Immunocompromised host

Question 1

neutropenia

Answer 1

decreased neutrophils in peripheral blood

ANC less than 1000

Question 2

ANC =

Answer 2

WBC x (%polys + %bands)

Question 3

risk for infection in neutropenic patients

Answer 3

ANC under 500 = high risk
ANC under 100 = risk of death greatest
inc risk of infection with rapid ANC decline
duration of neutropenia
severe neutropenia for more than 7-10 days = high risk of serious infections

Question 4

common pathogens in neutropenia

Answer 4

Bacteria: S. aureus, S. epidermidis, streptococci, enterococci, E. coli, K. pneumoniae, P. aeruginosa,
Fungi: Candida, Aspergillus, Zygomycetes (Mucor, Rhizopus)
Viruses: Herpes simplex virus (HSV)

Question 5

defects in T-lymphocyte and macrophage function

Answer 5

cell-mediated immunity**
Result of underlying disease (Hodgkin’s lymphoma) or immunosuppressive drug therapy in transplant patients (cyclosporine, tacrolimus, sirolimus, mycophenolate, corticosteroids, antineoplastic agents, azathioprine)
Result in reduced ability of the host to defend against intracellular* pathogens
Common pathogens:
-Bacteria: Listeria, Nocardia, Legionella, Mycobacteria
-Fungi: C. neoformans, Candida, Aspergillus, Histoplasma capsulatum
-Viruses: Cytomegalovirus (CMV), Varicella-Zoster virus (VZV), HSV
-Protozoal: Pneumocystis jiroveci

Question 6

defects in B-cell funciton

Answer 6

humoral immunity**
Due to underlying diseases (multiple myeloma, chronic lymphocytic leukemia), splenectomy, and immunosuppressive therapy (steroids, chemotherapy)
Common bacterial pathogens (encapsulated) – S. pneumoniae, H. influenzae, N. meningitidis

Question 7

destruction of skin

Answer 7

Venipuncture, bone marrow aspiration, vascular access devices, radiation, biopsies, surgery
Common pathogens – S. aureus, S. epidermidis, Candida species

Question 8

destruction of mucus membrane of the oropharynx and GI tract

Answer 8

Respiratory support equipment, endoscopy, chemotherapy, radiation
Common pathogens:
-Bacteria: S. aureus, S. epidermidis, Enterobacteriaceae, streptococci, P. aeruginosa, Bacteroides species
-Fungi: Candida species
-Viruses: HSV

Question 9

SOT

Answer 9

Bacteria: S. aureus, S. epidermidis, Enterobacteriaceae, P. aeruginosa, Bacteroides species
Fungi: Candida species
Viruses: HSV

Question 10

environmental contamination/alteration of microbial flora

Answer 10

Most infections in cancer patients are caused by organisms colonizing the skin, oropharynx, and GI tract (GI tract is most common site).
Bacteremias are caused predominantly by normal flora of the gut – develop as a result of microbial translocation across injured GI mucosa.
Organisms easily transferred from patient to patient on hands of health-care workers, contaminated equipment, contaminated water supplies, and fruits and green leafy vegetables (often colonized with gram-negative bacteria and fungi)
Alteration of normal flora; oropharyngeal flora rapidly change to primarily gram-negative bacilli in hospitalized patients
-Hospital environment, antimicrobial therapy, chemotherapy (cyclophosphamide, doxorubicin, 5-FU, methotrexate)
-≈ 50% of infections in hospitalized cancer patients due to colonizing organisms acquired after admission → more resistant and difficult to eradicate
-Common pathogens: Bacteria: Enterobacteriaceae, P. aeruginosa, S. aureus, S. epidermidis; Fungi: Candida, Aspergillus
-Broad spectrum antimicrobial therapy – greatest impact on normal flora

Question 11

epidemiology of infections in neutropenic cancer patients

Answer 11

30-40% microbiologically documente - some only have fever - TREAT EVERYONE
most are due to gram positive cocci

Question 12

bacterial infections in neutropenic cancer patients

Answer 12

Staphylococci – S. aureus (especially MRSA), coagulase-negative staphylococci
Viridans streptococci – may be β-lactam resistant; important pathogen in patients with chemotherapy-induced mucositis of the oropharynx
Gram-positive infections do not always cause immediate life-threatening infections and are associated with lower mortality rates than gram-negative infections.
Enterobacteriaceae – E. coli and Klebsiella species are most common (ESBL? CRE?); Enterobacter, Serratia, and Citrobacter increasing in prevalence
P. aeruginosa – incidence decreased in patients with solid tumors but not in patients with hematologic malignancies; morbidity and mortality remain very high
Organisms increasing as pathogens: enterococci including VRE (mortality rate >70% in neutropenic patients), Lactobacillus (intrinsic resistance to vancomycin); S. maltophilia, B. cepacia

Question 13

invasive fungal infections in neutropenic cancer patients

Answer 13

Extended periods of profound neutropenia with administration of broad spectrum antibiotics and/or corticosteroids – high risk
Up to 1/3 of febrile neutropenic patients who do not respond to 1 week of broad spectrum antibiotics will have a systemic fungal infection; a large international autopsy study found that up to 40% of patients with hematologic malignancies had deep fungal infections which were not diagnosed prior to death (65% due to Candida; 35% due to Aspergillus)
Candida albicans – most common cause of fungal infections
-Up to 60% of immunocompromised cancer patients develop thrush
-Candida may disseminate to involve esophagus, blood, and organs (liver, spleen)
-Mucus membranes damaged by chemotherapy or radiation → colonized by Candida → enter bloodstream → dissemination
-Isolated from blood in less than 25% of patients infected with Candida
Other Candida species increasing in frequency – C. glabrata, C. tropicalis, C. parapsilosis, C. krusei
Aspergillus species
-Seen primarily in patients with hematologic malignancies and in patients undergoing HSCT
-Acquired by inhalation of airborne spores
-After lung colonization, Aspergillus invades lung parenchyma and pulmonary vessels → hemorrhage, pulmonary infarcts → high mortality rate (35-80%)
-May cause other infections – sinusitis, cutaneous infections, disseminated disease
-Primary risk factor for invasive aspergillosis – prolonged neutropenia***

Question 14

HSV in neutropenic cancer patients

Answer 14

Clinical disease usually in patients with serologic evidence of prior HSV infection
Reactivation, manifesting as gingivostomatitis or recurrent genital infection
Untreated oropharyngeal HSV may spread to involve esophagus and may co-exist with Candida infection

Question 15

Pneumocystis jiroveci, Toxoplasma gondii in neutropenic cancer patients

Answer 15

routine prophylaxis with TMP/SMZ has substantially reduced the incidence

Question 16

clinical presentation of infections in neutropenic cancer patients

Answer 16

Presence of fever – most important clinical finding (may be only clinical finding)***
-Single oral temperature of ≥ 38.3°C (≥ 101°F) in the absence of other causes or oral temperature ≥ 38°C (≥ 100.4°F) persisting for 1 hour or longer
-Consider fever to be due to infection until proven otherwise
-Other causes of fever (unrelated to infection) – administration of blood products, chemotherapeutic agents, drug fever, cell lysis, underlying malignancy
Other signs and symptoms of infection are usually absent because of neutropenia

Question 17

lab and diagnostic tests in infections in neutropenic cancer patients

Answer 17

Blood cultures – at least 2 sets (1 from IV catheter, 1 from peripheral vein) for bacteria and fungi; if multi-lumen catheter, obtain a set from each lumen; if no IV catheter, 2 venipunctures from different sites.
Obtain other cultures as clinically indicated (e.g., urine, sputum, etc.)
CBC with differential, serum creatinine, BUN, electrolytes, LFTs, total bilirubin
Chest x-ray – if respiratory signs or symptoms
Aspiration, biopsy of skin lesions
Other diagnostic tests as indicated clinically based on PE and other assessments

Question 18

assessment of patient’s risk of infection

Answer 18

Evaluate at presentation of fever to help determine type of empiric antibiotic therapy (PO vs. IV), location of treatment (outpatient vs. inpatient), and duration of therapy
Low risk – neutropenia for ≤ 7 days; no or few comorbidities; clinically stable at onset of fever; no identified focus of infection or simple infection (e.g., UTI) → broad spectrum therapy initially in clinic or hospital setting, then may transition to outpatient IV or oral therapy
High risk – profound (ANC ≤ 100 cells/mm3) and prolonged neutropenia (> 7 days) and/or significant medical co-morbid conditions including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes → broad spectrum, parenteral (IV) therapy, admit to the hospital for empiric therapy

Question 19

antimicrobial treatment regimens overview

Answer 19

Empiric regimen should possess activity against the most likely pathogens
Antipseudomonal coverage should be included in regimen, despite decreasing frequency of P. aeruginosa infections

Question 20

algorithm for initial management of febrile neutropenic patients - low risk

Answer 20

patient presents with fever (>100.9 or >100.4 for 1 hour) AND ANC under 500 or under 100 with anticipated drop
cultures, eval, PE and risk assessment
low risk: Anticipated neutropenia ≤ 7 days,
clinically stable, no medical comorbidities, and
outpatient at fever onset
adequate outpatient infrastructure and candidate for oral: cipro + amox/clav
-Observe after first dose for 4-24 hours, patient remains stable, tolerates antibiotics, follow-up plan in place, close proximity, discharge to outpatient care
inadequate outpatient infrastructure or not a candidate for oral regimen - inpatient IV monotherapy antibiotics: Pip/tazo, antipseudomonal carbapenem, cefepime
-Consider step-down to PO therapy when appropriate (afebrile ≤ 72 hours of starting IV therapy, hemodynamic stability, absence of positive cultures or site of infection, ability to take PO medications

Question 21

algorithm for initial management of febrile neutropenic patients - high risk

Answer 21

patient presents with fever (>100.9 or >100.4 for 1 hour) AND ANC under 500 or under 100 with anticipated drop
cultures, eval, PE and risk assessment
high risk: Anticipated neutropenia > 7 days,
clinically unstable, any medical cormorbidities, HSCT,
or inpatient at fever onset
Inpatient IV antibiotics (monotherapy): Piperacillin/tazobactam, Antipseudomonal carbapenem, Cefepime
Add IV vancomycin for cellulitis, pneumonia, severe sepsis or shock, gram-positive bacteremia, suspected IV catheter infection, known colonization with MRSA, or resistant streptococci
For septic shock, gram-negative bacteremia or pneumonia: Add aminoglycoside or antipseudomonal fluoroquinolone. Consider empiric antifungal therapy for septic shock

Question 22

B-lactam monotherapy for empiric treatment of febrile neutropenia

Answer 22

Options: (ceftazidime 2 grams q8h;) cefepime 2 grams q8h; piperacillin/tazobactam 4.5 grams q6h; imipenem 500 mg q6h; meropenem 1 gram q8h
Advantages: comparable efficacy to combination regimens; decreased drug toxicities; ease of administration; possibly less expensive
Disadvantages: limited gram-positive activity with ceftazidime; no potential for additive or synergistic effects; selection of resistant organisms; increased colonization and superinfection rates

Question 23

addition of vanco to antipseudomonal B-lactam

Answer 23

IDSA does not* recommend vancomycin or other gram-positive agents as a standard part of the initial** antibiotic regimen.
Indications for addition of gram-positive agent to empiric regimen: Hemodynamic instability or other evidence of severe sepsis, Radiographically documented pneumonia, Positive blood cultures for gram-positive pathogen before final identification and susceptibility test results known, Clinically suspected serious catheter-related infection (e.g., cellulitis around the catheter entry/exit site), Skin or soft tissue infection at any site, Colonization with MRSA, VRE, or PRSP, Severe mucositis – if fluoroquinolone prophylaxis has been given or if ceftazidime used as empiric therapy

Question 24

pen-allergic patients - empiric antibiotic regimens for febrile neutropenia

Answer 24

Avoid β-lactams and carbapenems if history of immediate-type hypersensitivity reaction (e.g., hives, bronchospasm)
Ciprofloxacin plus aztreonam plus vancomycin

Question 25

oral antibiotic regimens for low-risk patients for empiric antibiotic regimens for febrile neutropenia

Answer 25

Examples: ciprofloxacin plus amoxicillin/clavulanate; ciprofloxacin plus clindamycin; levofloxacin monotherapy Advantages: comparable efficacy with parenteral therapy in low risk patients; less expensive; reduced exposure of patients to nosocomial pathogens Disadvantages – least studied treatment option; less potent than parenteral therapy; requires compliant patient with 24 hour access to medical care if clinical instability develops; should not be used in patients receiving fluoroquinolone prophylaxis

Question 26

management of antimicrobial therapy AFTER initiation of empiric therapy

Answer 26

Re-evaluate clinical status of patient after 48-72 hours of empiric antimicrobial therapy Addition or modification to initial regimen may be required, especially in patients with ANC under 500/mm3 for > 1 week -If MRSA – consider early addition of vancomycin, linezolid, or daptomycin -If VRE – consider early addition of linezolid or Daptomycin -If ESBL producer – consider early use of a carbapenem -If KPC producer – consider early use of polymyxin B or colistin in combination, ceftazidime/avibactam (? combination) Median time to defervescence in febrile neutropenic cancer patients receiving empiric antibiotic therapy is 5-7 days.

Question 27

Management of patients after 2-4 days of empiric antibacterial therapy - low risk

Answer 27

unexplained fever: -persistent fever or clinically unstable: hospitalize for broad-spectrum IV antibiotics - modify antibiotics to culture results and/or infection site - continue AB for 7-14 days as appropriate for infection or until ANC over 500 and rising -defeversed or cultures negative: continue oral or IV antibiotics until ANC over 500 and rising documented infection: modify antibiotics according to culture results and/or infection site -responding: continue AB for 7-14 days as appropriate for infection or until ANC over 500 and rising -non-responding: examine and re-image (CT, MRI) for new or worsening sites of infection; culture/biopsy/drain sites of worsening infection; assess for bacterial, viral and fungal pathogens; review antibiotic coverage for adequacy of dosing and spectrum; consider adding empiric antifungal therapy; broaden antimicrobial coverage for hemodynamic instability

Question 28

Management of patients after 2-4 days of empiric antibacterial therapy - high risk

Answer 28

unexplained fever: -persistent fever; stable clinically - no changes in empiric antibiotics; assess for infection sites -defeversed; cultures negative - continue antibiotics until ANC over 500 and rising - recurrent fever during persistent neutropenia documented infection: modify antibiotics according to culture results and/or infection site -responding: continue AB for 7-14 days as appropriate for infection or until ANC over 500 and rising -non-responding: examine and re-image (CT, MRI) for new or worsening sites of infection; culture/biopsy/drain sites of worsening infection; assess for bacterial, viral and fungal pathogens; review antibiotic coverage for adequacy of dosing and spectrum; consider adding empiric antifungal therapy; broaden antimicrobial coverage for hemodynamic instability

Question 29

management of high risk patient with fever after 4 days of empiric antibiotics

Answer 29

daily examination and history; blood cultures - repeat on limited basis; cultures for any suspected sites of infection unexplained fever: clinically stable; rising ANS; myeloid recovery imminent - oberve; no antimicrobial changes unless clinical microbiologic or radiographic; data suggest new infection unexplained fever: clinically stable; myeloid recovery not imminent; consider CT scan sinuses and lungs -receiving fluconazole prophylaxis: ---pre-emptive approach: start antifungal based upon results of: CT scans chest/sinuses; serial serum galactomannan tests ---empirical antifungal therapy with anti-mold coverage: echinocandin, voriconazole, AmpB preparation -receiving anti-mold prophylaxis - empiric antifungal therapy: consider switch to a different class of mold active antifungal documented infection: clinically unstable, worsening signs and symptoms of infection - examine and re-image for new or worsening sites of infection; culture/biopsy/drain sites of worsening infection; assess for bacterial, viral and fungal pathogens; review antibiotic coverage for adequacy of dosing and spectrum; consider adding empiric AF therapy; broaden antimicrobial coverage for hemodynamic instability

Question 30

initiation of antifungal therapy

Answer 30

Persistence of fever or development of new fever during broad-spectrum antibacterial therapy may indicate presence of fungal infection Begin empiric antifungal therapy in neutropenic patients who remain febrile with undocumented infection after 4-7 days of broad-spectrum antibiotics (if duration of neutropenia is expected to be > 7 days) High incidence of invasive fungal infection at autopsy Blood cultures are positive in under 50% of neutropenic patients with invasive fungal infections Antifungal treatment options -Amphotericin B or liposomal amphotericin -Azoles: fluconazole, itraconazole, voriconazole, isavuconazole, posaconazole -Echinocandins: caspofungin, micafungin, anidulafungin Continue antifungal therapy for at least 2 weeks in the absence of signs and symptoms of active fungal disease (may continue until resolution of neutropenia)

Question 31

initiation of antiretroviral therapy

Answer 31

Evaluate for HSV or VZV in neutropenic patients with vesicular or ulcerative skin or mucosal lesions Initiate aggressive antiviral therapy if viral infection is presumed or documented to aid healing of primary lesions and prevent dissemination HSV, VZV – acyclovir; CMV - ganciclovir

Question 32

catheter-related bacteremia

Answer 32

Most often due to S. aureus and coagulase-negative staphylococci Diagnose when blood cultures from peripheral blood and catheter are positive Indications for catheter removal -Subcutaneous tunnel infection -Failure to clear bacteremia within 72 hours of initiation of antimicrobial therapy -Persistence of fever -Septic emboli -Bacteremia due to fungi, Bacillus species, or C. jeikeium Removal of catheter may be adequate for resolution of fungal infection; 10-14 days of amphotericin or fluconazole may avoid development of disseminated candidiasis

Question 33

In documented infection, continue antimicrobial therapy until eradication of pathogen and signs/symptoms have resolved

Answer 33

Skin/soft tissue infection – 7-14 days Central line-associated bloodstream infection (CLABSI) – catheter removal and systemic antimicrobial therapy for at least 14 days; if complicated CLABSI (presence of deep tissue infection, endocarditis, septic thrombosis, or persistent bacteremia or fungemia > 72 hours after catheter removal in patient receiving appropriate therapy), treat for 4-6 weeks. Sinusitis – 10-21 days Bacterial pneumonia – 10-21 days Fungal: mold (e.g., Aspergillus) – minimum of 12 weeks Viral: HSV or VZV – 7-10 days; influenza – 5 days (oseltamivir)

Question 34

Most important determinant of patient outcomes

Answer 34

resolution of neutropenia******

Question 35

prophylaxis of infections in neutropenic cancer patients

Answer 35

Reverse isolation with strict adherence to infection control guidelines by HCWs Laminar air flow rooms to reduce risk of airborne pathogens (Aspergillus) Fluoroquinolone prophylaxis should be considered in moderate to high-risk patients with expected prolonged and profound neutropenia (ANC ≤ 100/mm3 for > 7 days; hematologic malignancy [acute leukemia], allogeneic and autologous HSCT, GVHD with high-dose steroids, use of alemtuzumab, multiple myeloma, lymphoma, CLL) Antifungal prophylaxis TMP/SMZ – substantially reduces risk of P. jiroveci pneumonia Anti-viral prophylaxis

Question 36

FQ for prophylaxis of infections in neutropenic cancer patients

Answer 36

Ciprofloxacin or levofloxacin FQ prophylaxis during periods of neutropenia decreases the incidence of fever and microbiologically documented gram-negative infections and may decrease risk of death. Poor activity of ciprofloxacin against gram-positive organisms (staphylococci, viridans streptococci, S. pneumoniae, E. faecalis) If patient develops breakthrough infection during FQ prophylaxis, do not treat with a FQ-based empiric antibiotic regimen.

Question 37

antifungal prophylaxis in neutropenic cancer patients

Answer 37

Goal: prevent development of invasive fungal infection during periods of risk (moderate to high-risk patients) Who should receive antifungal prophylaxis? -Allogeneic hematopoietic stem cell transplant recipient -Patients undergoing intensive remission-induction or salvage-induction chemotherapy for acute leukemia What drugs may be used for antifungal prophylaxis? -Azoles: fluconazole, itraconazole, voriconazole, posaconazole -Echinocandins: caspofungin, micafungin Posaconazole prophylaxis for invasive Aspergillus infections for selected patients ≥ 13 years of age undergoing intensive chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Question 38

antiviral prophylaxis in neutropenic cancer patients

Answer 38

Acyclovir prophylaxis in HSV-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy to reduce risk of HSV reactivation. Annual influenza vaccination with inactivated*** vaccine is recommended for all patients Varicella vaccine – provides good protection (90%) in leukemic children; may be useful in seronegative adults