Infectious Complications in Oncology 35
Lekha Mikkilineni and Juan C. Gea-Banacloche
FEVER
Fever is the most common sign of infection, and a common 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 is a very common manifestation of cytokine release syndrome (CRS), which is frequently seen following many current forms of immunotherapy (cellular therapies, monoclonal antibodies like blinatumomab). Management of fever during immunotherapy may be particularly challenging, but the general rules of neutropenic fever should apply when the absolute neutrophil count (ANC) is <500/ mm3.
FEVER IN THE NEUTROPENIC CANCER PATIENT (NEUTROPENIC FEVER)
Neutropenia, the most important risk factor for bacterial infection in cancer patients, is defined as an ANC <500/mm3, or ANC ≤1,000/mm3, with a predicted decline to <500/mm3 within 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 based on biological features and access to care (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 (e.g., typhlitis with negative blood cultures). 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 of choice may vary with the clinical situation and the preexistent use of antifungal prophylaxis. In the absence of antifungal prophylaxis, the most common fungal pathogen causing persistent fever is Candida albicans. If antifungal prophylaxis was being administered, Aspergillus and non-albicans Candida become more likely. Randomized controlled trials support the empirical addition of amphotericin B (deoxycholate or liposomal), voriconazole, and caspofungin for persistent fever. The choice varies based on what (whether) antifungal prophylaxis was being used and an estimate of the risk. It is appropriate to look for invasive fungal infection by blood cultures and computed tomography (CT) of chest and possibly 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 following the administration of broad-spectrum antibiotics for an episode of neutropenic fever. In this situation an infectious cause is identified in most cases (as opposed to the initial fever, in which most frequently no cause is found) and both breakthrough bacterial and fungal infections are possible. Management includes changing (or adding, if antifungals were not part of the regimen) both antibiotics and antifungals plus diagnostic studies (CTs as outlined above). Drug-resistant bacteria are increasing (e.g., extended-spectrum beta-lactamase-producing (ESBL) gram-negative bacilli, carbapenem-resistant Enterobacteriaceae (CRE), vancomycin-resistant enterococcus (VRE)), so the antibiotic choice should be guided by local prevalence. In institutions where CRE are common, early addition of colistin or substitution of ceftazidime-avibactam may be appropriate. Conversely, in an institution with high frequency of ESBLs early switch to imipenem or meropenem may be the best antibacterial strategy 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 35.1Approach 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 should be obtained. Evidence suggests a chest X-ray adds little information unless there are respiratory signs or symptoms, but we routinely recommend it as adding potentially useful baseline information.
Blood cultures: Two sets of blood cultures are more sensitive than a single set for the diagnosis of bacteremia. There are data supporting the practice of drawing all cultures from the central line (sampling all lumens) in cancer patients to simply diagnose bacteremia. However, 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 simultaneously. 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, not to initially cover any and all conceivable pathogens.
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 gram-negative bacilli including Pseudomonas. This may be achieved by using single agents (“monotherapy”) 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 (see Table 35.1)
Effective antibiotic combinations include one of the aforementioned β-lactams plus an aminoglycoside (choice based on local resistance) or colistin or polymyxin B. Ciprofloxacin could 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 polymyxin B are being used more frequently with the increasing prevalence of KPC and multiresistant Acinetobacter baumannii.
TABLE 35.1Resistant Bacteria: What Everybody Should Know
Resistant to | Treat With | Things to Remember | |
Gram positive | |||
Methicillin-resistant staphylococcus aureus (MRSA) | Semi-synthetic penicillins, first-, second- and third-generation cephalosporins, carbapenems | Vancomycin, daptomycin, ceftaroline | Community-acquired MRSA is frequently susceptible to clindamycin, doxycycline, and TMP/SMX |
Vancomycin-resistant enterococcus (VRE) | Vancomycin and all beta-lactams | Linezolid, daptomycin, quinupristin/dalfopristin. Maybe tigecycline and oritavancin | Microbiological success is no higher than 40%, there is no clinical evidence to prefer one agent over another |
Mycobacterium abscessus | Almost everything | Infectious Diseases support required. Combination therapy required, usually with meropenem + amikacin + azithromycin ± linezolid | Respiratory colonizer AND potential pathogen, particularly in patients with abnormal airways/lungs |
Gram negative | |||
SPICE Enterobacteriaceae (Serratia, Providentia, Indole-positive Proteus, Citrobacter, and Enterobacter) | They may seem susceptible, then become resistant to third-generation cephalosporins (like ceftriaxone and ceftazidime) during treatment | Carbapenems, fluoroquinolones (ciprofloxacin, levofloxacin), maybe cefepime | Your Micro lab should add a note saying that even if it looks susceptible by antibiogram, the isolate may become resistant during treatment |
ESBL-producing Enterobacteriaceae (most commonly E. coli and Klebsiella) | All cephalosporins | Carbapenems (use of piperacillin-tazobactam when the antibiogram shows the isolate is susceptible may be considered, but is discouraged by most authorities) | The antibiogram will show the resistance to third generation cephalosporins |
CRE (Carbapenem-Resistant Enterobacteriaceae) Any Enterobacteriaceae may carry a gene conferring resistance to carbapenems through carbapenemases like KPC, OXA, MBLs) | All cephalosporins and carbapenems | Infectious Diseases support required. Some may respond to ceftazidime-avibactam, many will require combination therapy with amikacin and/or colistin | It is important to be familiar with the methodology of the Micro lab and ask for help interpreting the antibiogram. CRE produce carbapenemases, and these are of great epidemiological (as well as clinical) significance. Other mechanisms of resistance to carbapenems (e.g., porin genes) are less severe. |
All commonly used antibiotics | Infectious Diseases support required. Combination of colistin + tigecycline + gentamicin ± doripenem has been used | Inhaled colistin has been used in cases of MDR Acinetobacter or Pseudomonas, but its efficacy is far from clear | |
MDR Pseudomonas aeruginosa | All commonly used antibiotics | Infectious Diseases support required. Combination of colistin (or polymixin B) and other agents may be required | |
Stenotrophomonas maltophilia | Intrinsically resistant to carbapenems and aminoglycosides | TMP/SMX is the treatment of choice, levofloxacin and moxifloxacin and ceftazidime (if susceptible in vitro) are other options. Tigecycline and colistin have been used with variable results | Think of it when a patient on meropenem develops breakthrough gram-negative bacteremia |
Role of Vancomycin and Other Agents with Gram-positive Coverage
Gram-positive coverage with vancomycin should be part of the initial empirical regimen under the following circumstances:
Severe sepsis or septic shock (to ensure coverage of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and Streptococcus mitis)
Pneumonia (consider it “healthcare-associated pneumonia”)
Soft tissue infection (cellulitis, necrotizing fasciitis)
Clinically suspected catheter-related infections (e.g., because of tenderness or purulent drainage at the exit site; NOT the mere presence of an intravascular device)
Severe mucositis or other risk factors for infection with Streptococcus mitis (oral infection, use of prophylaxis with fluoroquinolones or TMP/SMX, high-dose Ara-C, use of H2 blockers)
Known colonization with methicillin-resistant Staphylococcus aureus (MRSA) or penicillin-resistant Streptococcus pneumoniae (PRSP) (this is important, and frequently forgotten)
Addition of vancomycin to the initial regimen:
Persistent fever is NOT an indication for adding vancomycin, because a randomized controlled trial showed that adding vancomycin in this setting was not better than adding placebo.
Blood cultures that grow 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 as follows (see Table 35.2):
Gram positive cocci in clusters: usually Staphylococcus (it may be Staphylococcus aureus or coagulase-negative Staphylococcus)—vancomycin provides adequate coverage. Rarely (typically in acute leukemia patients already on broad Gram-negative coverage) it may mean Rothia mucilaginosa (previously Stomatococcus mucilaginosus) a dangerous cause of bacteremia and meningitis best treated by the combination vancomycin + meropenem.
Gram positive cocci in pairs and short chains: This may be Enterococcus or Streptococcus pneumoniae—the clinical setting should support one or the other (hospitalized patient, neutropenic, on a third generation cephalosporin: Enterococcus; outpatient with pneumonia at risk for encapsulated bacteria—e.g., multiple myeloma—Streptococcus pneumoniae). In an institution with high frequency of VRE, daptomycin or linezolid are adequate first line empirical agents here.
Gram-positive cocci in long chains: Streptococcus viridans, it may be Streptococcus mitis associated with mucositis—vancomycin is appropriate.
There is no good-quality evidence to suggest that patients known to be colonized with VRE should initially receive empirical coverage for it with linezolid or daptomycin.
In the case of documented VRE infection, the choice between daptomycin, linezolid, quinupristn–dalfopristin, and tigecycline is not based on clinical outcome data, but on theoretical considerations and local resistance patterns.
Daptomycin is inactivated by surfactant in the lungs and should not be used to treat pneumonia.There is good evidence, however, that it is as effective as vancomycin or oxacillin to treat staphylococcal bacteremia.
TABLE 35.2How to Interpret Preliminary Information from Blood Culture Reports
Micro report | What it means | What to Do | Caveats |
Blood culture positive for Gram-positive cocci in clusters | Coagulase-negative Staphylococcus, Staphylococcus aureus (In a patient with acute leukemia and prolonged neutropenia you may worry about Rothia mucilaginosa) | Repeat blood cultures from the line AND a peripheral stick (the peripheral is to check time to positivity and decide whether the line is the source of infection) and start vancomycin | Coagulase-negative Staphylococcus and Staphylococcus aureus are very different: S. aureus can kill your patient in hours, but almost no one dies of coagulase-negative Staph. bacteremia |
Blood culture positive for Gram-positive cocci in pairs | Enterococcus (including VRE) Streptococcus pneumoniae Rarely, Streptococcus agalactiae (Group B Streptococcus) | Repeat blood cultures and start either 1) vancomycin if Streptococcus pneumoniae is more likely or the prevalence of VRE is low OR 2) daptomycin if Enterococcus is more likely and there is high prevalence of VRE OR 3) linezolid if you can’t tell and are too tired to think | Enterococcus and pneumococcus may be indistinguishable by Gram stain, but patients are usually very different (e.g., a post allo-HCT with chronic GVHD and pneumonia is likely to have S. pneumoniae whereas a neutropenic patient on cefepime with abdominal pain is likely to have Enterococcus). Daptomycin should not be used for pulmonary infections |
Blood culture positive for Gram-positive cocci in chains | Streptococcus If there is severe mucositis, think S. mitis; if there are abscesses around, think of S. anginosus, S. constellatus or S. intermedius (the trio called S. milleri in the UK) Remember Streptococcus pyogenes (Group A Streptococcus) and Streptococcus agalactiae (Group B), particularly in patients with soft tissue infection and at risk for infection with encapsulated bacteria (e.g., multiple myeloma) | Add vancomycin | Two oncology scenarios worth remembering: Streptococcus mitis bacteremia in neutropenic patients with severe mucositis and other risk factors (it can cause ARDS and septic shock, see text) and Streptococcus gallolyticus, formerly Streptococcus bovis in patients with colon cancer (sometimes not previously known). |
Diphtheroids (skin contaminant) Corynebacterium JK (line infection) Listeria monocytogenes (bacteremia and meningitis in immunocompromised) Clostridium (typhlitis or metastatic gangrene with C. septicum) Bacillus (catheter-related bacteremia) Lactobacillus Propionibacterium acnes (contaminant) Mycobacteria (line infection) | Infectious Diseases support required. The possibilities are too many and with too different clinical implications | As you can see by the possible etiologies, there is no way to give a simple, straightforward recommendation. Vancomycin would be “the right answer” most of the time, but it does not cover Listeria, Lactobacillus or mycobacteria and treatment is probably not needed for “diphtheroids” and P. acnes. Just call for help. | |
Blood culture positive for Gram-negative rods, “enteric-like” or “lactose-fermenting” | Enterobacteriaceae (e.g., E.coli, Klebsiella, Enterobacter) | If your institution does not have CREs, imipenem or meropenem will cover 100% of these. If CREs are highly prevalent, add colistin or switch to ceftazidime-avibactam | The important information from Micro is that this SHOULD NOT BE Pseudomonas, Acinetobacter or Stenotrophomonas (remember, preliminary means NOT definitive). |
Blood culture positive for “Pseudomonas- like” gram-negative rods | Pseudomonas aeruginosa, much less likely Stenotrophomonas maltophilia or Burkholderia | Two antibiotics with activity against your institution’s P. aeruginosa (e.g., ceftazidime + tobramycin or colistin) | Pseudomonas aeruginosa should be covered empirically with two antibiotics until final susceptibilities are known. |
Blood culture positive for “non-fermenting Gram-negative rods” | This includes Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia and a long-list of not very pathogenic bacteria that commonly cause catheter infection in immunocompromised cancer patients (Alcaligenes, Chryseobacterium, Comomonas, Sphingomonas, Elizabethkingia among others) | Infectious Diseases support required. The general concept is that you should consider empirical addition of TMP/SMX or levofloxacin (depending what antibiotic the patient was on), as some of the possibilities are resistant to beta-lactams | No easy answer. Meropenem is the treatment of choice for Burkholderia, and completely ineffective against Stenotrophomonas. Just call for help. |
In the cancer patient, Acinetobacter should come to mind first | Institutional pattern of resistance dictates the choice | Acinetobacter may be difficult to identify on Gram stain. “Coccobacilli” is a term that should be avoided | |
Blood culture positive for Gram-negative cocci | Neisseria meningitidis and Neisseria gonorrheae are uncommon in the cancer patient. Moraxella is a possibility. If it is the anaerobic bottle only Veillonella should be considered | A carbapenem is the easy answer, but this is uncommon and it would be better to call Infectious Diseases |
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, significant comorbidities (e.g., COPD, heart failure) or with expected prolonged neutropenia. Low-risk patients do not exhibit any high-risk factors and their neutropenia is expected to be short lived (< 7 days). These patients may 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 the 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 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 after 48h 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
Candida and Aspergillus infections are most common and increase in frequency with increased duration of neutropenia. An antifungal agent (see Table 35.3) 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. Mould infections seldom cause septic shock.
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, aiming for a serum concentration >2 mcg/mL.
Caspofungin, 70 mg IV loading dose followed by 50 mg IV daily.
Posaconazole, 300 mg IV every 12 hours twice loading dose followed by 300 mg IV daily (no data on empirical treatment as opposed to the treatment of documented infection).
Isavuconazole, 200 mg IV every 8 hours for six doses loading followed by 200 mg IV daily (no data on empirical treatment as opposed to treatment of documented infection).
TABLE 35.3Basic Information about Commonly Used Systemic Antifungal Agents
Antifungal | Spectrum | Notable resistant fungi* | When to use | Special concerns |
Polyene | ||||
Amphotericin B (deoxycholate and lipid formulations) | Most candida, aspergillus and agents of mucormycosis | Candida lusitaniae, Aspergillus terreus, Paecilomyces lilacinus | Treatment of choice for mucormycosis. Treatment of choice for cryptococcosis. As effective as echinocandins for candidiasis. Effective in persistent fever. Inferior to voriconazole for aspergillosis. | Nephrotoxicity. Loss of glomerular filtration rate may be minimized by “salt loading,” but tubulopathy with loss of Mg and K cannot be prevented. |
Echinocandins Different trials have used different echinocandins in different ettings, but they are considered essentially interchangeable for practical purposes | Candida and Aspergillus | Cryptococcus and all moulds other than Aspergillus | Treatment of choice for candidiasis. | Poor penetration in eye, CSF and urine |
Caspofungin | Good data for persistent fever Weak (but some) data for aspergillosis. | |||
Micafungin | Good data for prophylaxis during neutropenia. Weak (but some) data for aspergillosis. | |||
Anidulafungin | Good data for combination therapy with voriconazole in aspergillosis | |||
Azoles | All the azoles interfere with the hepatic metabolism of multiple drugs used in Oncology (e.g., corticosteroids, vincristine, cyclophosphamide, calcineurin inhibitors) and have the potential for significant drug interactions. | |||
Candida albicans | Candida krusei. All moulds | Best evidence for prophylaxis during neutropenia and for Candidiasis. Cryptococcosis. Coccidioidomycosis. | Hepatotoxicity | |
Voriconazole | Candida, Cryptococcus, Aspergillus, most hyaline moulds | Agents of mucormycosis Paecilomyces variotii | Treatment of choice for aspergillosis | Significant individual variability on serum levels achieved makes therapeutic drug monitoring advisable Hallucinations, visual disturbances and hepatotoxicity Photosensitivity and possibly fluorosis with long-term use |
Posaconazole | Candida, aspergillus, most moulds including some agents of mucormycosis | Best data for antifungal prophylaxis during prolonged neutropenia. Probably as effective as voriconazole for aspergillosis (but no RCT yet). Active against some agents of mucormycosis. | Hepatotoxicity may be less than with voriconazole | |
Isavuconazole | Candida, Aspergillus, most moulds including some agents of mucormycosis | Equivalent to voriconazole for aspergillosis in a RCT. FDA-approved for mucormycosis based on comparison with registry controls. | Less variability in levels than voriconazole or posaconazole. Less hepatotoxicity than voriconazole. No prolongation of Q-T interval. Activity against mucormycosis still questionable |
For persistent fever, amphotericin, caspofungin, and possibly voriconazole (not-FDA approved for this indication) 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 (CT chest, possibly CT sinus, CT of abdomen and pelvis if there are signs of intraabdominal infection or abnormal liver enzymes). A different approach suggests 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.
The IV formulation of posaconazole allows loading and obtaining therapeutic levels early, so it may be now considered another alternative for treatment of suspected or proven fungal infections (the previous oral formulation did not achieve therapeutic levels for 5 to 7 days) but clinical evidence supporting is use as treatment (as opposed to prophylaxis) is still scant. Isavuconazole has shown to be non-inferior to voriconazole in a randomized controlled trial and similar to amphotericin for the treatment of mucormycosis in a case-control study.
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, we recommend 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.
Limited evidence suggests that if no infection is found and the patient becomes afebrile it is possible to discountinue antibiotics after 48 hours without fever, being aware that some patients will become febrile again and require restarting the antibiotics.
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 the 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 35.4).
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
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. 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 of S. aureus bacteremia 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 (Streptococcus mitis) 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). Early information from the microbiology lab would likely be “gram-positive cocci in long chains.”
Risk factors for Streptococcus mitis bacteremia include severe mucositis (particularly following treatment with cytarabine), active oral infection, prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) or a fluoroquinolone and H2-blockers.
Enterococci (intrinsically resistant to all cephalosporins) often cause bacteremia in debilitated patients who have had prolonged hospitalization and have been on broad-spectrum antibiotics.
VRE is 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). Tigecycline (100 mg IV loading followed by 50 mg IV every 12 hours) has also been used. The overall success rate of treatment for VRE bacteremia is only around 40%.
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 and other neurosurgical devices.
Gram-negative Bacteremia
Gram-negative bacteria in the blood should never be considered contaminants and must 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 (See Table 35.2). Depending on institutional patterns and preliminary information 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 over single agent 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 which may carry an inducible β-lactamase (AmpC) 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.
Klebsiella pneumoniae carrying the KPC carbapenemase and other CRE 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 of the combination. Some CRE may be successfully treated with ceftazidime-avibactam 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) every 8 hours IV.
P. aeruginosa is one of the most lethal agents of gram-negative bacteremia in the neutropenic patient. Pending susceptibility results, combination therapy should be started to broaden the antimicrobial spectrum and 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 (frequently carbapenems) or who have intravascular catheters; TMP/SMX is the treatment of choice. For the allergic patient, ceftazidime or moxifloxacin may be effective. S. maltophilia may show in vitro susceptibility to tigecyline and colistin, but the clinical efficacy of these agents is unknown.
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.
The treatment of choice for candidemia is an echinocandin or amphotericin B.
Fluconazole is reliably effective against Candida albicans. 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) C. neoformans, always resistant to echinocandins, should be considered. In neutropenic patients, Fusarium, Scedosporium, and Trichosporon species may also cause fungemia. Treatment for these relatively uncommon fungal isolates should be chosen in consultation with infectious diseases.
Intravascular Catheter-associated Infections
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 peripheral blood cultures (or a positive catheter-tip culture) and evidence that the catheter is the source of the bacteremia. The most readily 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 drawn through the catheter (where the bacteria-colonized biofilm lays) is higher. Of note, this definition makes necessary to draw blood cultures from the catheter as well as directly from a vein via a peripheral stick to make the diagnosis of catheter-related bacteremia.
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 should 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 VZV or 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). The addition of clindamycin to penicillin G or ampicillin results in improved outcome, possibly because its action inhibiting protein (hence toxin) synthesis.
Perianal cellulitis may develop in neutropenic patients. Antibiotic therapy should include gram-negative and anaerobic coverage (e.g., imipenem–cilastatin or meropenem or piperacillin-tazobactam 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.
In immunocompromised hosts, sinusitis 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 consult 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) as well as Fusarium and, occasionally, dematiaceous molds like Alternaria, 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 or isavuconazole given IV, with a very broad antifungal spectrum that covers most agents of fungal sinusitis, may be an alternative. If there is suspicion of mucormycosis we consider amphotericin the treatment of choice.
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 antibiotic active against Legionella and other agents of community-acquired pneumonia (e.g., newer generation fluoroquinolone like levofloxacin or moxifloxacin, or macrolide like azithromycin in addition to cefepime).
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 moulds and their activity against Aspergillus is not known to be equivalent to voriconazole or amphotericin B.
Fungal pneumonia is rare in the absence of neutropenia or corticosteroids.
Aspergillus species are the most common disease-causing molds in cancer patients.
Lack of systemic toxicity is characteristic. 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 cannot 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. We routinely add an echinocandin to voriconazole until we document a therapeutic serum voriconazole level.
Other options include
•Isavuconazole, 200 mg IV every 8h for six doses loading followed by 200 mg IV daily
•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 and isavuconazole. 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, isavuconazole, 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 infectious diseases is strongly advised.
Pulmonary Infiltrates in Patients on High-dose Corticosteroids or with Other 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 and Nocardia. Consideration should also be given to antifungal and antiviral agents, depending on the clinical presentation.
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, stem cell transplant recipients, and patients on ibrutinib.
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 mm Hg or there is an A-a gradient >35 mm Hg).
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. Radiologically it may be indistinguishable from aspergillosis.
Diagnosis is made from material obtained at bronchoscopy, either by pathology or culture. Culture may take 4 to 7 days.
Antibiotic susceptibility varies with the species, although most are susceptible to TMP/SMX. Imipenem–cilastatin or meropenem and amikacin are also effective against the majority of isolate. Treatment is usually given for 6 months to 1 year. Depending on the species, Nocardia frequently causes disseminated infection involving the CNS. We recommend obtaining MRI with gadolinium in any patient with nocardiosis.
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. In immunocompromised patients respiratory virus have been associated sometimes with high fever, and once pneumonia is established there is risk of progression to respiratory failure and death.
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). The unproven efficacy and high cost of inhaled ribavirin have resulted in an increase of the use of oral ribavirin 600 to 800 mg PO bid for RSV infectio. 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 and some to ribavirin. Control of this infection, however, seems to be mainly related to the recovery of adenovirus-specific immunity.
CMV pneumonia 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. Late CMV pneumonia (after day 100) may be becoming more common and should be considered in patients with a history of previous CMV infection.
CMV infection and disease, typically restricted to allogeneic stem cell transplant recipients and AIDS patients, have also been rarely observed in patients with HTLV-I associated adult T-cell leukemia/lymphoma and patients treated with alemtuzumab.
After allogeneic stem cell transplant, the detection by culture of CMV in the BAL 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 pneumonia (the test is too sensitive, quantitative PCR may help).
Treatment of CMV pneumonia is with ganciclovir 5 mg/kg IV every 12 hours. The addition of IVIG 500 mg/kg every 48 hours for 3 weeks may be considered, but there is little evidence IVIG helps . Foscarnet (90 mg/kg every 12 hours) may be substituted for ganciclovir.
Gastrointestinal Infections
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. Milder infection may be treated with valaciclovir 1,000 mg PO every 12 hours or famciclovir 500 mg PO every 12 hours.
Candidiasis can be treated locally with clotrimazole troches 10 mg dissolved in the mouth 5×/day, nystatin “swish and swallow” 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.
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.
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 immunoassays 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. In fact, PCR cannot differentiate between a patient colonized with C. difficile and diarrhea caused by some other reason and a patient with true C. difficile–associated disease (CDAD).
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.
Recalcitrant CDAD has been successfully treated by fecal microbiota transplantation.
Bacteria such as E. coli, Salmonella, Shigella, Aeromonas, and Campylobacter species, as well as parasites like Giardia and Cryptosporidium and viruses like norovirus and rotavirus are less common causes of diarrhea in cancer patients. Defects in cell-mediated immunity increase the likelihood of some of these pathogens. Stool should be sent for culture of bacterial pathogens. Stool should be sent for ova and parasites (O & P) on three consecutive days. Multiplex PCR in the stool is available and can detect more than 20 different pathogens.
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, although it is most common during prolonged, profound neutropenia during the treatment of acute leukemia.
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) and anaerobes.
Patients should be monitored closely for complications that may require surgical intervention, such as bowel perforation, bowel necrosis, or abscess formation.
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 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.
Blood cultures are typically negative. A liver biopsy is recommended, since other fungal infections, tuberculosis and lymphoma may show similar findings. 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 virus (HBV) 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.
Entecavir prophylaxis (0.5 mg/d) is recommended for patients with serological evidence consistent with past Hepatitis B, including those with undetectable HBV DNA, beginning 1 week before chemotherapy and for several months after completion of treatment. Entecavir has shown to be superior to lamivudine in randomized trials.
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 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 subsequently 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.
Toxoplasmosis may present with multiple intracranial ring-enhancing lesions, frequently involving the basal ganglia. It is mainly an early complication of allogeneic stem cell transplant, but it has also been described after alemtuzumab.
Nocardia (discussed above under pulmonary infections) may present as single of multiple brain abscess, usually on patients who are receiving corticosteroids.
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 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
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 acyclovir 250 mg/m2 IV every 12 hours or 800 mg PO twice daily or valaciclovir 500 mg PO once or twice daily.
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 may result in a higher frequency of myelosuppression if the dose is not adjusted for weight and renal function.
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 prophylaxis options include (a) dapsone 100 mg PO daily (rule out G6PDH deficiency before using dapsone and monitor for methemoglobinemia), (b) inhaled pentamidine 300 mg every 4 weeks, or (c) atovaquone 1,500 mg daily with a fatty meal.
Antifungal Prophylaxis
Fluconazole 400 mg PO/IV daily has been the regimen of choice. Of note, fluconazole has no activity against molds like Aspergillus.
Posaconazole 200 mg PO three times a day (older liquid formulation) proved to be more effective than fluconazole/itraconazole in patients with prolonged neutropenia, and it also resulted in less cases of aspergillosis in patients receiving corticosteroids for GVHD. With the newer oral and IV forms of posaconazole it is appropriate to consider it the antifungal prophylactic agent of choice when the risk of mould 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 glabrata and C. krusei.
TABLE 35.4Specific Infectious Disease Syndromes in Oncology Patients and Approach to Diagnosis and Management
Clinical Syndrome | Diagnostic Considerations | Management |
Intravascular catheter-associated infections | Infections can be local involving the exit site or subcutaneous tunnel, or systemic causing bacteremia For local infections, check culture of exit-site discharge as well as blood cultures | For tunnel and systemic infections, empirical therapy should include vancomycin as well as gram-negative coverage (e.g., ceftazidime, cefepime, ciprofloxacin) Temporary intravascular catheters should always be removed. Permanent catheters should be removed in most cases, and we always remove them in the following situations: |
|
| Tunnel infections |
|
| Persistently positive blood cultures after 72 h of adequate therapy regardless of pathogen |
|
| Specific pathogens: Mycobacteria spp, Bacillus spp, S. aureus, fungi; case-by-case decision for Corynebacterium jeikeium, VRE, and gram-negative organisms |
|
| Consider antibiotic lock if feasible |
Skin/soft tissue infections | Prompt biopsy with histologic staining and culture for bacteria, mycobacteria, viruses, and fungi Pathogens: S. aureus, S. pyogenes, gram-negative bacilli (e.g., Pseudomonas), VZV, HSV, Candida For vesicular lesions, scrape base for DFA or PCR for VZV and HSV | Ecthyma gangrenosum: coverage of Pseudomonas (e.g., ceftazidime, cefepime, ciprofloxacin) Infections with S. pyogenes: treat aggressively with penicillin G, clindamycin, IVIG, and surgical debridement Perianal cellulitis: broad-spectrum coverage including anaerobes (e.g., imipenem) VZV, HSV: acyclovir |
Sinusitis | Evaluate with CT scan and examination by otolaryngologist | Nonneutropenic: levofloxacin or amoxicillin/clavulanate |
| Tissue should be biopsied if there is suspicion of fungal infection or no response to antibiotic therapy after 72 h | Neutropenic: broad-spectrum coverage including Pseudomonas (e.g., carbapenem, cefepime) and MRSA and consider fungal coverage (e.g., amphotericin B, voriconazole) |
| Pathogens: S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, gram-negative bacilli (e.g., Pseudomonas), fungi including agents of mucormycosis (Mucorales) |
|
Pulmonary infections | CT scan and BAL should be performed early Pneumonias in any cancer patient are often caused by | For all patients, ensure adequate coverage of community-acquired pneumonia including Legionella (e.g., levofloxacin) |
gram-negative bacilli and S. aureus as well as community-acquired pneumonia pathogens: S. pneumoniae, H. influenzae, Legionella spp, and Chlamydia pneumoniae | Neutropenic: coverage of S. pneumoniae, S. aureus, and Pseudomonas (e.g., levofloxacin and ceftazidime and vancomycin); add antifungal coverage empirically (e.g., amphotericin B, voriconazole) if pneumonia develops while on antibiotics | |
| Neutropenic patients are at risk for invasive fungal infections, particularly aspergillosis Patients with cell-mediated defects are at risk for infections with PCP, viruses (CMV, VZV, HSV), Nocardia spp, and Legionella | Cell-mediated immunodeficiency: consider coverage of Pneumocystis with TMP/SMX, CMV with ganciclovir, and Nocardia with TMP/SMX |
| Mycobacteria should also be considered, particularly in patients with previous exposure |
|
Gastrointestinal tract infections | Lesions associated with mucositis can be superinfected with HSV or Candida | Mucositis or esophagitis: acyclovir and fluconazole |
| Esophagitis can be caused by Candida, HSV, CMV | C. difficile: metronidazole or vancomycin if refractory |
| Diarrhea is most commonly caused by C. difficile (send toxin assay) but can also be caused by Salmonella, Shigella, Aeromonas, E. coli, Campylobacter, viruses, parasites, etc. | Neutropenic enterocolitis: broad-spectrum coverage including Pseudomonas and anaerobes (e.g., carbapenem, piperacillin–tazobactam, cefepime + metronidazole) |
| Enterocolitis in neutropenic patients is most commonly caused by a mix of organisms including Clostridium spp and Pseudomonas |
|
Urinary tract infections | Pathogens: gram-negative bacilli, Candida Consider whether candiduria may represent disseminated candidiasis | Remove catheter to clear colonization Neutropenic patient: treat bacteriuria/candiduria regardless of symptoms Nonneutropenic patient: reserve treatment for symptomatic episodes Antibiotic treatment should be tailored to organism |
Bacteria cause most cases of meningitis (S. pneumoniae, Listeria, N. meningitidis) In patients with cell-mediated immunodeficiency, also consider Listeria or Cryptococcus Encephalitis is most commonly caused by HSV but consider other viruses (HHV-6, JC virus) | Bacterial meningitis: ceftriaxone, vancomycin, and ampicillin Cryptococcal meningitis: amphotericin B with flucytosine Encephalitis: treat Listeria and start ganciclovir, foscarnet, or both to cover both HSV and HHV-6 | |
| Brain abscesses may be confused with tumor |
|
BAL, bronchoalveolar lavage; CMV, cytomegalovirus; HHV-6, human herpesvirus-6; HSV, herpes simplex virus; IVIG, intravenous immunoglobulin; VZV, varicella zoster virus.
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