Renal infections in cancer patients

Epidemiology

Cancer patients are at a higher risk of infections with a mean annual incidence rate of 1465 cases per 100,000 cancer patients and a relative risk [RR] of 9.77 compared with noncancer patients (95% confidence interval [CI], 9.67–9.88). Bacterial urinary tract infections (UTIs) can commonly be seen both in patients with genitourinary tract cancers and nongenitourinary tract malignancies. Because of their immunosuppression, both hematopoietic stem cell transplant and solid organ transplant patients are at increased risk of viral, fungal, and other atypical bacterial infections, in addition to bacterial infections. Very few studies have described the incidence of kidney infections in cancer patients. In a study among 3355 French patients with primarily hematologic malignancies, 170 UTIs were observed, with an attack rate (number of diagnosed infections/100 patients) of 5.1 and an incidence rate of 2.9 per 1000 patient-days at risk. In this study enterobacteria (60%) were the predominant pathogens. Some 10% of the patients had fungal infections, whereas viruses accounted for only 3%. These rates are higher than the documented UTI rates among hospitalized patients in both the United States of 0.34% (2015) and Europe 1.32% (2010). ^,

Although early recognition and management of sepsis in an intensive care setting has improved survival in cancer patients, cancer patients with sepsis continue to have disproportionately higher rates of mortality and morbidity and consequently, incur higher health care costs compared with noncancer patients with sepsis.

Infections including UTIs leading to sepsis have been well described in cancer patients and can lead to significant morbidity and mortality. Sepsis is the most common cause of intensive care admissions in cancer patients. In some studies, about 20% of the cancer patients admitted to ICUs had sepsis. In a study of 1332 patients that were admitted to an oncology-dedicated ICU, 563 (42%) patients met criteria for sepsis. Of these, 8% of patients had UTIs. Patients with UTIs were shown to have lower mortality rates in this study than those with pneumonias or bacteremias.

Immune dysfunction caused by cancer

The innate immune system is the first line of defense of the body and refers to immune responses that are present from birth and are not acquired or adapted as a result of exposure to microorganisms. Host components include mucosal barriers, secretory enzymes, such as lysozyme, certain inflammatory proteins including C-reactive protein, antimicrobial peptides, cell receptors such as Toll-like receptors, phagocytic cells, like neutrophils and macrophages, mast cells and natural killer cells, which release cytokines. On the other hand, the adaptive immune system consists of the T and B lymphocytes, which continually learn, adapt, and help mount immune responses upon recognition of different foreign and tumor antigens. A variety of microorganisms that colonize the skin, respiratory tract, and the gastrointestinal tract constitute the human microbiome and are thought to contribute to the maturation of immune response and controlling the overgrowth of pathogenic microbes.

Cancers can alter both innate and adaptive immune responses. In certain hematologic cancers, like multiple myeloma and chronic lymphocytic leukemia, reduced antibody production and clearance of immune complexes can lead to an increased risk of infections from encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae . Other malignancies like lymphomas can cause defects in cell-mediated immunity, and lead to increased risk of infections with intracellular organisms, like listeria, salmonella, cryptococcus, and mycobacteria.

Chemotherapy and radiotherapy

Chemotherapy can have several effects on the immune system, leading to infections. The suppression of hematopoiesis by chemotherapy can lead to pancytopenia and functional impairment, thereby decreasing the quantitative and qualitative ability of the immune system to contain infections.

Neutropenia with an absolute neutrophil count (ANC) below 500 cells/microliter increases the risk of bacterial infections in patients. If neutropenia is prolonged, the risk of fungal infections also increases in these patients. In addition to causing neutropenia, chemotherapeutic agents may impair chemotaxis and phagocytosis and decrease the ability of neutrophils to eliminate intracellular pathogens. Other chemotherapeutic agents, such as calcineurin inhibitors, which inhibit T-cell activation, or fludarabine, which affects lymphocyte function, can have severe and longstanding effects on the cell-mediated immunity and can increase the risk for certain infections like Pneumocystis jiroveci pneumonia, and viral infections.

Stem cell transplants can have a profound effect on cell-mediated immunity; the use of aggressive chemotherapy and prolonged immunosuppression after stem cell transplants can impair immunity further, leading to increased susceptibility to infection.

Radiotherapy-induced inflammation also contributes to UTIs. In one prospective study, pelvic radiotherapy led to development of UTIs in 17% of the patients studied. Even though patients of both sexes with various pelvic malignancies were included, there was an increased risk of infections in women with bladder and cervical malignancies. In another study of 36 patients with gynecologic malignancies, 25% of patients developed bacteriuria during radiotherapy; a higher risk of infection was associated with advanced stages of cancer. The authors suggested preradiation urine cultures, particularly in patients undergoing cystoscopy and periodic screening in women with advanced cervical cancers, as they were at higher risk.

Glucocorticoids and other medication-induced immune dysfunction

The use of glucocorticoids can impair migration of granulocytes to sites of inflammation and negatively affect phagocytosis and intracellular killing. The opsonization of bacteria and phagocytosis of pathogens by neutrophils and macrophages is also affected adversely by the use of steroids. Furthermore, the introduction of monoclonal antibodies, like alemtuzumab, ibritumomab, and rituximab, has also resulted in an increase in opportunistic infections because of lymphopenia, impaired T-lymphocyte response, and phagocyte dysfunction.

Mucositis

Cachexia and malnutrition are frequently seen in cancer patients and lead to a catabolic state. This is further exacerbated by anorexia because of malignancy and chemotherapy-induced gastrointestinal effects, including nausea and vomiting. All these together cause mucosal atrophy and loss of the epithelial lining, leading to mucositis.

Mucositis results in decreases in secretory defenses, including lysozymes and immunoglobulin (Ig)A, and alterations in the classic and alternative complement pathway. The associated loss of inhibitory substances, such as lactoferrin, lysozyme, defensins, peroxidase, and IgA, can contribute to the impaired clearance of pathogenic organisms and increase the risk of infections.

Chemotherapy and radiotherapy-induced mucositis

Chemotherapy and radiation therapy can cause mucositis and translocation of the normal microbial flora of the gastrointestinal and genitourinary tract; this in turn leads to invasive infections and bacteremia. ^, Chemotherapy-induced hematopoiesis suppression can cause pancytopenia and functional impairment, thereby decreasing the quantitative and qualitative ability of the immune system to contain infections. Various chemotherapeutic agents, including anthracyclines (daunorubicin and doxorubicin), plant alkaloids (vinblastine and vincristine), paclitaxel, cisplatin, melphalan, bleomycin, etoposides, and radiation, have been shown to cause aberrant activation of the immune cascade by activation of nuclear factor (NF)-κβ. Activation of NF-κβ in turn results in macrophages and endothelial cells releasing various proinflammatory cytokines and chemokines like interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-α, and interferon-gamma. The activation of NF-κβ can lead to apoptosis and both tumor and “innocent bystander” mucosal cell death. As a consequence, ulceration, crypt hypoplasia, and villous atrophy follows, and matrix metalloproteinases are activated, which in turn leads to cleavage of collagen and fibronectin. Mucositis is further amplified by the breaching of natural barriers by bacteria and their proinflammatory cell wall products, such as peptidoglycan and lipopolysaccharides. The destruction of residual symbiotic microflora disrupts the microbiome and leads to the overgrowth of pathogenic microorganisms, thereby causing infections.

Mechanical factors, devices

Cancer patients have an elevated risk of infections because of the increased use of medical devices, including catheters, stents, and prostheses. The anatomic changes associated with transplantation and various postsurgical complications also predispose these patients to infections. The risk of inflammation is increased in malignancies. UTIs may be caused by invasive gynecologic surgery (for malignancy), associated surgical complications, and invasive instrumentation, which also includes catheterization or cystoscopy. Tumors, by obstructing and invading normal tissue, can cause local organ dysfunction and predispose patients to infections.

Cystitis

The signs and symptoms of UTIs in patients with cancer are similar to those in patients without malignancies. Lower tract UTIs may present with dysuria, urgent or frequent urination, and suprapubic pain or tenderness. In general, the presence of fevers in UTIs is indicative of parenchymal inflammation or upper tract involvement.

Separate guidelines for diagnosis and management of UTIs in cancer patients have not been published. Thus management is mostly based on guidelines in noncancer patients ( Table 36.1 ). For uncomplicated lower tract infections including cystitis, nitrofurantoin, trimethoprim-sulfamethoxazole (160/800 mg [1 double-strength tablet] twice daily for 3 days) or fosfomycin trometamol (3-g single dose) have been recommended in recent guidelines for nonimmunocompromised and noncancer patients. The presence of resistance above 20% to an antimicrobial class in a particular area is thought to preclude its use empirically. ^{, ,} Given the higher prevalence of antimicrobial resistance in cancer patients to fluoroquinolones, cephalosporins, aminoglycosides, and sulfa agents, the use of these agents empirically is thus not recommended. The higher prevalence of resistance, including to carbapenems, and even multidrug resistance necessitates obtaining urine cultures in these cases essential. ^{, ,}

There is frequent resistance to fluoroquinolones, and they have higher potential for Clostridium difficile . Hence alternatives are preferred. There have been studies documenting inferior efficacy of amoxicillin-clavulanate in shorter 3 day courses as compared with fluoroquinolones. However, beta-lactam antibiotics including cephalosporins such as cefdinir, cefaclor, and cefpodoxime-proxetil, and aminopenicillin derivatives including amoxicillin-clavulanate are considered reasonable alternatives in 3- to 7-day regimens, when other agents cannot be used. Other beta-lactams, such as first-generation cephalosporins, including cephalexin, have a narrower gram-negative spectrum, and data supporting their use are scant. However, if susceptibility is confirmed, their use may be reasonable in certain situations. ^{, , ,}

Upper urinary tract infections including pyelonephritis

Upper tract infections manifest with new onset or worsening of fever, rigors, altered mental status, malaise, or lethargy with no other identified cause, flank pain, costovertebral angle tenderness, acute hematuria, or pelvic discomfort. Catheter-associated UTIs have similar signs.

In patients suspected of having pyelonephritis, a urine culture and susceptibility test should always be performed, and initial empirical therapy should be tailored appropriately based on the infecting pathogen. Guidelines in nonimmunocompromised patients indicate that oral ciprofloxacin is an appropriate therapeutic choice in patients not requiring hospitalization, provided the prevalence of resistance of community-acquired bacteria to fluoroquinolones is known to be below 10% ( Table 36.2 ). The higher resistance and increasing use of fluoroquinolones for prophylaxis in cancer patients makes them unreliable empiric options. In the presence of more than 10% fluoroquinolone resistance, an initial intravenous dose of a long-acting antimicrobial, such as ceftriaxone or an aminoglycoside, is considered reasonable. If susceptibility is confirmed, oral trimethoprim-sulfamethoxazole for 14 days is considered a reasonable option.

Awaiting susceptibilities, an initial parenteral antimicrobial, like 1-g ceftriaxone or a once-a-day aminoglycoside, is recommended in noncancer patients and would be considered necessary in immunocompromised patients, given the higher probability of resistance. As in cystitis, beta-lactam agents are less effective than other available agents for treatment of pyelonephritis. Efficacy/outcomes for beta-lactams, including cephalosporins, were inferior compared with trimethoprim-sulfamethoxazole and fluoroquinolones. ^,

Seven-day regimens for fluoroquinolones in noncancer patients have been recommended to treat pyelonephritis. However, most recent guidelines suggest that there are not enough data to treat pyelonephritis with a similar short course of a beta-lactam agent. ^{, ,} Patients with pyelonephritis requiring hospitalization should be initially treated with intravenous antibiotics, such as a fluoroquinolone, an aminoglycoside (with or without ampicillin), an extended-spectrum cephalosporin or extended-spectrum penicillin (with or without an aminoglycoside), or a carbapenem. The choice between these agents should be based on local resistance data, and the regimen should be tailored based on susceptibility results (see Table 36.2 ). ^,

Treatment with agents for longer periods (> 14 days) may result in the development of resistant pathogens by selection pressure. Two weeks of trimethoprim-sulfamethoxazole were shown to be as efficacious as a 6-week course of ampicillin in a study of 60 women with uncomplicated pyelonephritis. The shorter course had fewer adverse effects, lower costs, and also led to the selection of fewer resistant organisms.

Catheter-associated urinary tract infections

Guidelines indicate that if an indwelling catheter has been in place for more than 2 weeks and still needs to be retained, replacement of the catheter helps in treatment of the episode and the prevention of any future recurrences. Urine culture should be obtained from the newly placed catheter before starting antibiotics and used to tailor the antimicrobial choice. However, if the catheter can be removed, a midstream urine sample should be obtained before starting antibiotics and the result used to guide the choice. ^,

If symptoms resolve rapidly, 7 days of treatment is considered adequate for most patients with catheter-associated (CA)-UTI. Shorter duration of fluoroquinolones, particularly levofloxacin, has been recommended in patients who are not severely ill. There is some literature supporting a shorter duration (3 days) in nonimmunocompromised patients with no upper tract symptoms in whom the catheter has been removed, although there are no trials to guide therapy in cancer patients. ^, In patients with delayed response and immunocompromised patients, a longer (10–14 day) course of treatment may be considered, but data on the optimal duration of therapy are scant, particularly in cancer patients. Given the immunocompromised state, we feel that a 10- to 14-day course would be reasonable in these cases.