Introduction
Guideline development, grading of recommendations, and definitions
Strength of recommendation
|
AGIHO
|
Grade A | Strongly supports a recommendation for use |
Grade B | Moderately supports a recommendation for use |
Grade C | Marginally supports a recommendation for use |
Grade D | Supports a recommendation against use |
Quality of evidence
| |
Level I | Evidence from at least 1 properly designed randomized, controlled trial |
Level IIa
| Evidence from at least 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from ≥ 1 center); from multiple time series; or from dramatic results of uncontrolled experiences |
Level III | Evidence from opinions of respected authorities, based on clinical experience, descriptive case studies, or reports of expert committees |
Definitions
Risk stratification
-
Standard risk: expected duration of neutropenia of up to 7 days and
-
High risk: expected duration of neutropenia of at least 8 days.
Characteristic | Weight |
---|---|
Burden of febrile neutropenia with no or mild symptomsa
| 5 |
No hypotension (systolic blood pressure > 90 mmHg) | 5 |
No chronic obstructive pulmonary disease | 4 |
Solid tumor or hematologic malignancy with no previous fungal infection | 4 |
No dehydration requiring parenteral fluids | 3 |
Burden of febrile neutropenia with moderate symptomsa
| 3 |
Outpatient status | 3 |
Age < 60 years | 2 |
General | No signs of CNSa infection, severe pneumonia, or venous catheter infection |
No signs of sepsis or shock | |
None of the following: associated organ failure, pronounced abdominal pain (±diarrhea), dehydration, recurrent vomiting, intravenous supportive therapy, necessity of permanent or close monitoring (e.g., metabolic decompensation, hypercalcemia) | |
No new ECG abnormalities requiring treatment | |
No new severe organ impairment | |
Oral antibiotics | No fluoroquinolone prophylaxis or therapy within the last 7 days |
Oral medication feasible | |
Good compliance with oral medication expected | |
Outpatient management | Medical care ensured (different options) |
Patient does not live alone; patient/helpers have a telephone; patient can reach clinic skilled at treatment of neutropenic patients within 1 h | |
Patient is conscious, knows, and understands the risks |
Epidemiology
Most common pathogens identified in febrile neutropenic patients with microbiologically documented infections
Local epidemiology and impact of oral fluoroquinolone prophylaxis
Diagnosis
Baseline diagnostic procedures before immunosuppressive therapy
Screening of asymptomatic neutropenic patients for invasive fungal infections
Diagnostic procedures at onset of fever in neutropenia
Clinical signs and symptoms | Frequently involved pathogens |
---|---|
Erythema and/or pain at venous access | Coagulase-negative staphylococci |
Mucosal ulcers | Alpha-hemolytic streptococci, Candida spp. |
Single point-like skin lesions | Gram-positive cocci, Candida spp. |
Necrotizing skin lesions |
Pseudomonas aeruginosa, filamentous fungi |
Diarrhea, meteorism |
Clostridium difficile
|
Enterocolitis, perianal lesions | Polymicrobial (incl. anaerobes) |
Lung infiltrates ± sinusitis | Filamentous fungi, Pneumocystis jirovecii
|
Retinal infiltrates | Candidemia |
Antimicrobial therapy
Antibacterial agents for empirical first-line therapy
Antibacterial combination therapy
Empirical first-line antibacterial therapy in standard-risk patients with FUO
Monitoring of inflammatory laboratory parameters during first-line empirical antibacterial therapy
Re-evaluation of patients after ≥ 96 h of first-line empirical antibacterial therapy
Modifying antibiotic treatment in non-responders
Risk groups | ||
---|---|---|
Standard risk (≤ 7 days) | High risk (≥ 8 days) | |
First-line | Outpatient therapy possible: • Amoxicillin/clavulanate + ciprofloxacin • Clindamycin + ciprofloxacin • Cefuroxime axetil + ciprofloxacin • Moxifloxacin | • Piperacillin/tazobactam • Ceftazidime, cefepime • Imipenem, meropenem |
Hospitalization required: • Ceftazidime, cefepime • Piperacillin/tazobactam • 3rd/4th-generation cephalosporin + aminoglycoside | ||
2nd-line, if indicated | • Imipenem, meropenem | • After piperacillin/tazobactam or ceftazidime or cefepime: imipenem, meropenem |
• After failure of outpatient regimen also consider piperacillin/tazobactam | • After imipenem or meropenem: addition of vancomycin or teicoplanin or aminoglycosidea
plus
• Mold-active antifungal |
Empirical antifungal treatment in high-risk patients
Level | Evidence | |
---|---|---|
cAmB | D | I |
ABLC | D | I |
ABCD | D | I |
L-AmB | A | I |
Caspofungin | A | I |
Itraconazole IV | C | I |
Micafungin | C | I |
Voriconazole | B | I |
Empirical antiviral treatment
Adjunctive measures
Granulocyte colony-stimulating factor
Polyclonal immunoglobulins
Removal or change of a central venous catheter and hygiene
Duration of empirical antimicrobial therapy after defervescence
Summary of recommendations Tables 7, 8, 9, and 10
Patient population | Intention | Intervention | Strength of recommendation | Quality of evidence |
---|---|---|---|---|
High-risk neutropenia | Identify previous infection | Take history and perform physical examination | A | III |
High-risk neutropenia | Identify previous infection | Order chest radiograph (2 views)a
| C | III |
High-risk neutropenia | Identify previous infection | Order abdominal ultrasounda
| C | III |
High-risk neutropenia | Identify colonization with VRE or MRSA | Take nasal/pharyngeal (MRSA) or rectal (VRE) swabs | B | III |
High-risk neutropenia | Identify colonization with ESBL | Take rectal swabs | B | IIt |
Patient population | Intention | Intervention | Strength of recommendation | Quality of evidence |
---|---|---|---|---|
Febrile neutropenia | Identify focus of infection | Take history and perform physical examination | A | III |
Febrile neutropenia | Diagnose blood stream infection | Take at least 2 separate sets of blood cultures (BC) prior to start of antimicrobial therapy | A | II |
Febrile neutropenia, indwelling central venous catheter (CVC) | Diagnose CVC infection | Take at least 1 set of BC from peripheral vein and 1 set of BC from CVC | A | II |
Febrile neutropenia, no respiratory symptoms | Diagnose pneumonia | Order chest radiograph | D | II |
Febrile neutropenia, respiratory symptoms | Diagnose pneumonia | Order thoracic CT scan | B | III |
Persistent (≥ 96 h) febrile neutropenia | Diagnose pneumonia | Order thoracic CT scan | B | II |
Patient population | Intention | Intervention | Strength of recommendation | Quality of evidence |
---|---|---|---|---|
Febrile neutropenia | Cure | Start antibiotic therapy (ABT) within 2 h | A | III |
Outpatient febrile neutropenia, standard risk | Cure | Consider oral ABT with amoxicillin/clavulanate + ciprofloxacin or with moxifloxacin | A | I |
High-risk febrile neutropenia | Cure | Intravenous ABT with piperacillin/tazobactam, imipenem, meropenem, cefepime, or ceftazidime | A | I |
Persistent (≥ 96 h) high-risk febrile neutropenia, no mold-active prophylaxis | Cure | Empirical antifungal therapy with caspofungin or liposomal amphotericin B | A | I |
Substance | Application | Dosage |
---|---|---|
Amoxicillin/clavulanate | Oral | 1000 mg twice or 3 times daily |
Ciprofloxacin | Oral | 500–750 mg twice daily |
Levofloxacin | Oral | 500 mg twice daily |
Moxifloxacin | Oral | 400 mg once daily |
Piperacillin/tazobactam | Intravenous | 4.5 g 3 or 4 times daily |
Meropenem | Intravenous | 1 g 3 times daily |
Imipenem | Intravenous | 0.5–1 g 4 times daily |
Ceftazidime | Intravenous | 2 g 3 times daily |
Cefepime | Intravenous | 2 g 3 times daily |
Gentamicina
| Intravenous | 1.5–2.0 mg/kg 3 times daily or 4.5–6.0 mg/kg once daily |
Tobramycina
| Intravenous | 1.5–2.0 mg/kg 3 times daily or 5.0–6.0 mg/kg once daily |
Amikacina
| Intravenous | 7.5 mg/kg twice daily or 15 mg/kg once daily |
Vancomycina
| Intravenous | 1 g twice daily |
Teicoplaninb
| Intravenous | 400 mg once daily with one additional loading dose 12 h after the first dose |
Caspofungin | Intravenous | 70 mg day 1, 50 mg once daily from day 2 onwards |
Liposomal amphotericin B | Intravenous | 3 mg/kg once daily |