Vascular Catheter Infection in a Patient With Neutropenic Fever Case File
Eugene C. Toy, MD, Gabriel M. Aisenberg, MD
Case 42
A 24-year-old man presents to the emergency department complaining of a fever with shaking chills for the past 12 hours. He is currently being treated for acute lymphoblastic leukemia. His most recent chemotherapy session with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone was 7 days ago. He denies any cough or dyspnea, headache, abdominal pain, or diarrhea. He has had no sick contacts or recent travel. On physical examination, he is febrile to 103 °F and tachycardic with a heart rate of 122 beats per minute (bpm). His blood pressure is 118/65 mm Hg, and respiratory rate is 22 breaths per minute. He is ill appearing; his skin is warm and moist but without any rashes. His chest is clear to auscultation. His heart rate is regular with a soft systolic murmur at the left sternal border. The abdominal examination is benign. The perirectal area is normal. The digital rectal examination is deferred, and his stool is negative for occult blood. He has a tunneled vascular catheter at the right internal jugular vein without erythema overlying the subcutaneous tract or purulent discharge at the catheter exit site. He states he flushes the catheter each day and that yesterday he experienced a 20- to 30-minute episode of shaking chills about 10 minutes after flushing the catheter. Laboratory studies reveal a total white blood cell (WBC) count of 1100 cells/mm3, with a differential of 10% neutrophils, 16% band forms, 70% lymphocytes, and 4% monocytes (absolute neutrophil count [ANC] 286/mm3). Chest radiograph and urinalysis exams are normal.
▶ What is the most likely diagnosis?
▶ What are your next therapeutic steps?
ANSWERS TO CASE 42:
Vascular Catheter Infection in a Patient With Neutropenic Fever
Summary: A 24-year-old man presents with
- Acute lymphoblastic leukemia
- Fever of 103 °F
- History of immunosuppressive chemotherapy 7 days ago
- ANC of 286/mm3
- Central venous catheter (CVC) with history suggestive of possible infection
Most likely diagnosis: Neutropenic fever and possible vascular catheter infection; the high suspicion for these diagnoses is due to the symptomatic chills after the flushing of a catheter in a cancer patient with neutropenia.
Next therapeutic step: Blood cultures should be drawn on this patient, ideally simultaneously from the catheter and a peripheral vein. Immediately afterward, the patient should undergo broad-spectrum intravenous antibiotic administration, including coverage for gram-positive organisms such as Staphylococcus spp. The vascular catheter should be removed, if possible.
ANALYSIS
Objectives
- Recognize the possible sources of infection in a neutropenic patient. (EPA 1, 2)
- Discuss the management of a patient with neutropenic fever. (EPA 4)
- Explain how to diagnose and treat a catheter-related infection. (EPA 3, 4)
- Describe the strategies to prevent infection in immunosuppressed patients, including granulocyte colony-stimulating factor (G-CSF) and vaccination of household contacts. (EPA 4, 12)
Considerations
This patient is being treated for a hematologic malignancy with combination chemotherapy, which has a common side effect of leukopenia, especially neutropenia. Generally, the nadir of the white cell count occurs 7 to 14 days after the chemotherapy. This patient has neutropenia, defined as an ANC less than 1000 cells/mm3. The ANC is calculated by neutrophil percent multiplied by total WBC count. Infection in this immunosuppressed condition is life threatening, and immediate antibiotic coverage is paramount. Neutropenic patients are at risk for a variety of bacterial, fungal, or viral infections, but the most common sources of infection are the skin or oral cavity (gram-positive bacteria) and the bowel (gram-negative bacteria). Because of the absence of WBCs, the patient may not manifest the cardinal inflammatory signs. The spectrum of coverage of empirical antibiotics should include enterobacteria, Pseudomonas species, and penicillin-resistant pneumococci. Methicillin-resistant Staphylococcus aureus (MRSA) should also be considered in neutropenic patients with skin infections, pneumonia, suspected indwelling catheter infections, or sepsis. Rapid initiation of empiric antibiotic therapy is critical while attempts to find a source of infection are in progress.
APPROACH TO:
Neutropenic Fever
DEFINITIONS
CENTRAL LINE–ASSOCIATED BLOODSTREAM INFECTION (CLABSI): A primary bloodstream infection (ie, there is no apparent infection at another site) that develops in a patient with a central line in place within the 48-hour period before onset of the bloodstream infection that is not related to infection at another site. Culturing the catheter tip or peripheral blood is not a criterion for CLABSI.
CATHETER-RELATED BLOODSTREAM INFECTION (CRBSI): The presence of bacteremia originating from an intravenous catheter.
CENTRAL VENOUS CATHETER: A CVC is a catheter that is inserted into a large vein such as the subclavian, internal jugular, or femoral vein.
FEVER: Single oral temperature measurement greater than or equal to 101 °F (38.3 °C) or a temperature greater than or equal to 100.4 °F (38.0 °C) for 1 hour or more.
MUCOSITIS: Breakdown of skin and mucosal barriers as a result of chemotherapy or radiation. Mucositis can result in bacteremia or fungemia.
NEUTROPENIA: ANC less than 1000 cells/mm3. It is considered severe when the number is lower than 500 cells/mm3.
CLINICAL APPROACH
Pathophysiology
Fever in a neutropenic patient with cancer should be considered a medical emergency. Approximately 5% to 10% of cancer patients will die of neutropenia-associated infection. Individuals with a hematologic malignancy (leukemias or lymphomas) are at an even greater risk for sepsis as a result of lymphocyte or granulocyte dysfunction or because of abnormal immunoglobulin production. Chemotherapy often causes further bone marrow suppression and neutropenia. The incidence of an occult infection in a neutropenic patient increases with the severity and duration of the neutropenia (high risk if > 7-10 days, and especially if ANC < 100 cells/mm3). Some neutropenic patients (eg, the elderly or those receiving corticosteroids) may not be able to mount a febrile response to infection; thus, any neutropenic patient showing signs of clinical deterioration should be suspected of having sepsis.
CVCs are in widespread use and are common sites of infection in hospitalized patients and patients receiving outpatient infusion therapy. Infection may occur as a consequence of contamination by gram-positive skin flora or by hematogenous seeding, usually by enteric gram-negative organisms or Candida spp. Erythema, purulent drainage, and induration are signs of infection.
In the absence of obvious tunnel or exit-site infection, authorities recommend obtaining two or more blood cultures to try to diagnose catheter-related bacteremia, with at least one from the CVC. Catheter-related infection is suspected when a patient has two or more positive blood cultures obtained from a peripheral vein; clinical manifestations of infection (eg, fever, chills, and/or hypotension); and no alternative apparent source of bloodstream infection. In some institutions, quantitative blood cultures (counting colony-forming units [CFUs]) are obtained under the assumption that a four-fold higher colony count will be obtained from blood drawn from an infected catheter than blood drawn from a peripheral vein, supporting the diagnosis of catheter-related bacteremia. A blood culture that is drawn from the CVC that becomes positive at least 20 minutes before the peripheral blood cultures is an indication that the CVC is the likely source of infection. If the catheter is removed, the tip of the catheter may be cut off and rolled across a culture plate, using a quantitative culture method.
Clinical Presentation
The typical signs and symptoms of infection noted in immunocompetent patients are the result of the host’s inflammatory response. This may be minimal or absent in neutropenic patients. Soft tissue infections may have diminished or absent induration, erythema, or purulence; pneumonia may not show discernible radiologic infiltrates; meningitis may not reveal cerebrospinal fluid (CSF) pleocytosis; and urinary tract infection may be present without pyuria. Infected catheters may manifest as an infection of the subcutaneous tunnel, infection at the exit site, or catheter-related bacteremia and sepsis.
Treatment
Empiric antibiotic therapy should be administered promptly to all neutropenic patients at the onset of fever. Historically, gram-negative bacilli, mainly enteric flora, were the most common pathogens in these patients. Empiric coverage for gram-negative bacteria, including Pseudomonas aeruginosa, is almost always indicated for neutropenic fever. Early treatment is associated with reduced mortality. Currently, as a consequence of frequent use of CVCs, gram-positive bacteria account for 60% to 70% of microbiologically documented infections. Another clue that the infection is likely to be a gram-positive organism includes the presence of obvious soft tissue infections, such as cellulitis or oral mucositis. This causes breaks in the mucosal barriers and allows oral flora to enter the bloodstream. If any of these factors is present, an appropriate agent, such as vancomycin, should be added to the regimen. If patients continue to be febrile despite antibacterial therapy, empiric antifungal therapy should be considered. Figure 42–1 shows a useful algorithm for patient management.
Catheter-Related Infection. The two main decisions impacting suspected catheter-related infection are (1) whether the catheter is really the source of infection and, if it is, and (2) must the catheter be removed or can the infection be cleared with antibiotic therapy alone? Most nontunneled or implanted catheters should be removed. For more permanent catheters, the decision to remove the catheter depends on the patient’s clinical state, identification of the organism, and the presence of complications, such as endocarditis or septic venous thrombosis.
S. aureus and coagulase-negative Staphylococcus are the most common causes of catheter-associated infections. For coagulase-negative Staphylococcus bacteremia, response to antibiotic therapy without catheter removal is possible up to 80% of the time. Generally, erythema overlying the subcutaneous tract of a tunneled catheter necessitates catheter removal. Leaving the catheter in place may result in severe cellulitis and soft tissue necrosis. If there is only erythema at the exit site, it may be possible to salvage the line using antibiotics, usually vancomycin, through the CVC.
Considerations for removal would be those infections caused by fungi or nontuberculous mycobacteria or if there is persistent bacteremia after 48 to 72 hours of appropriate antimicrobial treatment. Keeping the catheter in place is also usually not advisable in critically ill or hemodynamically unstable patients. Bacteremia as a consequence of S. aureus, gram-negative organisms, and fungemia caused by Candida spp responds poorly to antimicrobial therapy alone. Therefore, prompt removal of the catheter is recommended.
Prevention. Because of the serious complications associated with neutropenia, preventive measures are critical in cancer patients who are receiving chemotherapy. Patients should be immunized against pneumococcus and influenza. Administration of live virus vaccines, such as measles-mumps-rubella or varicella zoster, is generally contraindicated. G-CSF, which stimulates the bone marrow to produce neutrophils, is frequently used prophylactically in patients receiving chemotherapy to shorten the duration and depth of neutropenia, thereby reducing the risk of infection. It is sometimes used after a neutropenic patient develops a fever, but its use at this point is controversial and may result in more harm than benefit.
Prophylactic use of oral quinolones to prevent gram-negative infection or the use of antifungal agents to prevent Candida infection may reduce certain types of infection, but it may also lead to the emergence of resistant organisms. Thus, this is recommended for patients who are anticipated to have an ANC < 100 cells/mm3 for more than 7 days; antiviral agents are also recommended to reduce the risk of herpes simplex virus and varicella zoster reactivation in this setting. Other recommendations include avoiding sick contacts and overcrowded areas, as well as proper handwashing and cough etiquette. Slight trauma to mucosal surfaces can cause bacteremia, so careful oral hygiene, avoidance of rectal thermometers or rectal examinations, and skin care are also important.
CASE CORRELATION
- See also Case 40 (Anaphylaxis/Drug Reactions) and Case 41 (Urinary Tract Infection and Sepsis in the Elderly).
COMPREHENSION QUESTIONS
42.1 A 64-year-old man has been hospitalized for intravenous antibiotics due to osteomyelitis. A CVC was placed to infuse antibiotics. After 5 days, he developed a fever, and 48-hour blood cultures were positive for growth. The clinician suspects that an infected CVC is responsible. Which of the following is the most likely offending organism?
A. Candida albicans
B. Coagulase-negative Staphylococcus
C. Klebsiella pneumoniae
D. Pseudomonas aeruginosa
E. Streptococcus pyogenes
42.2 A 32-year-old man with acute myelogenous leukemia is undergoing chemotherapy. He was hospitalized 7 days ago for fever to 102 °F with an ANC of 100 cells/mm3, and he has been placed on intravenous imipenem and vancomycin. He continues to have fever to 103 °F without an obvious source. Which of the following is the best next step?
A. Add an aminoglycoside antibiotic.
B. Add an antifungal agent.
C. Continue present therapy.
D. Perform lumbar puncture to assess CSF.
E. Stop all antibiotics because he likely has drug fever.
42.3 A 68-year-old woman is diagnosed with acute leukemia and is undergoing induction chemotherapy. Last cycle, she developed neutropenia with an ANC of 350 cells/mm3, which has now resolved. Which of the following is the most appropriate therapy?
A. Immunization against mumps
B. Immunization against varicella
C. Use of G-CSF after the next cycle of chemotherapy
D. Use of recombinant erythropoietin before the next cycle of chemotherapy
ANSWERS
42.1 B. Coagulase-negative staphylococci, such as Staphylococcus epidermidis, along with S. aureus are the most common etiology of catheter-related infections because they are part of the skin flora. The other bacteria are isolated at a much lower frequency, such as Klebsiella species and Pseudomonas species (answers C and D), and even less common is C. albicans (answer A).
42.2 B. Antifungal therapy should be added when the fever is persistent for 5 to 7 days despite broad-spectrum antibacterial agents. Patients with neutropenia, defined as an ANC less than 1000 cells/μL, are at greater risk for bacterial (gram-positive and gram-negative) and fungal infections such as caused by C. albicans and Aspergillus. Answer A (aminoglycoside) would not add much coverage to imipenem, which already has excellent gram-negative coverage. Answer C (continue present therapy) is not wise with the persistent fever. Answer D (lumbar puncture) is not indicated since there is no sign of meningeal irritation. Answer E (stop all antibiotics) is not prudent in this immunosuppressed patient.
42.3 C. Granulocyte colony-stimulating factor administered after chemotherapy may decrease the duration and severity of neutropenia and the subsequent risk of sepsis in these patients. Live vaccines, such as varicella (answer B) and mumps (answer A), are contraindicated in immunosuppressed individuals. Erythropoietin (answer D) is not indicated since the patient is not anemic.
CLINICAL PEARLS
▶ Fever in a neutropenic patient should be considered a medical emergency and is associated with a high mortality rate.
▶ The usual sources of bacterial infection in neutropenic patients are the skin and mouth (gram-positive organisms) and the intestine (gram-negative enteric flora, including Pseudomonas.
▶ Antibiotics should be started within 60 minutes of presentation of neutropenic fever.
▶ Antifungal therapy should be started in neutropenic patients who have persistent fever despite broad-spectrum antibiotic therapy and who have no obvious source of infection.
▶ Vascular catheters should be removed if there is apparent evidence of a purulent infection or subcutaneous tract at the catheter site, there is an infection caused by a nontuberculous mycobacteria or fungi, or the infection is not properly controlled after 48 to 72 hours of appropriate antibiotic therapy.
▶ If a catheter is deemed necessary but is infected with coagulase-negative staphylococci, antibiotic treatment may sterilize the catheter, allowing it to remain in place.
REFERENCES
Finberg R. Infections in patients with cancer. In: Jameson JL, Fauci AS, Kasper SL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2015:484-492.
Hall K, Farr B. Diagnosis and management of long-term central venous catheter infections. J Vasc Interv Radiol. 2004;15:327.
Pizzo PA. Fever in immunocompromised patients. N Engl J Med. 1999;341:893-900.
Schiffer CA, Mangu PB, Wade JC, et al. Central venous catheter care for the patient with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncl. 2013;31:1357-1370.
Tapliz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36:3043-3054.
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