Most febrile neutropenic episodes are assumed to represent infection. The diagnosis of a febrile state in a neutropenic patient requires a complete but directed clinical history and physical examination designed to identify potentially infected foci for which those patients are at special risk.
Important historical facts may be obtained from the patient, from significant others, and from the patient's medical record. The physician must verify that the patient is neutropenic, the degree of neutropenia, and when the patient is a recipient of cytotoxic therapy, the day of the chemotherapy cycle. The latter is determined relative to the first day of the last cycle of chemotherapy, or in the case of BMT recipients, the day of the BMT.
To avoid omitting the consideration of other noninfectious causes of fever in neutropenic patients, the clinical evaluation should include questions pertaining to the temporal association of the febrile episode to the administration of blood products, to a history of fever associated with the underlying disease, to the administration of chemotherapeutic agents or amphotericin B, to the presence of thrombophlebitis, and to the possible association of the febrile episode with thromboembolic or hemorrhagic events. For example, in a series of neutropenic patients undergoing remission-induction therapy for acute leukemia,17 26 of 72 (36%) febrile episodes were due to noninfectious causes (blood products in 33%, underlying disease or cytotoxic drugs in 15%, and unexplained causes in 47%). However, the majority of these patients had further febrile episodes for which a diagnosis of infection could not be excluded confidently.
The physical signs of inflammation and infection are influenced by the ANC. The incidence and magnitude of localizing findings such as exudate, fluctuance, ulceration, or fissure formation are reduced in a direct relationship to the ANC.64 Other localizing findings, such as erythema and focal tenderness, appear to remain as useful and reliable signs of infection regardless of the ANC.
The body systems most often involved with infection in neutropenic patients are those associated with integumental surfaces (i.e., the upper and lower respiratory tracts, the upper and lower GI tracts, and the skin).42,64,65 Table 47-2 lists the pertinent historical and physical clues to be sought in the clinical evaluation of a febrile neutropenic patient.
Table 47–2. Clinical Evaluation of the Febrile Neutropenic Patient ||Download (.pdf)
Table 47–2. Clinical Evaluation of the Febrile Neutropenic Patient
|FINDINGS TO BE SOUGHT|
|Eye||Blurring of vision||Scleral abnormalities|
|Double vision|| Icterus|
|Loss of vision|| Hemorrhage|
|Pain|| Local swelling|
| Focal erythema|
| “Cotton wool” exudates (e.g., candidal endophthalmitis)|
|Skin||Skin rash||Central venous catheters|
|Pruritus (focal or diffuse)|| Insertion site erythema/pain|
|History of drug reactions|| Tunnel site erythema/pain|
|Focal pain/swelling|| Exit site erythema/pain/exudate|
|IV catheter site(s)||Peripheral IV catheters|
| Focal tenderness|
| Focal erythema|
| Exudate at the insertion site|
| Focal areas of necrosis (e.g., ecthyma gangrenosum)|
|Upper respiratory||Painful ear||External auditory canals|
|Nasal stuffiness||Thympanic membrane erythema|
|Increased respiratory secretions||Tachycardia|
|Upper gastrointestinal||Odynophagia||Gingival bleeding|
|Dysphagia||Pseudomembranous exudate over buccal and gingival surfaces and tongue|
|History of denture use||Mucosal erythema|
|History of herpes stomatitis||Mucosal ulceration|
|Lower gastrointestinal||Abdominal pain||Focal abdominal pain|
|Constipation|| Right upper quadrant (e.g., biliary tree)|
|Diarrhea ± bleeding|| Right lower quadrant (e.g., cecum/ascending colon)|
|Perianal pain with defecation|| Left lower quadrant (e.g., diverticular disease)|
| Focal tenderness|
| Focal/diffuse erythema|
| Hemorrhoidal tissues|
Examination of the head and neck area should include eyegrounds, the external auditory canals and tympanic membranes, the anterior nasal mucosa, the vermilion border of the lips, and the mucosal surfaces of the oropharynx. The eyeground examination should look for retinal hemorrhages as evidence of a bleeding diathesis and retinal exudates (often described as “cotton wool” exudates) that would suggest endophthalmitis associated with disseminated candidiasis. Examination of the external auditory canals and tympanic membranes for erythema or vesicular lesions can implicate this as a focus for infection by respiratory pathogens or herpes viruses. The anterior nasal mucosal surfaces should be examined for ulcerated lesions that might suggest the presence of a local filamentous fungal infection such as that due to Aspergillus species. The skin of the external nares should be examined for vesicular or crusted lesions that would suggest HSV infection. Nasal stuffiness and tenderness over the maxillary sinuses suggests that sinusitis is the infectious problem.
The oropharyngeal examination consists of inspection of the dentition, gingival surfaces, mucosal surfaces of the cheeks, hard and soft palate, tongue surfaces, and posterior pharyngeal wall. The presence of decaying teeth and gingival hyperemia implicates those sites as possible sources of bacteremic infection. The presence of shallow, painful mucosal ulcers on an erythematous base suggests herpes mucositis. Progression of this kind of lesion with local tissue necrosis can suggest a polymicrobic infection due to oropharyngeal anaerobic bacteria (e.g., Fusobacterium nucleatum, Bacteroides melaninogenicus, and peptostreptococci), particularly if cultures for HSV are negative or if such lesions develop during prophylactic or therapeutic administration of acyclovir. Oral thrush or pseudomembranous pharyngitis evolves from an overgrowth of opportunistic yeasts such as Candida species. These lesions are characterized by a thick creamy pseudomembrane consisting of masses of fungi existing in both the yeast and the mycelial phases. The distribution may be patchy, confluent, or discrete. The pseudomembrane is frequently closely adherent to the underlying mucosal surface such that attempts at removal reveal an erythematous or hemorrhagic base. The diagnosis is suspected by the clinical appearance and confirmed by the demonstration of the pathogen in culture and by the microscopic appearance of budding yeasts and pseudohyphae on a Gram's stain or potassium hydroxide preparation.
Chest examination should emphasize evaluation of the lower respiratory tract and central venous catheter sites. The typical signs of pulmonary consolidation may be muted or absent in neutropenic patients; however, localized crepitation on auscultation often precedes the appearance of pulmonary infiltrates radiologically, and thus often represents the earliest clue (and often the only clue) to a developing pneumonia in a neutropenic patient. Purulent sputum is similarly reduced in incidence and amount. Therefore the symptoms of the neutropenic patient with a developing pneumonia may manifest only as febrile illness associated with an increased respiratory rate and a few localized crepitations, with or without an associated cough or radiologic changes.66 The clinician must search for additional differential diagnostic clues such as the origin of the suspected pneumonia (community- or hospital-acquired), the tempo of the illness, the association of the illness with other potentially noninfectious factors such as pulmonary edema, exposure to certain chemotherapeutic agents associated with lung injury (bleomycin, busulfan, or cytarabine), radiation therapy, pulmonary thromboemboli, pulmonary hemorrhage, or hyperleukocytosis. The physical assessment of the chest can do little to differentiate infectious or noninfectious causes of pulmonary findings, but it can help identify the lower respiratory tract as the potential infected focus.
The symptoms and signs of an intra-abdominal infection may be obvious or muted, focal or diffuse. The most important finding is focal tenderness.64 For example, tenderness in the right lower quadrant might suggest neutropenic enterocolitis (typhlitis); right upper quadrant tenderness might suggest a biliary tract focus or hepatomegaly; epigastric pain suggests an upper GI focus; and left lower quadrant tenderness suggests colitis or diverticular disease. It is important to examine the perianal tissues for signs of excoriation, local erythema, swelling, tenderness, fissure formation, or hemorrhoidal tissues, since this area is frequently the site of major life-threatening infection in neutropenic patients. Digital examination of the rectum is not recommended in neutropenic patients because of the additional risk of tissue damage, bleeding, and infection. However, a light perianal digital examination can be informative about focal areas of cellulitis without increasing the risk of bacteremic infection.
The examination of the skin should consist of a thorough search for focal areas of pain, swelling, or erythema, especially in association with indwelling vascular access devices. Particular attention should be paid to the venous insertion, tunnel, and exit sites associated with central venous catheters. In contrast, nonspecific local pocket tenderness may be the only clue to infection associated with the totally implantable venous access port-reservoir systems.
Skin rashes are a common phenomenon among neutropenic patients. The differential diagnosis must include both infectious and noninfectious causes. Among the former group are focal ulcerative and necrotic lesions caused by metastatic pyogenic bacterial infection such as that associated with bacteremic P. aeruginosa or Staphylococcus aureus (infections causing ecthyma gangrenosum), or by disseminated angioinvasive filamentous fungi such as that due to Aspergillus species, Pseudallescheria boydii (formerly called Allescheria boydii; the conidial [asexual] state is Scedosporium apiospermum), or Fusarium species (Fig. 47-2). Pustular erythematous lesions diffusely distributed over the skin surface suggest the possibility of disseminated fungal infection such as that caused by Candida tropicalis. Vesicular skin lesions suggest the possibility of infection due to HSV or herpes zoster virus.
A. Necrotic ulcerated skin lesion in a 53-year-old man on day 15 of remission-induction therapy for acute myeloid leukemia (AML). This lesion was caused by skin infarction secondary to angioinvasive infection due to Aspergillus flavus. B. Periodic acid–Schiff stain of a biopsy from this lesion demonstrates the invasion of broad, acutely branching septate hyphae into blood vessels.
The list of possible noninfectious causes of skin rash is long. The three most important considerations are hemorrhagic petechial or ecchymotic rashes associated with profound thrombocytopenia; hypersensitivity rashes associated with specific drugs such as β-lactam antibacterial drugs, allopurinol, or trimethoprim-sulfamethoxazole (TMP-SMX); and specific chemotherapy regimen–related rash syndromes (e.g., the exfoliative palmar/plantar syndrome associated with high-dose cytarabine; Fig. 47-3). These skin rash syndromes may coexist simultaneously. For example, experience has shown that patients undergoing remission-induction therapy with high-dose cytarabine for AML may develop hemorrhagic petechial rashes due to thrombocytopenia, palmar/plantar erythema, and edema due to cytarabine; macular penicillin-related hypersensitivity rash; and hemorrhagic cutaneous infarcts secondary to angioinvasive bacteremic or fungemic infection, all simultaneously. Only careful attention to the pertinent details of history and thorough laboratory investigations can increase the likelihood that the correct diagnosis and therapeutic decisions will be made.
Palmar/plantar desquamation occurring on day 9 of treatment in a patient receiving high-dose cytarabine.
Once the relevant historical details and physical findings are established, the complete evaluation of the febrile neutropenic patient should include a series of laboratory and radiologic investigations designed to complement the clinical examination. Specimens of body fluids such as blood, urine, cerebrospinal fluid, and lower respiratory secretions should be submitted to the clinical microbiology laboratory for culture and antimicrobial susceptibility testing where appropriate. At least two sets of blood cultures should be obtained, at least one of which should be taken from a peripheral venous site. Furthermore, it has been recommended that for patients with multilumen indwelling central venous catheters, each lumen of the catheter should be sampled in addition to blood from the peripheral venous site.55
The basic radiologic investigation is the chest radiograph (posteroanterior and lateral views). When suggested by clinical clues, sinus radiographs are useful for detecting sinus opacification or fluid levels. Panoramic x-ray radiographs can be helpful for evaluating periodontal infection. High-resolution computed tomographic (HRCT) examinations of the lungs has a high yield of abnormalities in febrile neutropenic patients despite normal or nondiagnostic chest radiographs.67,68 In one study, 60% of febrile neutropenic patients with normal chest radiographs had a pulmonary infiltrate demonstrable on the chest HRCT.67 Computed tomography (CT) of the abdomen or hepatic ultrasonography is valuable for assessing the significance of abnormalities in cholestatic enzymes (γ-glutamyltransferase [GGT] and alkaline phosphatase). This is particularly important if the possibility of hepatosplenic candidiasis exists. Abdominal pain and tenderness with diarrhea in a persistently febrile neutropenic patient suggests the possibility of neutropenic enterocolitis. Abdominal CT examination looking for evidence of bowel wall thickening, pneumatosis, wall nodularity, mucosal enhancement, bowel dilation, ascites, and mesenteric stranding is very useful in making the diagnosis.69
Tissue obtained by biopsy of infected sites can be important in the diagnostic evaluation. Biopsied material should be submitted to the clinical microbiology laboratory for culture and to the pathology laboratory for histopathologic or etiologic evaluation. It is relatively common for pathogens to be observed histopathologically in infected tissue specimens without recovery of the organism by culture. Such is the case in the syndrome of hepatosplenic candidiasis, where budding yeasts and pseudohyphae observed in liver biopsy specimens frequently fail to grow in microbiologic cultures. Skin biopsies are often helpful to distinguish drug-related lesions from those caused by specific pathogenic microorganisms. Although ideally desirable for a complete evaluation, tissue biopsies of suspect sites in neutropenic thrombocytopenic patients carry the additional risks of further infection and bleeding. In addition to skin, the body sites most often considered for biopsy are esophagus (to differentiate mucositis secondary to fungi, pyogenic microorganisms, herpes viruses, or chemotherapeutic agents), liver (to evaluate hepatic lesions due to fungi, herpes viruses, pyogenic bacteria, and drug-related or disease-related hepatic damage), and lung (to evaluate the etiology of progressive infiltrates). Institutions caring for these patients should have a protocol for specimen collection and handling developed in consultation with the appropriate laboratories, the operating theaters, and surgical services.
Neutropenia-related febrile episodes are heterogeneous with respect to the cause of neutropenia, the duration of neutropenia, the risks of developing fever, the cause of fever, and the cause of infection. Furthermore, patients differ in their response to treatment and in the risks of complications, including those which are serious and life threatening. Accordingly, the practice standard has been to hospitalize all febrile neutropenic patients for assessment, administration of empiric broad-spectrum intravenous antimicrobial therapy,55 and monitoring for and management of complications. Such complications include management of hemodynamic instability and hypotension; respiratory insufficiency requiring oxygen administration; control of pain, nausea, vomiting, and dehydration; investigation and management of confusion, delirium, and altered mental status; hemorrhage requiring blood product transfusion; cardiac dysrhythmia requiring monitoring; changes in metabolic function requiring intervention; and death.
Investigators from the Dana-Farber Cancer Institute70 examined the natural history of febrile neutropenic patients to identify patients at risk for complications due to the neutropenia, the infection, the underlying cancer, and other comorbid conditions. Concurrent comorbidity included hypotension (defined by a systolic blood pressure of <90 mm Hg), altered mental status, respiratory failure (defined by a partial pressure of arterial oxygen of <60 mm Hg), uncontrolled bleeding, severe thrombocytopenia (defined by a platelet count of <40 × 109/L), inadequate outpatient fluid intake or pain control, suspected spinal cord compression, symptomatic hypercalcemia, the need for hospitalization for induction therapy, serious localized infections, acute abdomen, new deep venous thrombosis, syncope, bowel obstruction, and poor performance status (Karnofsky performance status of <50%). Medical complications included hypotension, respiratory failure, new cardiac dysrhythmia or electrocardiographic changes, altered mental status, new focal neurologic abnormalities, hemorrhage requiring >3 units of packed red blood cell transfusion within 24 hours, congestive heart failure, emergency surgery, acute abdomen, pulmonary thromboembolism, acute renal failure, and diabetic ketoacidosis. Based on these comorbidities and complications, febrile neutropenic patients could be classified into three groups at high risk for complications and one low-risk group. Group 1 (39% of the total) was comprised of hospitalized patients usually with hematologic malignancies or hemopoietic stem cell transplant. Complication and morbidity rates were 34% and 23%, respectively. Group 2 (8% of the total) was comprised of outpatients with concurrent comorbidity and had complication and mortality rates of 55% and 14%, respectively. Group 3 (10% of the total) was comprised of outpatients with as yet uncontrolled or progressive cancer and had complication and mortality rates of 31% and 15%, respectively. Group 4 (the low-risk group, 43% of the total) was comprised of outpatients with controlled or responding cancer and no comorbid processes. This group had a complication rate of 2% and no deaths. These observations were prospectively validated in follow-up studies.70,71 These results suggest that high-risk patients with characteristics corresponding to groups 1 to 3 should be admitted and managed as inpatients with careful monitoring for serious complications, whereas low-risk patients corresponding to group 4 can be managed safely and effectively on an outpatient basis.71–79
The Multinational Association for Supportive Care in Cancer developed a scoring system to identify low-risk patients for serious medical complications that would require admission to the hospital.26,80 Identifying factors included absence of symptoms, hypotension, airflow obstruction, hematologic malignancy, invasive fungal infection, or dehydration. Furthermore, status as an outpatient at the onset of the febrile neutropenic episode and age <60 years were also identifying factors. A score of >21 of a possible 26 identified low-risk patients with a positive predictive value of 91%, specificity of 68%, and sensitivity of 71%. This system has been offered as a strategy for identifying patients eligible for studies of more cost-effective, safe, outpatient-based management strategies.
Empiric Antimicrobial Therapy
The empiric initial therapy for suspected infection in febrile neutropenic patients is based on three assumptions:
The majority of infections are due to bacteria.81
The principal pathogens are aerobic gram-negative bacilli (E. coli, Klebsiella pneumoniae, and P. aeruginosa).42,81
Inappropriate therapy for aerobic gram-negative bacillemia is associated with high mortality with a median survival of less than 72 hours.82
Accordingly, the antibiotic regimens that have been recommended for empiric first-line therapy of first fever in neutropenic cancer patients are designed to have excellent activity against these pathogens. With the recognition of various factors favoring infection by gram-positive organisms,83 the addition of agents with an improved spectrum of activity against these pathogens when appropriate also has been recommended.84
Empiric antibacterial therapies may be administered either as combination regimens or as single-agent regimens (monotherapy) (Tables 47-3 and 47-4). Combination regimens include β-lactam agents combined together18,85,86 (double β-lactam regimens), combined with aminoglycosides,42−44,47,49,50,87 or combined with fluoroquinolones.41,88 Single-agent regimens consist of β-lactam agents48−50,52,89−92 with or without β-lactamase inhibitors (tazobactam, clavulanic acid, or sulbactam) or fluoroquinolones.93–95 Monotherapy with aminoglycosides is not recommended.55
Table 47–3. Antimicrobial Therapy Used for Therapy in Febrile Neutropenic Patients ||Download (.pdf)
Table 47–3. Antimicrobial Therapy Used for Therapy in Febrile Neutropenic Patients
| Ticarcillin ± clavulanic acid|
| Piperacillin ± tazobactam||200–300 mg/kg per day IV|
| Azlocillin||4–6 divided doses daily|
| Mezlocillin||3 g q4–6h IV|
| Cefoperazone||2 g q12h IV|
| Ceftriaxone||2 g q24h IV|
| Ceftazidime||2 g q8h IV|
| Imipenem/cilastatin||500 mg q6h IV|
| Meropenem||1 g q8h IV|
| Gentamicin||1.5–2 mg/kg q8h IV|
| Netilmicin||1.5–2.0 mg/kg q8h IV|
| Tobramyicn||1.5–2 mg/kg q8h IV|
| Amikacin||7.5 mg/kg q12h IV|
| Ciprofloxacin||400 mg q12h IV|
|500–750 mg q12h PO|
| Ofloxacin||400 mg q12h PO|
| Perfloxacin||400 mg q12h PO|
| Enoxacin||400 mg q12h PO|
| Vancomycin||1.0 g q12h IV or 30 mg/kg per 24 h|
| Metronidazole||500 mg q8h IV/PO|
| Erythromycin||0.5–1.0 g q6h IV|
| TMP-SMX||10–20 mg/50–100 mg/kg per day in 4 divided doses|
| Acyclovir||250–500 mg/m2 q8h IV|
| Ganciclovir||5 mg/kg q8-12 h IV|
| Amphotericin B||0.5–1.5 mg/kg per day IV|
| Amphotericin B lipid complex||5 mg/kg per day IV|
| 5-Fluorocytosine||150 mg/kg per day PO in 4 divided doses|
| Fluconazole||200–400 mg IV/PO qd|
| Itraconazole||200–400 mg PO qd|
Table 47–4. Considerations Governing the Choice of Empiric Antibacterial Regimen ||Download (.pdf)
Table 47–4. Considerations Governing the Choice of Empiric Antibacterial Regimen
|+||Risk of P. aeruginosa infection|
|Fluoroquinolone or aminoglycoside||Nosocomial infection|
|Prolonged severe neutropenia|
|Monotherapy||Patients with renal impairment|
|Recipients of other nephrotoxic agents|
|Oral therapy||Short-term neutropenia|
| Vancomycin||Suspect coagulase-negative staphylococcal infection|
|Suspect vascular catheter infection|
|Skin or soft tissue infection|
| Metronidazole||Suspect intra-abdominal infection|
|Severe oral mucositis|
|Suspect perianal infection|
β-Lactam antibacterial agents may be categorized as extended-spectrum antipseudomonal penicillins (e.g., carbenicillin, ticarcillin with or without clavulanic acid, piperacillin with or without tazobactam, azlocillin, or mezlocillin), third- or fourth-generation antipseudomonal cephalosporins (e.g., moxalactam, ceftriaxone, ceftazidime, cefoperazone with or without sulbactam, cefpirome, or cefepime), or as carbapenems (e.g., imipenem-cilastatin, meropenem, or ertapenem). The addition of β-lactamase inhibitors to the broad-spectrum antipseudomonal penicillins, ticarcillin and piperacillin, enhances their spectrum of activity against β-lactamase–producing bacteria and their roles in the management of the febrile neutropenic patient.47,51,96−115
In a recent review of physician prescribing behavior for 214 febrile neutropenic patients in Canadian centers, initial empiric therapy with a single agent was administered in 42% of cases in which a third-generation cephalosporin such as ceftazidime was used in 32%, a carbapenem in 2.3%, and a fluoroquinolone in 0.9%.116 Combination therapy was administered in 58% of cases in which an antipseudomonal penicillin plus an aminoglycoside was given in 29% of cases, an antipseudomonal cephalosporin plus an aminoglycoside in 15%, and an antipseudomonal β-lactam plus a glycopeptide in 11%.116Vancomycin was part of the initial empiric antibacterial therapy in 15% of cases. First modification with second-line therapy for persistent fever was administered in 87% of the 214 cases after a median of 5 days. Systemic empiric amphotericin B was administered for persistent fever in 48% of the 214 febrile neutropenic episodes after a median of 9 days. Previous studies have demonstrated that glycopeptides are employed as empiric second-line therapy in 40% to 50% of cases in which extended-spectrum cephalosporins are administered as first-line empiric therapy.48,51,97−100,117−128
The Role of Aminoglycosides in Treatment of Febrile Neutropenic Patients
Aminoglycosides were part of the standard combination empiric antibacterial therapy for the management of febrile neutropenic patients from the early 1970s to the 1990s. The combination of an aminoglycoside with an antipseudomonal β-lactam antibacterial agent was designed to have a broad spectrum of antibacterial activity, achieve bactericidal serum concentrations, exert a synergistic antibacterial effect, and prevent emergence of resistance. Such combinations have been recommended in published guidelines by the Infectious Diseases Society of America (IDSA),55 the National Comprehensive Cancer Network,129 and the Infectious Diseases Working Party of the German Society of Hematology and Oncology,53 but not the Spanish guidelines, however.130 The aminoglycoside antibiotics having proven roles for use with β-lactam antibiotics in neutropenic patients include gentamicin, netilmicin, tobramycin, and amikacin. The choice of aminoglycoside must be based on local institutional bacterial susceptibility patterns, the availability of a mechanism for serum aminoglycoside concentration monitoring, and drug cost.
A recent large randomized controlled trial from the University of Perugia, Italy, compared piperacillin-tazobactam to piperacillin-tazobactam plus amikacin.51 The primary outcome was defervescence of all signs and symptoms of infection without modification of the initial antibacterial regimen. Response was observed in 179 of 364 (49%) monotherapy recipients and in 196 of 369 (53%) combination recipients (p = 0.2). The response rates in single-pathogen gram-positive bacteremias were low (27% and 32 %, respectively) because of the high proportion of coagulase-negative staphylococcal bacteremias (response rates 17% and 18%, respectively; p = 0.8). In contrast, the response rates for streptococcal and enterococcal bacteremias between the two groups were significantly higher (60% and 71%, respectively, p = 0.7). The response rates for single gram-negative bacteremias were also similar (36% and 34%, respectively; p = 0.9). The aminoglycoside failed to enhance the response rates in any circumstance. Studies such as this question the therapeutic value of combination antibacterial therapy with an aminoglycoside.
Two systematic reviews of the literature have examined the safety and efficacy of β-lactam plus aminoglycoside combinations in febrile neutropenic patients.131,132 Furno and associates reviewed 4795 heterogeneously treated febrile neutropenic episodes entered into 29 randomized controlled clinical trials comparing monotherapy (ceftazidime, 9 trials; cefepime, 2 trials; cefoperazone, 1 trial; imipenem-cilastatin, 9 trials; meropenem, 4 trials; ciprofloxacin, 2 trials; and ofloxacin, 2 trials) and aminoglycoside-based combination therapy. The pooled odds ratios for overall treatment failure and for treatment failure in bloodstream infections were 0.88 (95% CI, 0.78 to 0.99) and 0.70 (95% CI 0.54 to 0.92), respectively, demonstrating fewer failures in the monotherapy groups.131 Paul and colleagues examined 7807 febrile neutropenic patients entered into 47 randomized controlled trials comparing β-lactam monotherapy to β-lactam plus aminoglycoside combination therapy. The main outcome was overall mortality. While there was no significant difference in overall mortality (relative risk 0.85; 95% CI 0.72 to 1.02), there were fewer failures among β-lactam monotherapy recipients (relative risk 0.92; 95% CI 0.85 to 0.99).132 Monotherapy recipients also experienced fewer adverse events overall (relative risk 0.85; 95% CI 0.73 to 1.00) and less nephrotoxicity (relative risk 0.42; 95% CI 0.32 to 0.56).132 On the basis of these analyses, β-lactam plus aminoglycoside combinations offer no advantages over broad-spectrum β-lactam monotherapy. Rather they present significant disadvantages with respect to toxicity and costs related to drug monitoring and administration. Based on these observations and considerations, investigators are now recommending that the standard of care for initial therapy of febrile neutropenic cancer patients should be with a broad-spectrum β-lactam agent as monotherapy.132
Fluoroquinolones in the Treatment of Febrile Neutropenic Patients
The fluoroquinolones evaluated in studies of the empiric treatment of febrile neutropenic patients include ciprofloxacin,41,133 perfloxacin,134ofloxacin,73,74levofloxacin,135 and clinifloxacin.94,95 These agents have the advantage of availability in both oral and intravenous formulations, which can facilitate intravenous-to-oral conversion.133,136,137
The studies of empiric fluoroquinolones as first-line therapy for febrile neutropenic patients have largely targeted those patients at lower risk for medical complications.129Ciprofloxacin as well as other agents such as clindamycin, aztreonam, or amoxicillin have been the most completely studied.72,73,75−78,108,135,138−142 The administration of ciprofloxacin 750 mg orally and amoxicillin-clavulanate 625 mg orally both every 8 hours was well tolerated and as effective as intravenous ceftriaxone plus amikacin138 or ceftazidime139 administered on an inpatient basis. Similar results have been reported for trials comparing oral ciprofloxacin-based regimens and intravenous regimens on an outpatient basis.72,73,75−78,108,135,138−142 These strategies appear to be safe and effective for low-risk patients. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology have included as an alternative regimen for initial empiric antibacterial therapy of higher-risk febrile neutropenic cancer patients the use of ciprofloxacin plus an antipseudomonal penicillin.129 One large trial compared piperacillin plus ciprofloxacin and piperacillin plus tobramycin in a group of intermediate- to high-risk febrile neutropenic cancer patients.41 Success rates (i.e., defervescence with initial regimen modification) were similar, 27% and 22% for the piperacillin-ciprofloxacin and piperacillin-tobramycin groups, respectively; however, times-to-defervescence were faster among the piperacillin-ciprofloxacin recipients, 5 days versus 6 days (p = 0.005).
Reports of fluoroquinolone resistance among aerobic gram-negative bacilli associated with bloodstream infections in neutropenic cancer patients began to emerge in the early 1990s.143–145 The incidence of fluoroquinolone-resistant Escherichia coli (FREC) bacteremia among patients treated on the EORTC-IATCG clinical trials from 1983 to 1993 increased from zero during the period from 1983 to 1990 to 28% during the period from 1991 to 1993.143 Of note, the incidence of resistance among strains of Pseudomonas aeruginosa and Klebsiella pneumoniae remained largely unchanged at less than 10%.143 This has been more of a problem among cancer patients treated in institutions with high prevalence rates for gram-negative bacillary fluoroquinolone resistance (>10%) despite community-related resistance prevalences of less than 1%.146 Carratala and colleagues reported in 1995 a 37% incidence of fluoroquinolone resistance in 35 of 230 neutropenic cancer patients previously treated with norfloxacin.145
Fluoroquinolone resistance among community-derived gram-negative bacilli, and FREC in particular, has emerged in parallel with the increased prescribing of these products in the community.147–149 There is a significant correlation between the incidence of ciprofloxacin-resistant Escherichia coli bloodstream infection and the increased community and hospital use of fluoroquinolones (r = 0.974, p = 0.005 and r = 0.975, p = 0.005, respectively).147 Among those who had not heretofore received fluoroquinolone therapy, Garau and colleagues reported the prevalence of FREC in the stools of adults and children in the Province of Barcelona, Spain, to be 24% and 26%, respectively.149 These investigators also observed a very high prevalence of FREC in the stools of pigs (45%) and poultry (90%) and argued that the increased prevalence of human carriage of FREC may be linked to the high prevalence in animal-based food products. The increased use of fluoroquinolones in animal feeds and in humans is believed to play a role in the selection for FREC. In an environment with a high (15%) prevalence of fluoroquinolone resistance among gram-negative bacilli, cancer patients receiving ciprofloxacin antibacterial chemoprophylaxis while undergoing high-dose chemotherapy with stem cell rescue became colonized with FREC in one third of cases,150 a phenomenon that increases the likelihood of FREC bloodstream infections in such patients.151
In addition, inappropriate use of fluoroquinolones is common. A recent case-control study of fluoroquinolone use in emergency departments in Philadelphia demonstrated inappropriate prescription of these agents in 81% of cases.152 Lastly, gram-negative bacilli that are co-resistant to fluoroquinolones and other antibacterials such as aminoglycosides, cefotaxime, ampicillin, amoxicillin-clavulanate and trimethoprim-sulfamethoxazole are more frequently being reported.149,153 Thus overuse and inappropriate use of fluoroquinolones in the community is common and is strongly linked to resistance, and ultimately will reduce the likelihood that this class of agents will be useful in a variety of patient populations, including neutropenic cancer patients, who require critical care services.143,145 It is incumbent upon prescription writers of empiric antibacterial therapy to have some understanding of the prevalence of gram-negative bacillary resistance in the institution and the community.
Double Beta-Lactam Combinations
Regimens consisting of an antipseudomonal broad-spectrum β-lactam plus an extended-spectrum third-generation cephalosporin are relatively safe and effective alternatives to regimens of a β-lactam plus an aminoglycoside,18,85,86 but they are costly and do not offer any advantages over those of broad-spectrum β-lactam monotherapies. Cost, hypokalemia, selection of bacterial resistance, and antagonism have been cited as potential disadvantages, although these regimens may have an occasional role in the setting of preexisting renal insufficiency, in which the patient is receiving concomitant nephrotoxic agents such as cyclosporine or cisplatin-containing chemotherapeutic regimens, or where gram-positive organisms such as viridans streptococci are suspected.18,54 The availability of effective β-lactam and fluoroquinolone or β-lactam monotherapy-based regimens has largely rendered double β-lactam regimens obsolete. Of note, these combinations appear in the National Comprehensive Cancer Network guidelines.129
The intrinsic activity of many of the third- and fourth-generation cephalosporins such as ceftriaxone, cefoperazone, ceftazidime, or cefepime against aerobic gram-negative bacilli is high. These agents have been used effectively as single agents for empiric treatment of suspected infection.42−45,47−50,87,92,154 Empiric monotherapy has been shown to be effective in both low- and high-risk febrile neutropenic patient populations and in those in whom the expected duration of severe neutropenia (ANC <0.5 × 109/L) is either longer or shorter than 7 days. The experience to date suggests that single-agent empiric regimens will require modification, usually by the addition of other antimicrobials, in one third to one half of patients with neutropenic periods in excess of 1 week.48−50,87 There is a lower likelihood that modifications will be necessary for patients with short-term (<1 week) neutropenia.
A meta-analysis examining the efficacy of ceftazidime monotherapy compared to standard combination therapy for the empiric treatment of febrile neutropenic patients failed to demonstrate a difference with respect to the odds of overall treatment failure and failure in bloodstream infections (odds ratio 1.27; 95% CI 0.79 to 2.03 in 1077 patient episodes; and OR 0.72, 95% CI 0.33 to 1.58 in 248 patient episodes, respectively).92 Another meta-analysis154 compared the efficacy of ceftriaxone with (7 trials) or without (1 trial) an aminoglycoside and ceftazidime with (6 trials) or without (1 trial) an aminoglycoside or azlocillin plus an aminoglycoside (1 trial). The pooled odds ratio for overall treatment failure in the eight trials was 1.04 (95% CI 0.84 to 1.29), demonstrating no differences in the comparison for this outcome. There was also no difference in overall mortality (OR 0.84; 95% CI 0.57 to 1.24). These analyses demonstrate that empiric antibacterial therapy of febrile neutropenic patients with once-daily ceftriaxone is as effective as thrice daily ceftazidime. This has important implications for potential outpatient once-daily intravenous therapy.
Carbapenems for Treatment of Febrile Neutropenic Patients
Both imipenem-cilastatin and meropenem have been studied widely as empiric therapy in febrile neutropenic patients. A meta-analysis examined the efficacy of imipenem-cilastatin compared to a β-lactam plus aminoglycoside combinations (11 trials) and to β-lactam monotherapy (ceftazidime, 4 trials; cefoperazone-sulbactam, 1 trial), or β-lactam plus glycopeptide (ceftazidime, 3 trials) or double β-lactam therapy (cefoperazone-mezlocillin, 1 trial; cefoperazone-piperacillin, 1 trial). There were fewer treatment failures among imipenem-cilastatin recipients compared to β-lactam plus aminoglycoside combinations (OR 0.77; 95% CI 0.61 to 0.98) or to non–aminoglycoside-containing regimens (OR 0.67; 95% CI 0.54 to 0.84).91 These analyses support the superiority of imipenem-cilastatin over control arms largely based on third-generation cephalosporins.
Another meta-analysis comparing carbapenem monotherapy to β-lactam plus aminoglycoside combination therapy demonstrated fewer treatment failures among the carbapenem recipients (OR 0.80; 95% CI 0.66 to 0.96, Peto fixed effects model),131 in contrast to antipseudomonal cephalosporin monotherapy (OR 0.92; 95% CI 0.77 to 1.10, Peto fixed effects model). A similar analysis of the published clinical trials of meropenem monotherapy compared to ceftazidime-based regimens with or without an aminoglycoside demonstrated greater response rates among meropenem recipients (OR 1.28; 95% CI 1.08 to 1.51).155 These systematic observations suggest the inferiority of third-generation cephalosporin monotherapy regimens compared to the carbapenem monotherapy.
Piperacillin-Tazobactam for the Treatment of Febrile Neutropenic Patients
Piperacillin-tazobactam plus amikacin therapy was successful in 210 of 342 (61%) febrile neutropenic patients studied by the European Organisation for the Research and Treatment of Cancer, compared to 196 of 364 (54%) patients receiving ceftazidime plus amikacin (p = 0.05).47 Furthermore, the time-to-defervescence was shorter among piperacillin-tazobactam recipients (p = 0.01), and the frequency with which the initial regimen was modified by the addition of a glycopeptide was lower (24% versus 35%; p = 0.002) in that study. Another large Italian trial examined the role of the aminoglycoside amikacin, when combined with piperacillin-tazobactam.51 The response rates overall between the two groups were similar regardless of the classification of the febrile neutropenic episode as bacteremic, clinically documented, or unexplained fever. Clearly, the aminoglycoside offered no advantage over the piperacillin-tazobactam monotherapy. Piperacillin-tazobactam monotherapy has been studied compared to extended-spectrum cephalosporins with or without aminoglycosides.96–100 Overall unmodified success rates were significantly higher among piperacillin-tazobactam recipients (OR 1.39; 95% CI 1.08 to 1.79).100 Furthermore, the frequency of second-line therapy with glycopeptides was significantly lower among piperacillin-tazobactam recipients (OR 0.77; 95% CI 0.60 to 0.99).100 These observations demonstrate the superiority of initial piperacillin-tazobactam monotherapy over extended-spectrum cephalosporins with or without aminoglycosides. Furthermore, the need to modify the initial antibacterial regimen by the addition of a glycopeptide such as vancomycin or teicoplanin for persistent fever is also significantly less than for the cephalosporin-based comparator groups. This has important implications with respect to cost, drug-related toxicities, and for selection for resistant microorganisms such as vancomycin-resistant Enterococcus spp.
The Role of Glycopeptides as First-Line and Second-Line Therapy in Febrile Neutropenic Patients
There has been a significant increase in the proportion of the microbiologically documented infections observed in neutropenic patients that are due to gram-positive bacteria. Two decades ago approximately 70% of bacteremic isolates were gram-negative bacilli, whereas more recently approximately 60% to 70% are gram-positive cocci.41,83 Previously published clinical trials of ceftazidime-based empiric antibacterial therapy observed more fatal gram-positive superinfections than expected.156 A subsequent small study demonstrated that the addition of vancomycin to ceftazidime therapy reduced the superinfection rate from 24% to zero and the infection-related mortality rate by 91% (OR 0.07; 95% CI 0.01 to 0.63).157 Such observations have led investigators to advocate the inclusion of glycopeptides vancomycin or teicoplanin as part of the first-line empiric antibacterial therapy in febrile neutropenic patients. In contrast, two further studies from the National Cancer Institute suggested that the vancomycin therapy may be safely delayed without increased morbidity or mortality.49,158 In order to examine this question further, the European Organization for Treatment and Research in Cancer and the National Cancer Institute of Canada Clinical Trials Group conducted a large randomized trial comparing empiric therapy with ceftazidime plus amikacin (CA) and ceftazidime plus amikacin plus vancomycin (CAV).45 The overall response rate among the 377 CAV recipients was 288 (76%), whereas the response rate for 370 CA recipients was 232 (63%; p <0.001), the difference largely due to differential response rates for gram-positive bloodstream infections among CAV recipients. Despite the apparent superiority of the CAV arm, persistently febrile CA patients at day +3 received vancomycin, resulting in no differences in overall success rates or mortality.
Treatment failures were due to lack of prompt response and to persistent fever observed at a time very early after the initiation of the allocated regimen rather than objective indicators of failure such as persistence of resistant pathogens or progression at foci of infection. Patients receiving CA were more likely to receive vancomycin with persistence of fever at day +3 than recipients of the CAV regimen.159 Since the median time to defervescence among high-risk febrile neutropenic patients is day 5 (range = day +3 to day +7),41,47,48,50,128 many patients were considered failures unnecessarily because of regimen modification before they would have had a chance to defervesce. The physician compulsion to modify the initial antibacterial regimen for reasons of persistent fever at day +3 is driven in part by previously published protocols49 reinforced by previously published guidelines.160
Three other trials161–163 examining the role of initial glycopeptide therapy in febrile neutropenic cancer patients came to similar conclusions as for the EORTC/NCIC trial;45 that is, the inclusion of glycopeptides as initial therapy in febrile neutropenic patients results in modest improvements in response rates, particularly in the circumstances of gram-positive bacteremia, but has no impact on overall survival of the neutropenic episode. Accordingly, it is recommended in the recent American, German and Spanish guidelines that glycopeptides not be used as part of the initial empiric antibacterial regimen for the treatment of fever in neutropenic cancer patients unless there is evidence of gram-positive infection.53,55,130,164
The above trials demonstrated that among patients with persistent fever due to gram-positive infection at day +3 vancomycin could be added to the regimen at that time with no excess morbidity or mortality.45,49,158,163 Accordingly, second-line glycopeptide-based empiric antibacterial therapy for persistent fever has become quite common. As noted above, almost half of cases enrolled in clinical trials have a glycopeptide administered for these reasons.48,51,97−100,117−128 The efficacy of empiric second-line glycopeptide therapy has been studied in two randomized controlled trials.101,165 Both studies failed to demonstrate a significant treatment effect with regard to defervescence or overall mortality (OR 1.05; 95% CI 0.66 to 1.67 and OR 0.80; 95% CI 0.33 to 1.90, respectively) compared to placebo.166 The results of these two trials together with the small published meta-analysis confirm that in stable, persistently febrile, neutropenic patients, empiric second-line glycopeptide therapy after 48 to 96 hours is unnecessary.166 Furthermore, the initial antibacterial therapy can be safely extended in such patients unmodified for an additional 72 to 96 hours for a total of 4 to 8 days.
The use of glycopeptide antibiotics as part of the initial first-line regimen should be reserved for patients at highest risk for serious gram-positive infection.55,129 Such circumstances include clinical catheter-related infection, infection in patients receiving fluoroquinolone-based antibacterial chemoprophylaxis associated with severe mucositis predisposing patients to viridans group streptococcal bloodstream infections,34,35,167 infection in the setting of colonization by methicillin-resistant Staphylococcus aureus (MRSA), a bloodstream isolate characterized as gram-positive cocci in groups and clusters (suggesting Staphylococcus spp. and the likelihood of a methicillin-resistant coagulase-negative Staphylococcus), and the setting of hypotension or septic shock syndrome without an identified pathogen. The caveat is that the glycopeptide antibiotic should be discontinued in 2 to 3 days if a resistant gram-positive infection has not been identified.
The Role of Hematopoietic Growth Factors in the Management of Febrile Neutropenic Patients
The inclusion of hematopoietic growth factors (HGF), granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF; GM-CSF) in strategies for the prevention and management of febrile neutropenic patients remains unsettled.168 Berghmans and colleagues published a systematic review of the literature with a meta-analysis to critically examine the evidence for or against use of these products in the treatment of febrile neutropenic episodes.169 Eleven studies encompassing 1218 febrile neutropenic episodes published between 1990 and 1998 were considered in the analysis. Although six trials reported treatment effects for the primary outcome analyzed (mortality), overall there was no effect on mortality (relative risk 0.71; 95% CI 0.44 to 1.15). Furthermore, there were no differences when analysis was conducted by HGF and G-CSF versus GM-CSF. The impact of HGF on length of hospitalization was decreased in four trials, unaffected in four trials, and not reported in three trials. Only three of six trials reporting on the impact of HGF on duration of antibacterial therapy demonstrated a reduction in this outcome. In nine trials in which the impact of HGF on the duration of fever was reported, no treatment effects were observed in seven trials, fever reduction was observed in one trial, and no analysis was provided in one other. The studies included in this analysis were flawed by the failure to control for important variables, including the duration and intensity of neutropenia, type of cytotoxic therapy, and type of malignancy. On the basis of this review, Berghmans and colleagues could not recommend routine use of HGF in the treatment of febrile neutropenic episodes.169
The guidelines of the American Society of Clinical Oncology do not recommend their use as adjunctive therapy for neutropenic patients who are febrile and have suspected infection.170 However, less than half of specialists follow these guidelines, given that usage appears to be influenced more by reimbursement than evidence.171–173
HGF have been evaluated in other non-neutropenic patient populations including patients with community-acquired pneumonia, human immunodeficiency virus–infected patients, neonatal sepsis, diabetic foot ulcer infections, acute hepatic failure or cirrhosis, in orthotopic liver transplantation, and in the critical care unit. While there appears to be some promising results in some subgroups of patients, HGF have no proven clinical benefit in non-neutropenic critically ill patients with regard to morbidity or mortality.174
The Role of Second-Line Therapy for Persistent Fever in Neutropenic Patients
Patients with fever persisting beyond 72 hours on broad-spectrum antibiotic therapy should be re-evaluated carefully.55,129Table 47-5 lists several of the possible explanations for this. A nonbacterial etiology for the febrile episode should be considered. The various noninfectious causes have been discussed already. Factors such as localized tenderness, change in sensorium, hyperventilation, hypotension, progressive renal insufficiency, and acidosis suggest an infectious cause. The re-evaluation should occur between day 3 and day 5 and include a thorough examination to identify a focus. Cultures of blood (one set from each lumen of the central venous catheter and one set from a peripheral vein), urine, and other potentially infected sites should be submitted to the clinical microbiology laboratory. Repeat chest radiography or diagnostic imaging studies such as ultrasonography or high-resolution computed tomographic studies may be performed when abnormalities suggest a specific organ as a potential site for infection. When re-evaluation fails to identify the etiology of the persistent fever, the clinician may elect either to continue the initial empiric antibacterial regimen if the patient's condition shows no clinical change or deterioration, or to modify the empiric regimen appropriate to the findings of the re-evaluation (Table 47-6).
Table 47–5. Differential Diagnosis of Fever >72 Hours Despite Broad-Spectrum Antibacterial Therapy ||Download (.pdf)
Table 47–5. Differential Diagnosis of Fever >72 Hours Despite Broad-Spectrum Antibacterial Therapy
|Fever is due to a nonbacterial process|
| Viral infection (HSV, CMV)|
| Fungal infection (candidiasis, invasive aspergillosis)|
| Noninfectious fever (blood products, drugs, etc.)|
|Bacterial infection is resistant to the antibiotic regimen|
|Second or subsequent infection has developed|
|Bacterial infection is not responding because of inadequate antibiotic serum/tissue levels|
|Infection is associated with an undrained focus (e.g., abscess or prosthetic material [IV catheters])|
Table 47–6. Considerations for Regimen Modification: Day 5 ||Download (.pdf)
Table 47–6. Considerations for Regimen Modification: Day 5
|Progressive necrotizing mucositis/gingivitis||Anaerobic coverage (metronidazole)|
|Progressive ulcerating mucositis/gingivitis||Antiviral therapy (acyclovir)|
|Dysphagia||Antifungal (± antiviral) therapy if pseudomembranous pharyngitis|
|Cellulitis or inflammatory changes at venous access sites||Antistaphylococcal therapy (vancomycin)|
|Interstitial pulmonary infiltrates||TMP-SMX ± erythromycin|
|Consider bronchoalveolar lavage|
|Focal pulmonary infiltrates||Observe if ANC is recovering|
|Consider lung biopsy|
|Empiric amphotericin B
|Anaerobic disease coverage|
Persistently febrile severely neutropenic patients despite administration of at least 3 to 5 days of broad-spectrum antibacterial therapy are at risk of having an invasive fungal infection as the cause for the ongoing fever.55 Such patients are candidates for empiric antifungal therapy with amphotericin B deoxycholate,175,176 a lipid formulation of amphotericin B,177 an echinocandin, or with an extended-spectrum azole.178,179 The two randomized clinical trials upon which the practice of empiric antifungal therapy was based failed to demonstrate a treatment effect with respect to defervescence compared to an untreated control group (OR 0.13; 95% CI 0.01 to 1.26 for the study by Pizzo and colleagues175 and OR 0.14; 95% CI 0.02 to 1.23 for the EORTC study176).
While it is widely felt that the majority of persistent fevers in the setting of severe neutropenia do not represent invasive fungal infections, approximately 20% may be related to invasive fungal infection with an attendant high mortality rate sufficient to compel physicians to administer empiric antifungal therapy. Such strategies may be considered in patients persistently febrile after 7 days of broad-spectrum antibacterial therapy. Patients should undergo a second work-up for persistent fever to investigate the possibility of invasive fungal infection which includes blood cultures from peripheral and indwelling central venous access sites and sensitive HRCT images of the chest.67,68 In 60% of persistently febrile neutropenic patients with normal or nondiagnostic chest roentgenograms the HRCT scan of the chest demonstrated a pulmonary infiltrate.67 Such procedures can permit the earlier diagnosis and management of invasive mold infections involving the lungs by approximately 1 week.180
Surveillance cultures for detecting potential fungal pathogens have had some limited usefulness for predicting fungal infection. The recovery of filamentous fungi (e.g., Aspergillus species) in a nasopharyngeal surveillance culture in the clinical setting of a persistently febrile, profoundly neutropenic patient receiving broad-spectrum antibiotics and who develops new focal pulmonary infiltrates are to some extent predictive of Aspergillus pneumonia.181 The recovery of Candida albicans from oropharyngeal, rectal, or urine surveillance cultures has had a positive predictive value of 10% to 15% for systematic candidiasis. The recovery of other non-albicans Candida species such as Candida tropicalis, particularly from multiple sites, has had a positive predictive value of >70% for systemic infection. In contrast, the failure to recover Candida species in surveillance cultures has been associated with a negative predictive value of >90% for invasive disease from C. albicans or C. tropicalis.182 This experience suggests that clinicians cannot use surveillance cultures to predict the presence of a candidal infection (except perhaps for C. tropicalis). However, the clinician may be reassured by negative surveillance cultures that are properly obtained and processed, that antifungal therapy may not be indicated.55
Surrogate molecular markers of yeasts and molds are showing promise in the diagnosis of invasive fungal infection. Galactomannan is a component of the cell wall of Aspergillus spp., certain dematiaceous fungi such as Alternaria spp., and some Penicillium spp.,183–185 and has been used to aid in the diagnosis of invasive aspergillosis.180,186 A enzyme-linked immunosorbent serum assay which uses a rat monoclonal antibody EB-A2 that targets the D-galactofuranoside side chains of the Aspergillus spp. galactomannan187 has been developed for the diagnosis of invasive aspergillosis.188 The antibody may cross react with galactomannan-like materials from other molds such as Penicillium spp., Paecilomyces spp., and Alternaria spp.,189 or from foods that are exposed to molds originating from the soil during growth or harvesting, such as rice, pasta, cereals, and vegetables,190 and even milk191 consumed by premature infants.192 Translocation of dietary antigens into the blood of healthy adults is well documented.193 The antibody also cross-reacts with Bifidobacterium spp. lipoteichoic acid, an organism that heavily colonizes the gut of neonates and infants.194 Translocation of Bifidobacterium spp. has occurred in the setting of reduced integrity of the intestinal mucosal barrier.195 The clinical setting of severe mucositis or intestinal graft-versus-host disease with intestinal mucosal damage may be circumstances in which false-positive serum galactomannan tests may be expected. In addition, false-positive serum tests have been reported in association with administration of certain antibiotics such as piperacillin-tazobactam or amoxicillin derived from cross-reacting species of mold such as Penicillium spp.190,196–198 This has implications for clinicians using this test to investigate the possibility of invasive aspergillosis while administering drugs like piperacillin-tazobactam for the treatment of infection.
Duration of Antibacterial Therapy
In general, the IDSA recommendations for duration of the antibacterial regimen encompass the period until neutrophil recovery (ANC >0.5 × 109/L for at least two consecutive days), all signs and symptoms of infections have resolved, and the temperature has remained normal for 48 hours or more.55 For patients with prolonged severe neutropenia who have defervesced and for whom no focus of infection appears to be ongoing, the antibiotic regimen may be discontinued after 2 weeks provided the patient remains under careful observation. Some investigators have advocated substituting a fluoroquinolone-based antibacterial chemoprophylaxis regimen for the systemic antibacterial regimen under these circumstances.199 The response assessment definitions used in clinical trials of antibacterial therapy have often included a stipulation that the patient must remain afebrile for 4 to 5 days in addition to resolution of other signs and symptoms of infection in order for a response to be valid. This seems prudent and consistent with the natural history of these episodes. While the time until response to empiric antibacterial therapy varies with the underlying causes of neutropenia,17,50,200 the median time to response (defervescence) for high-risk patients is 5 to 7 days41,45,47,50,87,88,100 and 2 to 4 days for low-risk patients.138,139 If the antibacterial regimen is to be administered for an additional 4 to 5 days by the above criteria, then high-risk patients and low-risk patients would be expected to have received a 9- to 12-day and 6- to 9-day course of antibacterial therapy, respectively.