Title: Infections in Patients with Cancer and Hematopoietic Stem Cell Transplantation: Approaches to Empiri
1Infections in Patients with Cancer and
Hematopoietic Stem Cell TransplantationApproache
s to Empirical Therapy and Prophylaxis
2What is the Impact of Infectious Diseases
Supportive Care in Patients with
Cancer/Transplantation?
- Infections cause significant morbidity and
mortality in children and adults with cancer. - Advances in infectious diseases supportive care
have been a critical factor in reducing morbidity
and in improving survival in oncology BMT. - Strategies of empirical therapy and prophylaxis
have been at the forefront of these advances in
infectious diseases supportive care.
3What are the Risk Factors for Infection in
Patients with Cancer/Transplantation?
- Malignancy per se
- Treatment of the malignancy
- Chemotherapy
- Immunotherapy
- Surgery
- Radiation
4What are the Risk Factors for Infection in
Patients with Cancer/Transplantation?
- Neutropenia
- Depth of Nadir
- Duration of Neutropenia
- Mucosal Disruption/Altered mucocutaneous flora
- Non-myeloablative Immunosuppression
- Effect on Other Limbs of Immune System e.g.
corticosteroids / CsA gt CMI - Splenectomy gt Ig synthesis
- Foreign body- CVCs
- Tumor obstruction of hollow visci
5Case 1
- A 14 year old child with newly diagnosed AML is
treated with doxorubicin and Ara-C. - She is discharged and four days later presents to
outpatient clinic with new onset of fever
(T38.7C) and anorexia. - PE reveals a tired appearing child but with no
localizing findings. - Laboratory ANC lt100/µl
6Case 1 What are the organisms most likely
etiological organisms as the initial cause of
fever in profound neutropenia?
- Escherichia coli
- Klebsiella pneumoniae
- Pseudomonas aeruginosa
- Coagulase negative Staphylococcus
- Aspergillus fumigatus
7Case 1 What are the organisms most likely
etiological organisms as the initial cause of
fever in profound neutropenia?
- Escherichia coli
- Klebsiella pneumoniae
- Pseudomonas aeruginosa
- Coagulase negative Staphylococcus
8Case 1 What option do you choose for initial
management?
- Return to home for further monitoring (your
colleague says that only 5-10 of patients ever
develop real infections). - Return to home on oral outpatient therapy (your
hospital administrator says that it will save
money for the hospital). - Admit for empirical antibacterial therapy.
9Case 1 What option do you choose for initial
management?
- Admit for empirical antibacterial therapy.
10Case 1 Among the following regimens, what are
the appropriate agents for initial management of
febrile neutropenic patients?
- Ceftazidime
- Cefepime
- Ciprofloxacin
- Imipenem or meropenem
- Piperacillin-tazobactam aminoglycoside
11Case 1 Among the following regimens, what are
the appropriate agents for initial management of
febrile neutropenic patients?
- Ceftazidime
- Cefepime
- Imipenem or meropenem
- Piperacillin-tazobactam aminoglycoside
12Case 1 Results of blood cultures, treatment,
and outcome
- Ceftazidime
- E. coli in 2/2 bottles
- Susceptible to ceftazidime
- Patient recovered from neutropenia with no squeal
- Her ANC recovered to gt1,000/µl and she was
treated with a second cycle of chemotherapy
13Case 1 If this patient had a history of
anaphylaxis to beta-lactam antibiotics, what
would be an appropriate option?
14Impact of Antibacterial Antibiotics on Febrile,
Neutropenic Patients
- Highly Successful
- Mortality 3-5
- Choice of Antibacterial Therapy
- Improved pharmacokinetics/penetration
- Extended spectrum and lower MICs
- Greater beta-lactamase stability
- Modification of therapy
- Aggressive intervention
- Improved diagnostics
- Microbiological detection systems
15Fever and Neutropenia
- DEFINITIONS
- Fever
- 38C 3 times in 24 hours
- 38.3C 2 times in 24 hours
- 38.5C 1 time
- Mode of Measurement
- Oral
- Axillary
- Core- Rectal Contraindicated
- Neutropenia
- Absolute neutrophil count lt 500/µL
- lt100/µL highest risk
16What are the Objectives of Managing Fever
Neutropenia?
- Paramount Assure Patient Survival and Prevent
Infectious Morbidity - Less than 5 mortality
- Decrease Days of Hospitalization
- Goal is to minimize time in hospital
- Decrease Number of Days of Antibiotic Use
- Minimize selection of resistant organisms
- Timely Modifications of Antibiotic Therapy
- Control breakthrough infections
- Reduce Cost in Time/Expense
17Neutropenia as a Risk Factor for Infection
- Neutropenia is a therapy-induced surrogate
marker of infectious risk - Preemptive intervention is based on risk
- Duration of Neutropenia
- Risk of infections directly related to duration
of neutropenia (esp. gt 7-10 days) - Depth of Neutropenia
- Risk of infections greater for lt100 ANC
- Risk is enhanced by concomitant
immunosuppressive agents
18What are the Causes of Fever and Neutropenia?
- 2/3 Are Undetermined
- 1/3 Identified
- Microbiological
- Clinical Syndrome
- Bacteremia
- Most important proven cause of initial fever
- Shift From Gram-negative to Gram-positive
organisms - However, GNRs remain the most deadly pathogens as
a group - Early Intervention
- Indwelling Catheters
- Mucosal Colonization Disruption Patterns
- Invasive Mycoses
- Major increase in incidence and severity
- e.g. Aspergillus spp.
19Is Coverage Required for FN in All Neutropenic
Patients?
- YES!
- Predictive Models
- Talcot et al
- Failed To Differentiate Pt Populations
- Cannot Convert to Zero Risk for Pts
- Incidence of serious events low
- Failure Model- Not Acceptable
- Disastrous Outcome in case of Failure
20Combination Therapy
- Early studies Penicillin-based or cephalosporin
PLUS aminoglycoside - Classical studies defined these regimens
- Diminish likelihood of emerging resistance
- Extended coverage
- Dual coverage for Pseudomonas aeruginosa
- Less need with 3-4th generation cephalosporins
and carbapenems - For Ceph/PCN allergic patients
- Aztreonam/Vancomycin
21Monotherapy
- Standard choices- well established
- Ceftazidime
- Imipenem
- Meropenem
- Cefepime
- UNLESS
- 1. Cardiovascular Instability
- Vancomycin/Aminoglycoside/Ceftaz or Imipenem
- 2. Site of Catheter Infection
- Vancomycin
- 3. Severe Perianal/Perirectal/Perioral Infection
- Anaerobic Coverage
22Ceftazidime Meta-Analysis
- Based on 12 Randomized Studies Comparing
Ceftazidime to Combination Therapy - 1077 Febrile Events
- 248 Bacteremic Episodes
- Conclusion- Equivalent Outcome As Long As
Clinically or Microbiologically Indicated
Modifications Are Made
Sanders JID 164907, 1992
23Carbapenems Imipenem and Meropenem
- Extended Antibacterial Spectrum Carbapenem
- Advantage-
- Anaerobic Coverage
- Enterococcal Coverage
- NCI Study IV
- Comparable Efficacy to Ceftazidime
- Fewer Modifications for Documented Infections
- Increased Toxicity
- GI distress- Diarrhea/Nausea
- C. difficile Colitis
- CNS-Lower Seizure Threshold
24Empirical Vancomycin Controversies
- 1. Overuse-gt in 95 of pts not indicated
- 2. Minimal Morbidity and No Mortality
- With exception of alpha-hemolytic Strep. and Gr A
Strep. - Associated with
- Myeloablative HSCT
- Ara-c
- Fluoroquinolone Prophylaxis
- 3. Cost
- 4. Monitoring
- 5. Selection for Resistant Organisms
- Vancomycin Resistant Enterococci
- NOT recommended by CDC
25Monotherapy
- UNLESS
- 1. Cardiovascular Instability
- Vancomycin/Aminoglycoside/Ceftaz or Imipenem
- 2. Site of Catheter Infection
- Vancomycin
- 3. Severe Perianal/Perirectal/Perioral Infection
- Anaerobic Coverage
26Antibiotics Used in Febrile, Neutropenic Patients
- Cephalosporins
- Ceftazidime (3rd generation)
- Cefepime (4th generation)
- Carbapenems
- Imipenem
- Meropenem
- Monobactam (Gram-negative coverage only)
- Aztreonam
- Piperacillin-tazobactam aminoglycoside (new
data (Bow et al, ICAAC 2003 may support
monotherapy with pip-tazo) - Fluoroquinolones
- Ciprofloxacin (not as a single agent)
- Problem with breakthrough
- Overuse for prophylaxis in neutropenic Hosts
27Ciprofloxacin and Other Fluoroquinolones in High
Risk Febrile Neutropenic Patients
- Inadequate as Single Agent
- Major Problem-gt Streptococcal Breakthrough
- Data Supports Use in Combination
- Ex For Pen/Ceph Allergic Pts But with
Aminoglycoside - Reserve for Multiply-Resistant Gram-negative
Infection - Future Indication
- Oral Therapy (with 2nd drug)
28Prophylactic Antibacterial Therapy
- NOT indicated in most patients with cancer
- Failure of Fluoroquinolones and TMP/SMZ
- Selection of Resistant organisms
- Drug interactions/toxicities
- Controversial in BMTX
- Minimal controlled evidence
- Institutional biases
- Use of oral or non-absorbable agents
29Vancomycin
- Pathogen Directed
- Not Indicated for Initial Therapy UNLESS
- Cardiovascular Instability
- Isolated Gram Positive
- Site of Catheter Insertion/Tunnel Infection
- SEVERE Mucositis
- Not Indicated for Day 3/4 Empiric Therapy with
Persistent Fever - NCI EORTC Studies-Average Time to
Defervescence-gt 4 days
30Role of Aminoglycosides
- Marginal Utility for Initial Therapy
- Unless High Incidence of Resistant Gram Negatives
is Observed - Required if a Ureido- or Carboxypenicillin is
Employed - Reserved for Pathogen Specific Use
- Reserved for Life-Threatening Presentation or
Development - Note single daily dose aminoglycoside therapy
(e.g., 5 mg/kg/day) in patients with normal renal
function is significantly less nephrotoxic and
may be more effective pharmacodynamically
31Oral Therapy for Low Risk Febrile, Neutropenic
Patients
- Outpatient Therapy With Combination Therapy
- Ciprofloxacin Amp/Clavulanate or Clindamycin
- Short-Term Inpatient Parenteral Therapy
Followed By Oral Outpatient Treatment - Identification/Stratification of Risk-gt
- Indication for Outpatient vs Inpatient Therapy
- Outpatient Oral Therapy is Investigational
- - compliance infrastructure
- - monitoring
- - access to care
-
32What are the Factors which Distinguish Low-Risk
Febrile, Neutropenic Patients?
- Remission
- Expected Duration of Neutropenia
- lt 7 Days
- Absence of Mucositis
- No Co-morbidity
- Hypotension
- Organ Failure
- gt 2 Years of Age
- No Previous Prophylactic Antibiotics
33Selecting Appropriate Initial Empiric Therapy
Additional Factors
- Choice of Antibiotic for Empirical Therapy
- Institutional Experience
- Incidence of Resistant Bacteria
- Recent Outbreak of Resistant Bacteria
- Cost/Availability
- Patient Characteristics
- Condition of Patient at Diagnosis
- Presence of Documented Site-Requiring Additional
Therapy - Allergies
- Drug Interactions
34What is the Duration of Therapy in High Risk
Patients?
- Empirical treatment until recovery from
neutropenia - Identification of pathogen
- Treat for recommended time or recovery from
neutropenia - Whichever is longer
- E.g. bacteremia with E coli 10-14 days despite
recovery of ANC
35Guidelines for Termination of Antibiotic Therapy
in Febrile, Neutropenic Patients
- Recovery from neutropenia
- (ANC gt 500/µl)
- Negative Blood Cultures
- At least 72 Hours
- Afebrile on Antibiotics
- At Least 48 Hours
- Absence of Localized Site
- Compliance
- Proximity
- Availability of Transportation
36What are the Risks of Premature Discharge of
Neutropenic Patients from Hospital?
- Poor Monitoring
- Modifications are Critical to Care of Neutropenic
Patients - Risk of Infection Persists with Neutropenia
- Masking of More Serious Infectious Process
- Problem of Defining Low Risk Patient
- Therapy Better than Underlying Disease
- Ceftriaxone Studies-Problematic
- Oral Outpatient Therapy-Too Early to Endorse
37Modifications of Initial Empirical Antibacterial
Therapy
- Principle no single agent or combination of
agents can initially treat all possible
infections. - The initial empirical antibacterial regimen
treats only the most common and lethal pathogens
38How Does One Manage Catheter-Related Bacteremia?
- Most episodes of catheter-related bacteremia can
be managed without removal of the catheter. - Infusion of antibiotics through all ports is
imperative - Rotate lumens
- Simultaneous infusion (split dose)
- Removal is warranted in
- Candida species
- Bacillus species
- Atypical mycobacteria
- Staphylococcus aureus
- Uncontrolled bacteremia due to any organism
39What is the Approach to a Patient with
Hemodynamic Instability and Suspected Resistant
Bacterial Infection
- P.E., blood and urine cultures, CXR
- Change therapy to imipenem 10 mg/kg Q6h
- PLUS
- gentamicin 5 mg/kg Q 24h
- PLUS
- vancomycin
40In a Patient Receiving Ceftazidime for Fever and
neutropenia, what are the most Common Causes of
Breakthrough Bacteremias Causing Hemodynamic
Instability?
- Most Common
- Enterobacter species
- Serratia species
- Citrobacter species
- Pseudomonas aeruginosa
- Less Common
- Enterococcus species
- Clostridium species
- Bacillus species
41Emerging Bacterial Pathogens and Infections
- Gram-positive cocci
- Steptococcus mitis
- Vancomycin-resistant Enterococci (VRE)
- Gram-negative bacilli
- Stably derepressed beta-lacatamase producing
Enterobacteriaciae - Extended spectrum beta-lactamase producers
42Emerging Bacterial Pathogens and Infections
Gram-Positive Cocci
- Steptococcus mitis
- Syndrome of septic shock, ARDS, and rash in
high-dose chemotherapy - Treatment vancomycin (penicillin resistance is
now occurring) - Vancomycin-resistant Enterococci (VRE)
- Superinfection esp. in complciated surgical
patients or prolonged antibiotics - Treatment quinupristin-dalfopristin linezolid
-
43Emerging Bacterial Pathogens and Infections
Gram-negative bacilli
- Stably derepressed beta-lacatamase producing
Enterobacteriaciae - Enterobacter, Citrobacter, Serratia, and
Providencia spp. (occasionally P. aeruginosa) - Treatment Carbapenem fluoroquinolone TMP-SMX
- Extended spectrum beta-lactamase (ESBL) producers
- E. coli, Klebsiella spp.
- Treatment Carbapenem fluoroquinolone
44What is the Approach to Patients with Suspected
or Proven Clostridium difficile Diarrhea?
- Stool for toxin assay
- R/O other causes Salmonella, Shigella,
Campylobacter, Yerisina, OP - Evaluate for concomitant typhlitis
- Start oral metronidazole, 5 mg/kg Q 8h PO or 10
mg/kg Q 8h - PO Vancomycin is used only as second line therapy
45What is the Approach to Neutropenic Patients with
Oral Ulcers?
- Mucositis is a diagnosis of exclusion
- R/O concomitant HSV by viral culture
- Start acyclovir, 5 mg/kg Q8h pending culture
results - Pain control local and systemic
46What are the Most Common Microbiological Causes
for Modification Initial Empirical Antibacterial
Therapy?
- Fungal infections
- Viral infections
- Resistant bacterial infections
- Protozoal and parasitic infections
47What are the Most Common Clinical Manifestations
of New Infections Requiring Modification of
Initial Empirical Antibacterial Therapy?
- Persistent or recurrent fever
- New pulmonary infiltrates
- New cutaneous lesions or ulcerations
- Diarrhea
- Hemodynamic instability
48What is the Approach to Patients with Persistent
or Recurrent Fever?
- If fever persists or recurs on or after 5 days of
empirical antibacterial therapy, the risk of
invasive fungal infection increases in direct
relation to duration of neutropenia
49What is the Approach to Patients with Persistent
or Recurrent Fever?
- Physical findings may be minimal
- Blood cultures insensitive marker for early
invasive candidiasis - Urine culture presence of yeasts may be early
marker of disseminated infection - Chest radiograph may be negative in early
invasive aspergillosis
50What is the Approach to Patients with Persistent
or Recurrent Fever?
- Empirical antifungal therapy
- Provides therapy for clinically occult invasive
fungal infections - Provides prophylaxis against invasive fungal
infections in high-risk patients
51What Agents are Used for Empirical Antifungal
Therapy in High Risk Patients?
- Lipid formulation of amphotericin B, 3.0
mg/kg/day, IV - Itraconazole, 100-200 mg BID IV
- Voriconazole, 6 mg/kgx2 loading followed by 3
mg/kg Q12h - Role of echinocandins new data (ICAAC 2003,
Walsh et al) support caspofungin - Conventional amphotericin B, 0.6 mg/kg/day, IV
52What is the Approach to Patients with Positive
Blood Cultures for a Yeast-like Organism?
- Start echinocandin or fluconazole
- If patient is refractory, begin LFAB
53What is the Approach to Patients with New
Pulmonary Infiltrates and Persistent or Recurrent
Fever?
- BAL submit sample to both clinical microbiology
and to cytology - If BAL is positive for hyphal elements or growth
of organism - OR
- If CT scan has characteristic features (halo
sign, nodular densities, wedge-shaped
infiltrate), treat for invasive pulmonary
aspergillosis (IPA) - Voriconazole, 6 mg/kg Q12h gt 4 mg/kg Q12h
- LFAB, 5 mg/kg/day, if patient is intolerant or
refractory
54What is the Approach to Patients with New
Pulmonary Infiltrates and Persistent or Recurrent
Fever?
- Target specific bacterial pathogen according to
susceptibility pattern - PCP TMP-SMX, 20 mg/kg/day
- CMV Ganciclovir, 2.5 mg/kg Q 8h IV IVIg 500
mg/kg QOD x 10 days or CMV Ig as initial therapy
55Augmentation of Host Response against Invasive
Fungal Infections
- Discontinue or rapidly taper corticosteroids
- GM-CSF or G-CSF
- Granulocyte transfusions for patients with
- refractory infection
- persistent but reversible neutropenia
56Emerging Fungal Pathogens Infecting Patients with
Cancer
- Non-fumigatus Aspergillus species
- Fusarium species
- Trichosporon species
- Pseudallescheria boydii
- Zygomycetes
- Dematiaceous moulds
57Remember to Adjust Dosages of Antimicrobials for
Renal Dysfunction
- Antibacterials
- Beta-lactams
- Ceftazidime
- Imipenem
- Monobactams
- Quinolones
- Aminoglycosides
- Trimethoprim-sulfamethoxazole
- Antivirals
- Acyclovir
- Ganciclovir
- Foscarnet
- Antifungals
- Fluconazole
- 5-FC
- Voriconazole considerations for SBECD
58Remember Drug Interactions
- Nephrotoxicity
- Aminoglycosides
- Polyenes
- Acyclovir
- Foscarnet
- Myelosuppression
- Ganciclovir
- 5-FC
- Cytochrome P-450 competitive antagonism
- Antifungal azoles-vincristine
59What are the Most Common Microbiological Causes
for Modification Initial Empirical Antibacterial
Therapy?
- Fungal infections
- Viral infections
- Resistant bacterial infections
- Protozoal and parasitic infections