral Infections
Apart from herpes simplex virus (HSV) reactivation, which occurs in up to 60% of HSV-seropositive patients with acute leukemia, other viral infections are rather infrequently reported outside the setting of allogeneic HSCT. For example, a positive pp65 antigenemia for CMV has been reported in 9% of non-HSCT recipients and in 12% of patients undergoing autologous HSCT, without necessarily being accompanied by CMV disease. For this reason, routine monitoring of CMV reactivation and preemptive therapy were not considered necessary in cancer patients other than HSCT recipients. However, the risk of viral reactivation might change significantly with the increasing use of novel T-cell–suppressing agents or drug combinations, such as alemtuzumab or idelalisib or a combination of bendamustine and rituximab.
Community-acquired respiratory viruses, such as influenza, parainfluenza, respiratory syncytial virus (RSV), metapneumovirus, adenoviruses, rhinoviruses, and coronaviruses, are a frequent cause of respiratory disease in cancer patients and are probably underestimated as a cause of fever. Whereas most cancer patients would experience self-limited upper respiratory illness, those with a severe immune deficit, such as those treated for leukemia, are at increased risk for progression from upper respiratory tract infection to pneumonia, with possible respiratory failure and fatal outcome. The incidence rate of viral respiratory infections in patients with acute lymphocytic and acute myelogenous leukemia is estimated to be 68 and 31 infections per 1000 new admissions, respectively. Almost half of these patients had pneumonia, and the mortality was 14%. In cancer patients with a viral respiratory disease, deferral of chemotherapy could be considered. Specific treatment is warranted for influenza and in some cases of RSV infection (e.g., in leukemic patients with risk factors for RSV-related mortality) (see Chapter 158 ).
Viral gastroenteritis, mainly caused by rotavirus but also norovirus or sapovirus, may be a frequent complication in pediatric oncology, with a potential to cause outbreaks in cancer centers because of persistent gastrointestinal shedding in immunocompromised hosts. Both adenoviruses and parvovirus B19 have been reported as rare causes of severe gastrointestinal disease in cancer patients.
Finally, the reactivation/exacerbation of infections due to hepatotropic viruses (HBV and hepatitis C virus) represents an important problem in areas of high endemicity. HBV reactivation is frequent in cancer patients with chronic inactive HBV infection (HBsAg positive, with negative or low-level serum HBV DNA), but it can occur also in patients with an occult HBV infection (HBsAg negative, HBcAb positive, or with low-level serum HBV DNA), particularly in association with the use of rituximab (up to 40% of patients). The possibility of chronic hepatitis E virus infection due to genotype 3, which is endemic in certain industrialized regions, has been recently reported in patients with hematologic malignancies and transplant recipients. Repeated transfusions might be a risk factor for hepatitis E virus infection.
Other Pathogens
The risk of rare infections or reactivations caused by protozoa (leishmaniasis, South American trypanosomiasis, and malaria), helminths (strongyloidiasis), endemic fungi and other tropical diseases should be considered in patients who lived in endemic areas. Obtaining a history to identify potential exposure is the most important screening, with additional serology to document past exposure. However, in the case of strongyloidiasis, for example, the suboptimal performance of stool examination or serologic screening may warrant empirical treatment with ivermectin in patients who present with unexplained eosinophilia and who lived in endemic areas, such as the tropics, the subtropics, or the southeastern United States and Europe.
Prevention of Infections in Cancer Patients
Prevention is obviously a desirable goal, given the remarkable mortality and morbidity associated with infections in cancer patients. Table 306.4 summarizes different regimens for primary chemoprophylaxis and other approaches that have been considered appropriate in cancer patients based on clinical trials and guidelines. In the following sections, advantages and disadvantages of different procedures are discussed.
TABLE 306.4
Suggested Prophylaxis for Infections in Cancer Patients
| DRUG | SCHEDULE | COMMENTS | |
|---|---|---|---|
| Antibacterial | Ciprofloxacin | 500 mg bid | Use of FQs should be based on local epidemiology and careful evaluation of potential drawbacks of FQ prophylaxis. Probably not active anymore in many sites. Some studies showed possible effects on increasing resistance. Traditionally administered to adults receiving chemotherapy for acute leukemia with expected neutropenia >7–10 d; starting with chemotherapy and continuing until resolution of neutropenia or initiation of empirical antibacterial therapy for febrile neutropenia. |
| Levofloxacin | 500 mg once daily | ||
| Antifungal | Posaconazole | 100-mg tablets: 3 tablets twice daily on the first day, then 3 tablets daily As alternative, oral solution 200 mg tid orally with a (fatty) meal or acidic drink |
Patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Therapeutic drug monitoring is warranted. |
| Fluconazole | 400 mg once daily | Patients receiving chemotherapy for acute myelogenous leukemia with cytarabine plus anthracycline regimens (administered for 7 and 3 d, respectively) and high-dose cytarabine-containing regimens. | |
| Other | Secondary prophylaxis according to isolated pathogen, clinical presentation, or both. | ||
| Anti– Pneumocystis jirovecii | Trimethoprim-sulfamethoxazole (TMP-SMX) | One double-strength tablet (160/800 mg) three times weekly, or 25 mg/kg TMP-SMX (5 mg/kg of TMP), max. 1920 mg (2 double-strength capsules) in 2 divided doses for 3 consecutive days/wk |
All patients receiving chemotherapy with steroids, including those with solid tumors (e.g., brain cancer). |
| Dapsone | 2 mg/kg/d (max. 100 mg), on alternate days three times/wk | In patients who cannot tolerate TMP-SMX. | |
| Aerosolized pentamidine | 300 mg once a month with nebulizer | In patients who cannot tolerate TMP-SMX; effective, but it is more difficult to administer. | |
| Atovaquone | 750 mg twice daily or 1500 mg once daily | In patients who cannot tolerate TMP-SMX. | |
| Antiviral | Acyclovir or |
40 mg/kg in children in 2 divided doses In adults >40 kg: 800 mg twice daily |
Patients with positive anti-HSV antibodies and severe mucositis or receiving treatment for acute leukemia. |
| Valacyclovir | For HSV or VZV prophylaxis: 500 mg twice daily or 1000 mg daily For VZV exposure: 1 g three times daily (see text) |
VZV-susceptible patients exposed to chickenpox who did not receive prompt administration of specific immunoglobulins. | |
| Lamivudine | 100 mg once daily | Patients with chronic inactive HBV infection (HBsAg positive, HBV DNA low level or negative). Patients with resolved HBV infection (HBsAg negative and HBcAb positive), particularly if receiving rituximab or allogeneic HSCT. |
|
| Entecavir | 0.5 mg daily | HBsAg-positive patients treated with rituximab with HBV DNA <2000 IU/mL. | |
| Antituberculosis | Isoniazid | 5 mg/kg (max. 300 mg) in adults, 10 mg/kg (max. 300 mg) once daily in children once daily for 6–9 mo | Patients with latent tuberculosis. Efficacy not specifically evaluated in cancer patients. See Chapter 249 and text for other regimens to treat latent tuberculosis. |
| Anti–CVC-associated infection | None | Good skin preparation and the use of sterile technique at time of device insertion. Good maintenance procedures. |
All patients with indwelling central venous catheter. |
| Others | Growth factors | Filgrastim either subcutaneously or as an intravenous infusion over at least 1 h, or pegylated filgrastim | For the prevention of febrile neutropenia in patients who have a high risk of this complication based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Secondary prophylaxis with G-CSFs recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in whom a reduced dose of chemotherapy may compromise disease-free or overall survival or treatment outcome. Efficacy not fully demonstrated for pegylated filgrastim. |
| Immunoglobulins | Polyclonal immunoglobulins: 400 mg/kg every 21–28 d | Patients with chronic lymphocytic leukemia after the second episode of severe bacterial infection. Patients with leukemia or lymphoma with hypogammaglobulinemia (<400g/dL) and severe bacterial infections (reasonable, but not proved). |
|
| Specific anti-VZV (VariZIG): 125 IU for every 10 kg of body weight (max., 625 IU) | In high-risk contact with a negative history of varicella preferably within 96 h after exposure to chickenpox. | ||
| Vaccines | Influenza | Influenza vaccination of patients, especially during less aggressive treatment phases. Vaccination of household contact and health care workers. |
|
| Varicella | VZV-seronegative household contacts and health care workers. | ||
| Pneumococcus | Conjugated 13-valent antipneumococcal vaccine. | ||
| Isolation procedures | Perform hand hygiene with an alcohol-based hand rub or by washing hands with soap and water if soiled, before and after all patient contacts or contact with the patients' potentially contaminated equipment or environment. Use contact precautions (gowns and gloves). Ensure adherence to standard environmental cleaning with an effective disinfectant. |
Patients colonized or infected with multidrug-resistant pathogens (such as VRE, CRE, etc.) or infected with other pathogens for which contact isolation precautions are advisable ( C. difficile, norovirus, etc.); of note, alcohol-based hand rubs are not cidal against C. difficile or norovirus. |
CRE, Carbapenem-resistant Enterobacteriaceae; CVC, central venous catheter; FQ, fluoroquinolone; G-CSFs, granulocyte colony-stimulating factors; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; IU, international unit; max., maximum; VRE, vancomycin-resistant enterococci; VZV, varicella-zoster virus.
Prevention of Bacterial Infections
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