Infections in Patients with Cancer and Hematopoietic Stem Cell Transplantation: Approaches to Empiri

1
Infections in Patients with Cancer and
Hematopoietic Stem Cell TransplantationApproache
s to Empirical Therapy and Prophylaxis
2
What 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.

3
What are the Risk Factors for Infection in
Patients with Cancer/Transplantation?

• Malignancy per se
• Treatment of the malignancy
• Chemotherapy
• Immunotherapy
• Surgery
• Radiation

4
What 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

5
Case 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

6
Case 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

7
Case 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

8
Case 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.

9
Case 1 What option do you choose for initial
management?

• Admit for empirical antibacterial therapy.

10
Case 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

11
Case 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

12
Case 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

13
Case 1 If this patient had a history of
anaphylaxis to beta-lactam antibiotics, what
would be an appropriate option?

• Aztreonam and vancomycin

14
Impact 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

15
Fever 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

16
What 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

17
Neutropenia 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

18
What 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.

19
Is 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

20
Combination 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

21
Monotherapy

• 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

22
Ceftazidime 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
23
Carbapenems 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

24
Empirical 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

25
Monotherapy

• UNLESS
• 1. Cardiovascular Instability
• Vancomycin/Aminoglycoside/Ceftaz or Imipenem
• 2. Site of Catheter Infection
• Vancomycin
• 3. Severe Perianal/Perirectal/Perioral Infection
• Anaerobic Coverage

26
Antibiotics 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

27
Ciprofloxacin 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)

28
Prophylactic 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

29
Vancomycin

• 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

30
Role 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

31
Oral 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

32
What 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

33
Selecting 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

34
What 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

35
Guidelines 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

36
What 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

37
Modifications 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

38
How 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

39
What 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

40
In 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

41
Emerging 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

42
Emerging 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

43
Emerging 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

44
What 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

45
What 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

46
What are the Most Common Microbiological Causes
for Modification Initial Empirical Antibacterial
Therapy?

• Fungal infections
• Viral infections
• Resistant bacterial infections
• Protozoal and parasitic infections

47
What 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

48
What 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

49
What 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

50
What 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

51
What 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

52
What is the Approach to Patients with Positive
Blood Cultures for a Yeast-like Organism?

• Start echinocandin or fluconazole
• If patient is refractory, begin LFAB

53
What 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

54
What 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

55
Augmentation 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

56
Emerging Fungal Pathogens Infecting Patients with
Cancer

• Non-fumigatus Aspergillus species
• Fusarium species
• Trichosporon species
• Pseudallescheria boydii
• Zygomycetes
• Dematiaceous moulds

57
Remember 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

58
Remember Drug Interactions

• Nephrotoxicity
• Aminoglycosides
• Polyenes
• Acyclovir
• Foscarnet
• Myelosuppression
• Ganciclovir
• 5-FC
• Cytochrome P-450 competitive antagonism
• Antifungal azoles-vincristine

59
What are the Most Common Microbiological Causes
for Modification Initial Empirical Antibacterial
Therapy?

• Fungal infections
• Viral infections
• Resistant bacterial infections
• Protozoal and parasitic infections