Mauricio Burotto Pichún, Sarah Read, and Juan C. Gea-Banacloche
FEVER
■Fever is the most common sign of infection, and a very usual problem in patients with cancer.
■Fever is conventionally defined as one oral temperature greater than 38.3°C or two oral temperatures greater than 38°C measured 1 hour apart.
■Old age, malnutrition, and corticosteroids may blunt the febrile response. From the practical management standpoint one must separate between fever in the neutropenic cancer patient (“neutropenic fever”) and fever in the absence of neutropenia.
FEVER IN THE NEUTROPENIC CANCER PATIENT
■Neutropenia, the most important risk factor for bacterial infection in cancer patients, is defined as an absolute neutrophil count (ANC) <500/mm3, or ANC ≤1,000/mm3, with a predicted decline to <500/mm3within 48 hours.
■Fever during neutropenia is always considered to be of infectious origin, and managed accordingly.
■The risk of infection increases with the rapidity of onset, degree, and duration of neutropenia.
■Febrile neutropenic patients require immediate evaluation and prompt initiation of empirical broad-spectrum antibiotics with activity against Pseudomonas aeruginosa (Fig. 35.1). Antibiotics are usually administered intravenously, but oral administration may be acceptable when patients are determined to be at low risk of severe morbidity and mortality (see below).
■Three distinct syndromes of fever during neutropenia are of practical importance.
•First fever: In 20% to 25% of patients with fever and neutropenia an infection is documented microbiologically (most commonly bacteremia). In 20% to 30% of patients an infection is documented only clinically, without microbiologic confirmation. In 50% of patients with fever and neutropenia no infection is found. The response to empirical management with antibiotics is similarly favorable in these three subgroups. Gram-positive and gram-negative bacteria are isolated with roughly similar frequency. Treatment emphasizes coverage of gram-negative bacteria because these infections tend to progress faster and have higher mortality.
•Persistent fever: The average time to defervescence for the first episode of neutropenic fever is 3 to 4 days. When fever persists for 5 days or more (4 to 7, depending on the study) the frequency of invasive fungal infection is high enough that it is standard practice to add empirical antifungal therapy. Candida and Aspergillus species are the most common causes of fungal infections in neutropenic patients and increase in frequency with longer duration of neutropenia. The antifungal agent used may vary with the clinical situation and the preexistent use of antifungal prophylaxis, but there are good data supporting the empirical addition of amphotericin B (deoxycholate or liposomal), voriconazole, and caspofungin. It is indicated to look for invasive fungal infection by blood cultures (including fungal blood cultures) and computed tomography (CT) of chest and sinuses.
•Recrudescent fever (new fever after resolution of the first episode): This term refers to the reappearance of fever after the patient has been afebrile for more than 48 hours. In this situation, both breakthrough bacterial and fungal infections are possible. The management includes changing or adding antibiotics and antifungals plus diagnostic studies as outlined above. Drug-resistant bacteria are increasing, for example, extended-spectrum beta-lactamase-producing (ESBL) gram-negative bacilli, vancomycin-resistant enterococcus (VRE), carbapenemase-producing Klebsiella (KPC). The specific bacteria vary depending on the institution, and their prevalence may play a role in determining the optimal choice of antibiotics (both as initial regimen and as “rescue” regimen for recrudescent fever).
■The importance of fever during neutropenia is that it is a good surrogate marker for infection. It is not the only one, however, and other signs or symptoms suggestive of infection (e.g., abdominal pain, erythema, hypotension, hypothermia) should be similarly treated empirically with antibiotics as well.
FIGURE 35.1 Approach to patients with fever and neutropenia without clinically or microbiologically documented infection. The choice between piperacillin–tazobactam (shown here emphasizing the higher dose required in neutropenic patients), cefepime, imipenem, meropenem, and ceftazidime will vary between institutions based on local resistance patterns. For specific infections, see the text and Table 35.1. * This antibacterial regimen for the neutropenic patient with sepsis will vary between institutions, depending on the local patterns of antibiotic resistance. Carbapenem + fluoroquinolone (or aminoglycoside or colistin) + vancomycin (or daptomycin or linezolid) + echinocandin is typical. We prefer meropenem and daptomycin because both can be “pushed” intravenously in a few minutes. The antifungal of choice will vary depending on previous antifungal prophylaxis. †The empirical gram-positive coverage should usually be discontinued after 48 to 72 hours if there is no bacteriologic documentation of a pathogen requiring its use, except in soft tissue or tunnel infections. Linezolid or daptomycin may be substituted for vancomycin if there is suspicion or high endemicity of VRE. For a detailed discussion of antifungal therapy options, as well as for the role of oral antibiotics in low-risk patients, see the text. AmB, amphotericin B; MRSA, methicillin (oxacillin)-resistant Staphylococcus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae.
EVALUATION
■History and physical examination should be performed with special attention to potential sites of infection: skin, mouth, perianal region, and intravenous catheter exit site.
■Routine complete blood count with differential, chemistries, including liver enzymes and creatinine, urinalysis, blood and urine cultures, and chest x-ray should be obtained.
■Blood cultures: Two sets of blood cultures are more sensitive than a single set for the diagnosis of bacteremia. To determine if a bacteremic episode is related to the catheter, it is advisable to draw blood from the intravenous catheter and a peripheral vein. A differential time to positivity of 2 hours or more (i.e., the cultures obtained from the catheter become positive earlier than the peripheral stick) has good predictive value for catheter-related bacteremia.
■Any accessible sites of possible infection should be sampled for gram stain and culture (catheter site, sputum, etc.).
■Ideally, blood cultures should be obtained prior to starting antibiotics, but failure to do so should not delay antibiotic administration.
EMPIRICAL ANTIBIOTIC THERAPY
■A summary of the initial management of the patient with fever and neutropenia and no localizing signs or symptoms is provided in Figure 35.1.
■The goal of treatment is to provide broad antibiotic coverage with minimal toxicity.
■Most bacterial infections during neutropenia are caused by microorganisms that colonize the oral mucosa, the bowel, and the skin of the patient. P. aeruginosa is particularly prevalent during neutropenia. Due to their potential for faster progression and higher morbidity, the emphasis is on coverage of enteric gram-negative bacilli and Pseudomonas. This may be achieved by using single agents or by combining several antibiotics.
Monotherapy
■Monotherapy with selected broad-spectrum β-lactams with activity against P. aeruginosa is as effective as combination antibiotic regimens (β-lactam plus aminoglycoside) for empirical therapy of uncomplicated fever and neutropenia, and has less toxicity. The following regimens are the options recommended by the 2011 guidelines from the Infectious Diseases Society of America (IDSA):
•Cefepime, 2 g IV every 8 hours
•Imipenem–cilastatin, 500 mg IV every 6 hours
•Meropenem, 1 g IV every 8 hours
•Piperacillin–tazobactam, 4.5 g IV every 6 hours
■The choice of one agent over another should be guided mainly by institutional susceptibilities, which may make one or more of the aforementioned agents a poor choice. Some institutions may still find ceftazidime (which is not on the IDSA’s list anymore), 2 g IV every 8 hours, perfectly adequate. By meta-analysis, all these agents seem to offer similar efficacy, but carbapenems may be associated with increased risk of Clostridium difficile colitis.
Combination Therapy with Expanded Gram-Negative Coverage
■Combination therapy aiming to broaden the anti–gram-negative activity may be used empirically in certain clinical circumstances, although there are no definitive data showing clinical benefit. Combination therapy should be used in cases of
•Severe sepsis or septic shock
•High prevalence of multidrug-resistant gram-negative bacilli
■Effective antibiotic combinations include one of the aforementioned β-lactams plus an aminoglycoside (choice based on local resistance) or colistin. Ciprofloxacin may be used instead of an aminoglycoside if the prevalence of quinolone-resistant bacteria is low or in patients at high risk of aminoglycoside toxicity. Colistin and polymixin B are being used more frequently with the increasing prevalence of KPC and multiresistant Acinetobacter baumannii.
Role of Vancomycin and Other Agents with Gram-Positive Coverage
Vancomycin should be part of the initial empirical regimen under the following circumstances:
■Severe sepsis or septic shock
■Pneumonia
■Soft tissue infection (cellulitis, necrotizing fasciitis)
■Clinically suspected catheter-related infections (not the mere presence of an intravascular device)
■Severe mucositis or other risk factors for infection with Streptococcus mitis (use of prophylaxis with fluoroquinolones, high-dose Ara-C, use of H2 blockers)
■Known colonization with methicillin-resistant Staphylococcus aureus (MRSA) or penicillin-resistant Streptococcus pneumoniae (PRSP)
Addition of vancomycin to the initial regimen:
■Adding vancomycin to the initial regimen because of persistent fever alone does not improve the outcome and is not recommended.
■Positive blood cultures for gram-positive bacteria are an indication for the addition of agents with gram-positive activity.
■Pending identification, the choice between vancomycin, linezolid, and daptomycin should be informed by the local prevalence of VRE and preliminary morphologic information from the gram stain (gram-positive cocci in pairs and short chains suggest enterococcus or S. pneumoniae, gram-positive cocci in clusters suggest Staphylococcus).
■It is not known at this time whether linezolid or daptomycin should be used empirically in patients known to be colonized with VRE, nor whether screening cultures result in improved outcomes.
■In the case of documented VRE infection, the choice between daptomycin, linezolid, and quinupristn–dalfopristin is not based on clinical outcome data, but on theoretical considerations and local resistance patterns.
Oral Therapy
■Empirical oral antibiotics may be acceptable for neutropenic patients who are not at high risk of severe morbidity or death.
■High-risk patients are those who received chemotherapy associated with prolonged and profound neutropenia (e.g., AML induction therapy), as well as patients with symptoms or signs of clinical instability or with significant comorbidities (e.g., COPD, heart failure). Low-risk patients do not exhibit any high-risk factors and their neutropenia is expected to be short lived. These patients could be considered for outpatient antibiotic treatment.
■A quantitative risk assessment, the Multinational Association for Supportive Care in Cancer (MASCC) scoring system, has been validated. Points are allocated for burden of illness (no or mild symptoms 5, severe symptoms 3), absence of hypotension (5), no chronic obstructive pulmonary disease (4), solid tumor or no previous fungal infection (4), absence of dehydration (3), outpatient status (3), and age <60 years (2) and the points are added up. Patients with a score of ≥21 points (of 26 possible) are at “low risk,” and can be considered for oral therapy.
■The two recommended oral regimens are
•Ciprofloxacin, 750 mg PO every 12 hours, plus amoxicillin/clavulanate, 875 mg (amoxicillin component) PO every 12 hours
•Ciprofloxacin, 750 mg PO every 12 hours, plus clindamycin 450 mg PO every 6 hours
We recommend starting oral antibiotics on an inpatient basis, and then consider discharge after 24 hours of observation and documentation that the blood cultures remain negative. Following discharge, patients should be seen daily and instructed to call or come in to clinic for new or worsening symptoms or persistent high fever. Approximately 20% of patients will need readmission to the hospital (factors associated with need for admission: >70 years old, poor performance, ANC <100/mm3).
Low-risk patients with no documented infection who respond to empirical IV antibiotics can be switched to oral antibiotics until their neutropenia resolves based on clinical judgment. We recommend observing these patients on oral therapy as inpatients for at least 24 hours before discharge.
Modifications of the Initial Antibiotic Regimen
■After patients are started on empirical antibiotics for fever and neutropenia, their course must be monitored closely for development of new signs or symptoms of infection; antibiotic therapy should be modified based on clinical findings.
■Therapy modification is necessary in 30% to 50% of cases during the course of neutropenia.
■Specific modifications are dictated by specific clinical syndromes (Table 35.1) or by microbiologic isolates.
■Persistent fever with no other clinical findings is not an indication for modification of the antibacterial regimen.
■If there is no documented gram-positive infection, gram-positive coverage may be stopped if it had been initiated.
■After 4 to 7 days of persistent fever, it is accepted practice to start some antifungal agent.
■In the case of recrudescent fever the antibacterial and antifungal agents should be changed and imaging studies performed.
Empirical Antifungal Therapy
Candida and Aspergillus infections are most common and increase in frequency with increased duration of neutropenia. An antifungal agent should be added empirically for neutropenic patients in the following circumstances:
■Severe sepsis or septic shock: it may be caused by Candida; amphotericin or an echinocandin should be added.
■Persistent fever after 4 to 7 days of broad-spectrum antibiotic therapy.
■Recrudescent fever.
■Candida colonization: candiduria, thrush.
Treatment options include
■Amphotericin B deoxycholate, 0.6 to 1 mg/kg/day IV.
■A lipid formulation of amphotericin B such as liposomal amphotericin B (Ambisome) or amphotericin B lipid complex (Abelcet), 3 to 5 mg/kg/day IV.
■Voriconazole, 6 mg/kg IV every 12 hours for 24 hours followed by 4 mg/kg IV every 12 hours.
■Caspofungin, 70 mg IV loading dose followed by 50 mg IV daily.
For persistent fever, these four options are well validated as empirical additions. Of note, an effort should be made to rule out the presence of active invasive fungal infection by performing a thorough physical examination and obtaining CT studies as clinically indicated. Some authorities have suggested to start antifungal agents only when there is ancillary evidence of fungal infection besides the fever (e.g., positive serologic tests like galactomannan and/or ß-D-glucan). The role of this so-called “preemptive” antifungal therapy as opposed to the traditional “empirical” addition of antifungal agents in persistent fever has not been clearly defined.
It should be noted that posaconazole (a new broad-spectrum antifungal agent given as 200 mg PO every 8 hours with food) has shown very good activity as antifungal prophylaxis, but has no role in the acute management of presumptive fungal infection, because therapeutic levels are not achieved for 5 to 7 days after starting.
Duration of Antibiotic Therapy
■Documented bacterial infection: Antibiotics should be continued for the amount of time standard for that infection or until resolution of neutropenia, whichever is longer.
■Uncomplicated fever and neutropenia of uncertain etiology: Antibiotics should be continued until the fever has resolved and the ANC is above 500 for 24 hours.
■If no infection was documented and the patient became afebrile on antibiotics, but the neutropenia persists, it is acceptable to complete 2 weeks of treatment. At that point one may discontinue the antibiotics and observe. Alternatively, it is acceptable to resume fluoroquinolone prophylaxis until marrow recovery.
■If there is no documented fungal infection, antifungal agents can also be discontinued at the time of resolution of neutropenia.
FEVER IN THE NONNEUTROPENIC CANCER PATIENT
■Noninfectious causes of fever in cancer patients include, among others, the underlying malignancy, deep venous thrombosis and pulmonary embolism, medications, blood products, and, in allogeneic stem cell transplant, graft-versus-host disease.
■Infections, however, are common in patients with all types of malignancies in all stages of treatment. In addition to neutropenia, there are several other factors that contribute to increased susceptibility to infection and should be considered when trying to diagnose an episode of fever and formulate a treatment plan.
•Local factors: Breakdown of barriers (mucositis, surgery) that provide a portal of entry for bacteria; obstruction (biliary, ureteral, bronchial) that facilitates local infection (cholangitis, pyelonephritis, postobstructive pneumonia).
•Intravascular devices, drainage tubes, or stents may become colonized and lead to local infection, bacteremia, or fungemia.
•Splenectomy increases susceptibility to infection due to S. pneumoniae and other encapsulated bacteria.
•Deficiencies of humoral immunity (multiple myeloma, chronic lymphocytic leukemia) lead to increased susceptibility to encapsulated organisms such as S. pneumoniae and Haemophilus influenzae.
•Defects in cell-mediated immunity (lymphoma, hairy cell leukemia, treatment with steroids, fludarabine, and other drugs, hematopoietic stem cell transplant [HSCT]) increase susceptibility to opportunistic infections caused by Legionella pneumophila, Mycobacteria, Cryptococcus neoformans, Pneumocystis jirovecii, cytomegalovirus (CMV), varicella zoster virus (VZV), and other pathogens.
Antibiotic Therapy in the Nonneutropenic Cancer Patient
■Antibiotics should be administered empirically in the setting of fever only when a bacterial infection is considered likely.
■Ideally one should formulate a “working hypothesis” as a fundamental basis to choose the appropriate regimen, for example, pneumonia, cholecystitis, and urinary tract infection would likely require different antibiotics.
■In the absence of localizing signs and symptoms, consider bacteremia, particularly in patients with intravascular devices. Many authorities recommend empirical antibiotics (levofloxacin, ceftriaxone) until bacteremia is ruled out.
■Clinically documented infections and sepsis should be treated with antibiotics as warranted by the clinical scenario.
■Whenever antibiotics are started, a plan with specific endpoints should be formulated to avoid unnecessary toxicity, superinfection, and development of resistance.
SPECIFIC INFECTIOUS DISEASE SYNDROMES
If a patient presents with clinical signs and symptoms of a specific infection, with or without neutropenia, the workup and therapy are guided by the clinical suspicion (see Table 35.1).
Bacteremia/Fungemia
■A positive blood culture should prompt immediate initiation of appropriate antibiotics in a neutropenic patient or in a nonneutropenic patient who is febrile or clinically unstable.
■If the isolated organism is one that is commonly pathogenic, such as S. aureus or gram-negative bacilli, antibiotics should be started even if the patient is afebrile and clinically stable.
■If the isolate is a common contaminant, such as a coagulase-negative Staphylococcus, and the patient is afebrile, clinically stable, and nonneutropenic, it may be appropriate to repeat the cultures and observe before starting antibiotics.
■In every case of bacteremia, follow-up blood cultures should be obtained to document the effectiveness of therapy, and the source of the infection should be sought.
Gram-Positive Bacteremia
Gram-Positive Cocci
■Coagulase-negative Staphylococcus species is the most common cause of bacteremia. The intravenous catheter is usually the source. In the setting of neutropenia or clinical instability, the patient should be treated with vancomycin.
■S. aureus bacteremia is associated with a high likelihood of metastatic complications if not treated adequately. Intravascular devices should be removed. Complicated S. aureus bacteremia (persistently positive blood cultures, prolonged fever, metastatic infection, and endocarditis) requires 4 to 6 weeks of treatment. Many authorities recommend that transesophageal echocardiogram should be performed in every case to rule out endocarditis.
■Oxacillin and nafcillin are the drugs of choice for treating methicillin-susceptible S. aureus; vancomycin should be reserved for MRSA or the treatment of penicillin-allergic patients. Daptomycin may also be an alternative as long as there is no pulmonary involvement.
■Bacteremia with viridans group streptococci may cause overwhelming infection with sepsis and acute respiratory distress syndrome (ARDS) in the neutropenic patient; vancomycin therapy should be used until susceptibility results are known (most, but not all, isolates are susceptible to ceftriaxone and carbapenems).
■Risk factors for viridans group streptococci bacteremia include severe mucositis (particularly following treatment with cytarabine), active oral infection, and prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) or a fluoroquinolone.
■Enterococci often cause bacteremia in debilitated patients who have had prolonged hospitalization and have been on broad-spectrum antibiotics.
■VRE are an increasingly common cause of bacteremia and should be treated with linezolid (600 mg every 12 hours IV), daptomycin (6 mg/kg every 12 hours IV), or quinupristin–dalfopristin (7.5 mg/kg every 8 hours IV). There is no evidence at this time whether empirical treatment with these agents should be initiated in febrile neutropenic patients with known VRE colonization.
Gram-Positive Bacilli
■Clostridium septicum is associated with sepsis and metastatic myonecrosis during neutropenia. Treat with high-dose penicillin or a carbapenem.
■Listeria monocytogenes may cause bacteremia with or without encephalitis/meningitis in patients with defects in cell-mediated immunity. Ampicillin plus gentamicin is the treatment of choice. TMP/SMX can be used in penicillin-allergic patients.
■Other gram-positive bacilli such as Bacillus, Corynebacterium, and Lactobacillus species are common contaminants of blood cultures, but in the setting of neutropenia can cause true infection that is usually catheter related. Propionibacterium is almost always a contaminant, but it can cause infection of Ommaya reservoirs.
Gram-Negative Bacteremia
■Gram-negative bacteria in the blood should never be considered contaminants and should be treated immediately.
■Depending on the preliminary result from the Microbiology lab (variable from one laboratory to another), preliminary information may be nonexistent or may be specific enough (e.g., “enteric-like” or “Pseudomonas-like” gram-negative bacillus, to guide antibiotic choice), it may be safer to initiate therapy with two antimicrobials to ensure adequate coverage until susceptibility results are available. Combination therapy offers no convincing benefit once susceptibilities are known.
■Escherichia coli and Klebsiella species are the most prevalent gram-negative pathogens in neutropenic patients; however, the use of prophylactic antibiotics such as ciprofloxacin or TMP/SMX may increase the prevalence of more resistant enteric organisms such as Enterobacter, Citrobacter, and Serratia species. Some of these have practical importance, as they may carry an inducible β-lactamase that may result in treatment failure with third-generation cephalosporins like ceftazidime. Carbapenems, fluoroquinolones, and piperacillin–tazobactam may be used in this setting.
■The prevalence of strains of Klebsiella and E. coli that produce ESBL is increasing; carbepenems are the drugs of choice for these organisms.
■KPC pneumoniae and other enterobacteriaceae resistant to carbapenems are becoming more prevalent and have caused institutional outbreaks with high mortality. There are no comparative data, and the treatment usually involves combination or several drugs including colistin, tigecycline, and gentamicin. In vitro data suggest that the addition of doripenem may result in synergistic antibacterial activity.
■P. aeruginosa is one of the most lethal agents of gram-negative bacteremia in the neutropenic patient. Combination therapy should be started to ensure the patient is receiving at least one agent to which the isolate is susceptible.
■Stenotrophomonas maltophilia causes infection in patients who have been on broad-spectrum antibiotics or who have intravascular catheters; TMP/SMX is the treatment of choice. For the allergic patient, ticarcillin–clavulanate or moxifloxacin may be effective.
■Acinetobacter baumannii bacteremia is frequently associated with infected intravascular catheters in cancer patients and is often resistant to multiple antibiotics, including imipenem–cilastatin. Ampicillin–sulbactam, tigecyclin, or colistin may be effective, but consultation with an infectious diseases specialist should be sought.
Fungemia
■Candida species cause most cases of fungemia in cancer patients. The frequency of non-albicans candidemia is increasing, probably as a consequence of the widespread use of fluconazole prophylaxis.
■Non-albicans species are likely to be resistant to fluconazole and should be treated with caspofungin, anidulafungin, micafungin, amphotericin B, or a lipid formulation of amphotericin B.
■All patients with candidemia should undergo ophthalmologic evaluation with fundoscopic examination. In most cases, intravascular catheters should be removed.
■Although Candida is the most common yeast found in blood cultures, other fungi with different susceptibility patterns may also cause fungemia: in patients with defects in cell-mediated immunity (e.g., AIDS, alemtuzumab use, allogeneic bone marrow transplantation) C. neoformans, always resistant to echinocandins, should be considered. In neutropenic patients, Fusarium, Paecilomyces, and Trichosporonspecies may also cause fungemia. Treatment for these relatively uncommon fungal isolates should be chosen in consultation with infectious diseases.
Intravascular Catheter-Associated Infections
Definitions
■Exit-site infections are diagnosed clinically by the presence of erythema, induration, and tenderness within 2 cm of the catheter exit site.
■A tunnel infection is characterized by erythema along the subcutaneous tract of a tunneled catheter that extends 2 cm beyond the exit site.
■Catheter-associated bloodstream infection requires positive blood cultures (or a positive catheter-tip culture) and evidence that the catheter is the source of the bacteremia. The most easily available evidence is a differential time to positivity of ≥2 hours between the peripheral blood culture and the culture drawn through the catheter. The blood drawn through the catheter grows faster because the bacterial inoculum in the blood culture bottles is higher. Of note, this definition makes mandatory to draw blood cultures from the catheter as well as directly from a vein via a peripheral stick.
Management
■If a local infection is suspected, a swab of exit-site discharge should be sent for culture, in addition to blood cultures.
■Uncomplicated catheter-site infections (no signs of systemic infection or bacteremia) can be managed with local care and oral antibiotics such as dicloxacillin.
■If the patient has fever or there is significant cellulitis around the catheter site, vancomycin should be used empirically while awaiting culture results.
■Tunnel infections require IV antibiotics and removal of the catheter; empirical therapy should include vancomycin, as well as coverage of gram-negative bacilli such as ceftazidime, cefepime, or ciprofloxacin. Therapy can then be modified if an organism is identified.
■Septic thrombophlebitis also necessitates catheter removal, and anticoagulation can be considered. Surgical drainage is occasionally necessary.
■Catheter-related bloodstream infections caused by coagulase-negative Staphylococcus or gram-negative bacilli should be treated for 14 days with antibiotics. After the cultures are negative, therapy may be completed with oral antibiotics (linezolid or a fluoroquinolone) in stable nonneutropenic patients.
Indications for Removal of Intravascular Catheters
■Infected temporary catheters must be removed. Removal of permanent (e.g., tunneled lines and implanted ports) catheters should always be considered, and we remove them in the following situations:
•Tunnel (or pocket, in the case of implanted ports) infections.
•Persistently positive blood cultures after 48 to 72 hours of appropriate therapy, regardless of the pathogen.
•Septic thrombophlebitis.
•Blood cultures positive for
•S. aureus
•Bacillus spp.
•Mycobacteria spp.
•Candida spp.
•For other pathogens, including VRE, Corynebacterium jeikeium, and gram-negative pathogens like Pseudomonas and Stenotrophomonas, we occasionally attempt salvage therapy with systemic antibiotics and antibiotic lock. This approach should be considered only when the global risk of removing the catheter (refractory thrombocytopenia, paucity of IV access) is considered too high.
Skin and Soft Tissue Infections
■Soft tissue infections may represent local or disseminated infection.
■A biopsy for staining and culture for bacteria, mycobacteria, viruses, and fungi should be considered early in the evaluation of skin and soft tissue infections.
■Ecthyma gangrenosum often presents in neutropenic patients as a dark, necrotic lesion but can be quite variable in appearance. Typically a manifestation of P. aeruginosa bacteremia, it may also be caused by bacteremia due to other gram-negative bacilli. Antibiotic therapy with coverage of Pseudomonas should be initiated and early surgical involvement for possible debridement is imperative.
■VZV and herpes simplex virus (HSV) generally present as vesicular lesions and may be indistinguishable. Scrapings from the base of vesicles should be sent for direct fluorescent antibody (DFA) testing to diagnose VZV and for shell–vial culture or PCR to diagnose HSV. Treatment of VZV in the immunocompromised host is acyclovir 10 mg/kg IV every 8 hours, and for HSV acyclovir 5 mg/kg IV every 8 hours. We prefer to use IV acyclovir in immunocompromised hosts. In immunocompetent patients, oral acyclovir, valacyclovir, and famciclovir have been used successfully.
■Cancer patients are at increased risk for streptococcal toxic shock syndrome and severe soft tissue infections caused by Streptococcus pyogenes. Treatment is aggressive surgical debridement as needed and antibiotic therapy with penicillin G and clindamycin, as well as, in the case of shock, IV immunoglobulin (IVIG).
■Perianal cellulitis may develop in neutropenic patients. Antibiotic therapy should include gram-negative and anaerobic coverage (e.g., imipenem–cilastatin or meropenem as single agents or ceftazidime + metronidazole). A CT scan should be obtained to rule out a perirectal abscess. Incision and drainage may also be required in the setting of abscess or unremitting infection, but if possible should be delayed until resolution of neutropenia.
■Rash, including skin breakdown, is a common side effect of many new targeted therapies. Patients should have a detailed skin examination at each visit to evaluate for superinfections of their rash, as well as dermatology consultation as needed. Drugs commonly implicated include mAb like cetuximab (head and neck cancer, CRC) and tyrosine kinase inhibitor (TKI) like erlotinib (lung cancer) and sorafenib (renal cancer, HCC).
■Sweet syndrome can present with fever and cutaneous lesions that may resemble cellulitis, and should be considered in the differential diagnosis of fever and rash, particularly in patients with myeloid malignancies.
Sinusitis
■In immunocompetent patients, acute sinusitis is usually caused by S. pneumoniae, H. influenzae, and Moraxella catarrhalis, as well as S. aureus. Treatment is levofloxacin 500 mg daily or amoxicillin–clavulanate 875 mg twice daily.
■Sinusitis in immunocompromised hosts can also be caused by aerobic gram-negative bacilli, including Pseudomonas. Neutropenic patients are at high risk for fungal sinusitis.
■During neutropenia, sinusitis should be treated with broad-spectrum antibiotics, including coverage of Pseudomonas, and sinus CT scan and otolaryngology are appropriate. Biopsy should be obtained if there is any suspicion of fungal infection (e.g., bony erosion on CT scan, necrotic eschar of nasal turbinates) or if there is no response to antibiotic therapy within 72 hours.
■Aspergillus is the most common cause of invasive fungal sinusitis, but other molds such as Mucor and Rhizopus (which are resistant to voriconazole, the treatment of choice for aspergillosis) are increasingly recognized. When patients have been receiving voriconazole prophylaxis, the relative frequency of mucormycosis increases.
■If fungal sinusitis is confirmed, treatment is with surgical debridement and antifungal treatment, which should be started at maximum dosing:
•Amphotericin B 1 to 1.5 mg/kg/day.
•Lipid formulation of amphotericin B 5 to 7.5 mg/kg/day.
•Voriconazole may be substituted only after it is certain that the infection is not caused by Zygomycetes (Mucor, Rhizopus), which are not susceptible to voriconazole.
•Posaconazole requires 5 to 7 days to achieve therapeutic levels and is only available as an oral formulation with poor absorption. It should never be used to treat an infection that can progress quickly (like fungal sinusitis during neutropenia) but it can be a possible treatment alternative once the diagnosis is established and the disease stabilized by another agent.
Pneumonia
■Pulmonary infiltrates in the immunocompromised host can be due to infectious or noninfectious causes. It is important to obtain an etiologic diagnosis. We recommend early use of bronchoalveolar lavage (BAL) if a diagnostic sputum specimen cannot be obtained.
Pulmonary Infiltrates in the Neutropenic Patient
■Most cases of pneumonia during neutropenia are caused by gram-negative bacilli, including P. aeruginosa.
■The treatment should include the standard regimen for fever and neutropenia plus vancomycin for S. aureus and some agent for Legionella and other agents of community-acquired pneumonia (e.g., newer generation fluoroquinolone like levofloxacin or moxifloxacin, or macrolide like azithromycin in addition to ceftazidime).
■CT scan and bronchoscopy for BAL should be performed early, particularly if there is no prompt improvement.
■If pulmonary infiltrates appear while the patient is on broad-spectrum antibiotic therapy, the likelihood of fungal pneumonia is high. Empirical antifungal coverage with voriconazole, liposomal amphotericin B, or amphotericin B should be started immediately. Echinocandins should not be used for empirical fungal therapy for pulmonary infiltrates in neutropenic patients, as they have no activity against non-Aspergillus molds.
Fungal Pneumonia
■Fungal pneumonia is rare in the absence of neutropenia or corticosteroids.
■Aspergillus species are the most common disease-causing molds in cancer patients.
■Clinical presentation includes the following:
•Persistent or recurrent fever
•Development of pulmonary infiltrates while on antibiotics
•Chest pain, hemoptysis, or pleural rub
■In the setting of allogeneic HSCT, most cases of Aspergillus pneumonia occur after engraftment, when the patient is no longer neutropenic. The most important risk factors in this setting are graft-versus-host disease, corticosteroid use, and CMV disease.
■Demonstration of fungal elements in biopsy tissue is necessary for definitive diagnosis. When a biopsy is not possible, positive respiratory cultures (sputum or BAL fluid) are highly predictive of invasive disease in a high-risk patient.
■Galactomannan (Aspergillus) and ß-D-glucan are serologic assays used to diagnose invasive fungal infections. Galactomannan can also be determined in the BAL, where it has high sensitivity and specificity for aspergillosis.
■There are molds that do not produce either galactomannan or ß-D-glucan (e.g., mucor, rhizopus). This means that a negative test does not rule out invasive fungal infection.
■Positive serum galactomannan and ß-D-glucan (usually defined as two consecutive rising values when the tests are obtained twice weekly or every other day) can be helpful to identify fungal infections early.
■The treatment of choice for invasive aspergillosis is voriconazole 6 mg/kg IV every 12 hours for 24 hours, then 4 mg/kg IV. Other options include:
•High-dose lipid formulation of amphotericin B (5 mg/kg/day).
•Amphotericin B (1 to 1.5 mg/kg/day).
•Caspofungin (70 mg loading dose followed by 50 mg/day IV) has been approved for patients with invasive aspergillosis who are unresponsive to or intolerant of amphotericin B.
■Mucorales (previously known as zygomycetes) such as Rhizopus, Mucor, and Cunninghamella species are less common causes of pulmonary infection in neutropenic patients. They are voriconazole resistant but have variable susceptibility to posaconazole. Treatment should include high-dose amphotericin B (deoxycholate or lipid formulation). Early consideration should be given to surgical excision where feasible.
■Fusarium is a less common cause of pulmonary infection in neutropenic patients. Voriconazole or high-dose amphotericin can be tried. Response is usually contingent on neutrophil recovery.
■Dematiaceous fungi such as Scedosporium, Alternaria, Bipolaris, Cladosporium, and Wangiella species are rare causes of pneumonia in neutropenic patients. The best treatment is not well established, and consultation with an infectious diseases specialist is strongly advised.
Pulmonary Infiltrates in Patients with Defects in Cell-Mediated Immunity
■In addition to the common bacterial causes of pneumonia, patients with defects in cell-mediated immunity are at risk for infections with P. jirovecii, Nocardia species, and viruses (see below), as well as Legionella, mycobacteria, and fungi.
■Bronchoscopy for BAL should be performed to aid in diagnosis.
■Empirical antibiotics should include newer generation fluoroquinolone for coverage of bacterial pathogens including Legionella and TMP/SMX for coverage of Pneumocystis. Consideration should also be given to antifungal and antiviral agents, depending on the clinical presentation.
PneumocystisPneumonia
■Patients with pneumonia from P. jirovecii usually present with rapid onset of dyspnea, nonproductive cough, hypoxemia, and fever. Pneumocystis pneumonia (PCP) may have a more indolent presentation in HIV-infected patients and stem cell transplant recipients.
■Radiologic studies generally show diffuse bilateral interstitial infiltrates but can show focal infiltrates. The initial plain radiograph may be normal, but CT will almost always show characteristic ground-glass opacities. Pleural effusions are uncommon.
■Treatment should be started based on clinical suspicion: TMP/SMX 5 mg/kg IV every 8 hours (prednisone should be added if the pO2 is <70 mmHg).
■In TMP/SMX-allergic/intolerant patients, alternatives for serious disease include IV pentamidine, and for moderate disease dapsone–trimethoprim, atovaquone, or clindamycin–primaquine. The combination clindamycin–primaquine may be the treatment of choice in cases of TMP/SMX failure.
Nocardia
■Pneumonia from Nocardia species can cause a dense lobar infiltrate or multiple pulmonary nodules with or without cavitation.
■Diagnosis is made from material obtained at bronchoscopy, either by pathology or culture.
■Treatment is with TMP/SMX, which is given for 6 months. Depending on the species, imipenem–cilastatin + amikacin may also be used.
Viral Pneumonia
■Pneumonia due to respiratory viruses (respiratory syncytial virus [RSV], influenza, parainfluenza, adenovirus, and metapneumovirus) is more common in patients with defects in cell-mediated immunity like stem cell transplant recipients.
■The effect of antiviral treatment on the outcome of these viral respiratory infections is unclear. Anecdotal successes reported in case reports and case series have not been reproduced in controlled trials. Results seem to be better when treatment is initiated at the time of upper respiratory tract infection before progression to pneumonia.
■Influenza should be treated with neuraminidase inhibitors (most experience is with oral oseltamivir, 75 mg PO twice daily).
■RSV may be treated with aerosolized ribavirin 6 g daily delivered at a concentration of 20 mg/mL for 18 hours per day by a small particle aerosol generator unit (SPAG-2) via a face mask, ideally inside a scavenging tent to prevent environmental contamination or intermittently (2 g inhaled every 8 hours). Some experts recommend adding intravenous immunoglobulin (IVIG) or even the monoclonal antibody palivizumab, although there is no evidence that any of these interventions result in better outcome.
■Metapneumovirus and parainfluenza are also inhibited in vitro by ribavirin, but there is even less evidence than for RSV.
■Many strains of adenovirus are susceptible to cidofovir. Control of this infection, however, seems to be mainly related to the recovery of adenovirus-specific immunity.
■CMV pneumonitis is a significant complication of allogeneic stem cell transplants that typically develops between 40 and 100 days posttransplant and presents with fever, dyspnea, hypoxemia, and diffuse interstitial infiltrates. CMV pneumonia after day 100 is becoming more common and should be considered in patients with a history of previous CMV reactivation.
■CMV reactivation and disease have also been rarely observed in patients with HTLV-I associated adult T-cell leukemia/lymphoma and in patients treated with alemtuzumab.
■After allogeneic stem cell transplant, the presence of CMV in the BAL by culture is considered sufficient to establish the diagnosis. In other settings, tissue is required. Of note, identifying CMV in the BAL only by PCR is not diagnostic of CMV pneumonitis.
■Treatment of CMV pneumonia is with ganciclovir 5 mg/kg IV every 12 hours with IVIG 500 mg/kg every 48 hours for 3 weeks. Foscarnet (90 mg/kg every 12 hours) may be substituted for ganciclovir.
■Human herpes virus-6 (HHV-6), VZV, and (very rarely) HSV have also been associated with pneumonitis in the immunocompromised patient.
Gastrointestinal Infections
Mucositis
■The shallow, painful ulcerations of the tongue and buccal mucosa caused by chemotherapy can become superinfected with HSV or Candida.
■If severe, HSV infection is treated with acyclovir 5 mg/kg IV every 8 hours for 7 days. If the infection is less severe, valacyclovir 1,000 mg PO every 12 hours or famciclovir 500 mg PO every 12 hours can be used.
■Candidiasis can be treated locally with clotrimazole troches 10 mg dissolved in the mouth 5×/day, or systemically with fluconazole 200 mg PO/IV once, then 100 mg daily.
■Patients with fever and neutropenia with thrush should be covered empirically with systemic antifungals with activity against Candida species.
Esophagitis
■Odynophagia, dysphagia, and substernal chest discomfort can be a result of chemotherapy but may also be due to herpes or candidal infections.
■Endoscopy with biopsy should be performed when possible.
■If endoscopy and biopsy are not possible, empirical therapy with fluconazole for Candida and acyclovir for HSV is recommended. In neutropenic patients with fever and clinical symptoms of esophagitis, antibacterial therapy appropriate for upper GI flora should be added (e.g., ceftazidime + vancomycin or piperacillin–tazobactam or imipenem or meropenem).
■CMV can also cause esophagitis.
Diarrhea
■Clostridium difficile is the most common pathogen to cause diarrhea in cancer patients.
■Diagnosis can be made by detecting C. difficile toxin in the stool by immunoassay (EIA) or the toxin gene by PCR. Less commonly used tests include cytotoxicity assay and stool culture. It is important to be familiar with the diagnostic test used, as some toxin assays are not sensitive enough to rule out the infection with certainty. Conversely, some tests like PCR are sensitive enough that repeating them is not associated with increased yield.
■Treatment for mild/moderate cases is with metronidazole 250 mg PO four times a day or 500 mg PO three times a day. The antiparasitic agent itazoxanide (500 mg PO twice a day) may offer similar efficacy. In severe and/or refractory cases, vancomycin 125 to 250 mg PO four times a day should be used. Fidaxomicin 200 mg PO twice daily was as effective as oral vancomycin in a randomized clinical trial. Metronidazole can be given IV if patients are unable to tolerate oral therapy or have ileus. Treatment is continued for 10 to 14 days. The stool should not be retested for C. difficile toxin, as many patients may remain asymptomatic carriers.
■Recurrent infection after metronidazole therapy should be treated with a longer course of metronidazole before oral vancomycin therapy is initiated.
■Bacteria such as E. coli, Salmonella, Shigella, Aeromonas, and Campylobacter species, as well as parasites and viruses, are less common causes of diarrhea in cancer patients. Stool should be sent for culture of bacterial pathogens and examined for ova and parasites. Specific therapy should be directed against recovered pathogens when indicated.
Neutropenic Enterocolitis (Typhlitis)
■Typhlitis typically presents as abdominal pain, rebound tenderness, bloody diarrhea, and fever in the setting of neutropenia. The diagnosis should be entertained in every case of abdominal pain during neutropenia.
■Characteristic CT scan findings include a fluid-filled, dilated, and distended cecum, often with diffuse cecal-wall edema and possibly air in the bowel wall (pneumatosis intestinalis). However, the CT may be unremarkable in the early stages; it has a reported sensitivity of only 80%.
■Pathogens are typically mixed aerobic and anaerobic gram-negative bacilli (including Pseudomonas) and Clostridium species.
■Treatment is with broad-spectrum antibiotics including coverage of Pseudomonas (e.g., imipenem or meropenem or the combination ceftazidime or cefepime plus metronidazole plus vancomycin).
■Patients should be monitored closely for complications that may require surgical intervention, such as bowel perforation, bowel necrosis, or abscess formation.
Perforations/Fistulas
■Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, has been associated with a gastrointestinal perforation/fistula rate of 1% to 5%.
■Patients with colon cancer and ovarian cancer have been found to be at greatest risk.
■Other risk factors may include prior abdominal/pelvic irradiation, bowel involvement by tumor, or unresected colon cancer.
■Any patient on bevacizumab with abdominal pain or new rectal bleeding should have prompt evaluation for perforation/fistula with imaging, as well as broad-spectrum antibiotic therapy covering gram-negative bacteria and anaerobes.
Hepatosplenic candidiasis
■Hepatosplenic candidiasis typically presents as fever during neutropenia (sometimes after resolution of neutropenia) without localizing signs or symptoms.
■When neutropenia resolves, the patient may continue to have fever, develop right upper quadrant pain and hepatosplenomegaly, and have significant elevation in alkaline phosphatase.
■CT scan, ultrasound, or MRI will show hypoechoic and/or bulls-eye lesions in the liver and spleen and sometimes the kidneys.
■Stable patients can be treated empirically without biopsy if suspicion is high. Blood cultures are typically negative. If the diagnosis is in question, a liver biopsy is recommended. The diagnosis will be established by pathology showing granulomatous inflammation and yeast, as biopsy culture results are usually negative.
■Treatment consists of a prolonged course of fluconazole 400 to 800 mg daily. Caspofungin has also been effective.
Hepatitis B
■Hepatitis B reactivation can occur in chronic carriers who are undergoing cytotoxic chemotherapy, with lymphoma patients being at highest risk especially with rituximab administration.
■Risk factors include positive hepatitis B DNA, HBsAg, HBeAg, and young age.
■Lamivudine prophylaxis is recommended, 100 mg daily beginning 1 week prior to chemotherapy and for 8 weeks after completion of treatment.
Urinary Tract Infections
■In the presence of neutropenia, it is reasonable to treat bacteriuria even in the absence of symptoms. In the nonneutropenic patient, treatment should be reserved for symptomatic episodes.
■Patients with indwelling stents may have persistent microbial colonization and pyuria. Treatment should be initiated in neutropenic patients with pyuria even with a history of chronic asymptomatic pyuria.
■Candiduria may represent colonization in a patient with an indwelling urinary catheter, particularly in the setting of broad-spectrum antibiotics. Removal of the catheter is frequently sufficient to clear it.
■Persistent candiduria can occasionally cause infections such as pyelonephritis or disseminated candidiasis in immunocompromised patients. Additionally, candiduria can be indicative of disseminated candidiasis. However, treatment of asymptomatic candiduria with systemic antifungals has not been associated with improved outcomes overall.
■If a decision is made to treat, fluconazole 400 mg per day for 1 to 2 weeks is the treatment of choice. In the case of non-albicans candiduria, another -azole or amphotericin should be used. Caspofungin is minimally present in the urine, and there is no clinical experience in this setting.
Central Nervous System Infections
■Changes in mentation or level of consciousness, headache, or photophobia should be evaluated promptly with MRI and lumbar puncture.
■In addition to the usual bacterial causes of meningitis (S. pneumoniae, Neisseria meningitidis), Listeria and Cryptococcus should also be considered, particularly when a defect in cell-mediated immunity is present.
■For Listeria, the treatment of choice is ampicillin 2 mg IV every 4 hours in combination with gentamicin.
■For Cryptococcus, treatment is with liposomal amphotericin B 3 mg/kg/day or amphotericin B 0.5 to 0.7 mg/kg/day in combination with flucytosine 37.5 mg/kg every 6 hours for 2 weeks. If the patient improves (afebrile, cultures negative), therapy can be changed to fluconazole 400 mg daily.
■Encephalitis in patients with cancer is most commonly caused by HSV. Diagnosis is made by the presence of viral DNA in CSF and should be treated with acyclovir 10 mg/kg IV every 8 hours. Potential clinical indications for empirical HSV treatment include predominance of altered mentation symptoms and focal changes on EEG or MRI, especially in the temporal lobes.
■VZV, CMV, and HHV-6 are other less common causes of encephalitis.
■Progressive multifocal leukoencephalopathy (PML), caused by JC virus, presents with multiple nonenhancing white matter lesions and has been associated with rituximab and mycophenolate mofetil (MMF).
■Brain abscesses that develop during neutropenia are typically caused by fungi (most commonly Aspergillus and Candida). Bacterial abscesses may also be a local extension of infection (sinusitis, odontogenic infection), caused by mixed aerobic and anaerobic flora (streptococci, Staphylococcus, Bacteroides). Pending results from biopsy and cultures, we recommend empirical treatment with ceftazidime plus vancomycin plus metronidazole plus voriconazole.
Infectious Issues Secondary to Monoclonal Antibody Therapy
■The increased use of monoclonal antibodies, in particular those targeting leukocytes, has important implications for infectious disease.
■Alemtuzumab, an anti-CD52 antibody approved for chronic lymphocytic leukemia, results in profound depletion of cell-mediated immunity and places patients at risk for viral reactivation and infection with intracellular pathogens. Pneumocystis, HSV, and EBV infection, as well as CMV reactivation, are being seen regularly.
■Rituximab, a monoclonal antibody against CD20 used in lymphoma and leukemia treatment, causes B-cell depletion from 6 to 9 months and can also result in prolonged hypogammaglobulinemia and reactivation of viral hepatitis.
■Perforation and fistula are rare but serious side effects of bevacizumab.
■Cetuximab (anti-EGFR) is associated with acneiform rash and secondary bacterial infection.
PROPHYLAXIS
Antibacterial Prophylaxis
■Fluoroquinolones are the most commonly used antibiotics for prophylaxis against bacterial infections in neutropenic patients and can significantly reduce the frequency of gram-negative infections. However, they may increase the frequency of gram-positive infections and could conceivably result in the emergence of resistance among enteric gram-negative bacteria. Meta-analyses suggest fluoroquinolone prophylaxis may be associated with improved overall survival in patients with prolonged neutropenia. This approach is currently recommended for high-risk patients who are expected to remain neutropenic for more than 7 to 10 days. We start levofloxacin 500 mg PO the first day of neutropenia and continue until the ANC is ≥500/µL.
Antiviral Prophylaxis
HSV and VZV
■Prophylaxis against HSV should be considered in patients who are seropositive or have a history of herpetic stomatitis and are undergoing allogeneic stem cell transplant or highly immunosuppressive chemotherapy, including high-dose steroids and alemtuzumab. Patients treated with bortezomib are at high risk for VZV reactivation and should be considered for prophylaxis,
■In allogeneic transplant recipients we institute acyclovir prophylaxis at the beginning of the conditioning chemotherapy prior to transplant and continue for 1 year. This approach is effective for VZV prophylaxis, although a significant fraction of patients will develop shingles in the first few months after discontinuing acyclovir. In general, it is not considered necessary to routinely administer prophylaxis for HSV beyond the immediate peritransplant period.
■The drugs of choice are valacyclovir 500 mg PO once or twice daily or acyclovir 250 mg/m2 IV every 12 hours or 800 mg PO twice daily.
CMV
■Prophylactic ganciclovir can reduce the incidence of CMV disease, but its use is limited by myelosuppressive toxicity. Valganciclovir (the prodrug of ganciclovir) is also effective, but it seems to result in a higher frequency of myelosuppression.
■Patients who have undergone allogeneic stem cell transplant should be monitored for CMV replication by following CMV antigenemia or PCR weekly.
■If positive, patients should be treated with ganciclovir 5 mg/kg IV every 12 hours for 14 days followed by 5 mg/kg IV daily until CMV antigenemia or PCR results are negative 1 week apart.
■Alternative treatments include (a) foscarnet 60 to 90 mg/kg IV every 12 hours for 14 days followed by 90 mg/kg daily, (b) valganciclovir 900 mg IV every 12 hours for 14 days followed by 900 mg daily, or (c) cidofovir 5 mg/kg IV weekly for 2 weeks followed by 5 mg/kg IV every other week (very limited evidence is available regarding use of cidofovir for this indication).
Pneumocystis jirovecii Pneumonia Prophylaxis
■Prophylaxis against Pneumocystis is generally administered to patients during the 6-month poststem cell transplant period or after being treated with alemtuzumab. Patients with a history of PCP or with brain tumors on high-dose steroids should also receive prophylaxis.
■The regimen of choice is 160 mg TMP/800 mg SMX PO daily 3 days a week.
■Alternative treatments include (a) dapsone 100 mg PO daily (rule out G6PDH deficiency before using dapsone), (b) inhaled pentamidine 300 mg every 4 weeks, or (c) atovaquone 1,500 mg daily.
Antifungal Prophylaxis
■Fluconazole 400 mg PO/IV daily has been the regimen of choice. Of note, fluconazole has no activity against molds like Aspergillus.
■An alternative regimen is itraconazole 200 mg IV every 12 hours for 2 days followed by 200 mg IV daily for 12 days followed by 200 mg PO every 12 hours, but this is frequently limited by gastrointestinal toxicity.
■Posaconazole 200 mg PO three times a day has been shown to be more effective than fluconazole/itraconazole in patients with prolonged neutropenia. It may also result in less cases of aspergillosis in patients receiving corticosteroids for graft-versus-host disease. It is reasonable to choose posaconazole when the risk of mold infection is considered significant.
■Prophylaxis should be continued until 100 days posttransplant and until immunosuppressants have been discontinued.
■Use of fluconazole has led to increased frequency of fluconazole-resistant infections such as Candida tropicalis, C. parapsilosis, and C. krusei.
REVIEW QUESTIONS
1.A 26-year-old woman with AML in second remission is undergoing allogeneic stem cell transplantation. On day +7 after an allogeneic BMT, she started with fever (38.6°C). The patient is hemodynamically stable. The physical examination reveals ulcers and redness in mouth and pharyngeal area. There is no erythema or tenderness around her right Hickman catheter exit site or tunnel. The rest of physical examination is unremarkable. The ANC is 0.07 (70/µL). Which of the following is the best answer regarding the recommended management?
A.Obtain blood cultures and start oral antibiotics because this is a low-risk patient.
B.Obtain blood cultures and start IV cefepime.
C.Start vancomycin and cefepime because the patient has a central line that may be the source of the fever.
D.Obtain blood cultures, and start cefepime and vancomycin, imipenem or meropenem because the patient has mucositis.
E.Obtain blood cultures and observe for 1 hour to be sure that the fever is real.
2.The patient was started on cefepime but the fever persisted and after 48 hours her blood pressure dropped from 130/80 to 90/65, and her heart rate was 130. Blood cultures came positive for coagulase-negative Staphylococcus(one out of six bottles). A report from a previous hospitalization stated that the patient was colonized with VRE and that she had had a UTI 3 months prior caused by an ESBL-producing Klebsiella pneumoniae. What is the best approach at this time?
A.Add empirical antifungal treatment with amphotericin B.
B.Add an antibiotic with VRE coverage to enterococcus (e.g., linezolid) and remove the catheter.
C.Add vancomycin to the cefepime, and do not remove the catheter.
D.Add vancomycin to the cefepime, and remove the catheter.
E.Change antibiotics to meropenem and daptomycin IV and add an echinocandin as empirical antifungal.
3.Cultures were positive for ESBL-producing Klebsiella pneumoniae. The patient’s blood pressure and heart rate recovered with the new antibiotic regimen and fluid resuscitation, but the fever never went away for more than 24 hours. Five days later the patient continues to be febrile and neutropenic. The blood pressure is stable. What do you think is the best strategy at this point?
A.Maintain same antimicrobial agents until the ANC more than 0.5, unless there is further hemodynamic instability.
B.Stop daptomycin because VRE was never found in the blood and continue with meropenem.
C.Get a CT scan of the chest looking for signs of fungal infection.
D.Get a CT scan of the chest and sinuses to look for signs of fungal infection and start amphotericin B.
E.Discontinue the meropenem to test for β-lactam-induced drug fever.
4.A patient with non-Hodgkin lymphoma will be treated with the combination of CHOP chemotherapy and rituximab mAb. Which of the following test has to be done before starting this treatment?
A.PPD
B.Galactomannan
C.Hepatitis B serology
D.Hepatitis C serology
Suggested Readings
1.Freifeld A, Bow E, Sepkowitz K, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):e56-e93.
2.Gea-Banacloche J, Palmore T, Walsh T, et al. Infections in the cancer patient. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Lipincott Williams & Wilkins; 2008.
3.Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer Risk Index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038-3051.
4.Mermel L, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:1-45.
5.Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001;32(9):1249-1272.
6.NCCN Practice Guidelines. Prevention and Treatment of Cancer-Related Infections. v.1.2008. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
7.Picazo JJ. Management of the febrile neutropenic patient: a consensus conference. Clin Infect Dis. 2004;39:S1-S6.
8.Pizzo PA. Fever in immunocompromised patients. N Engl J Med. 1999;341:893-900.
9.Tomblyn, M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143-1238.
10.Vidal L, Paul M, Ben Dor I, Soares-Weiser K, Leibovici L. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials. J Antimicrob Chemother. 2004;54:29-37.
11.Walsh TJ, Pappas P, Winston DJ, et al. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med.2002;346:225-234.
12.Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351:1391-1402.
13.Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clin Infect Dis. 2004;39:S38-S43.