1. Complications related to Treatment of Leukemia Fever and Neutropenia Aziza Shad, MD Lombardi Cancer Center Georgetown University Hospital Washington DC

2. Mortality Associated with Infection during Neutropenia Empirical therapy Mortality rate

3. Factors involved in decreasing mortality Empirical antibiotic therapy Supportive care strategies Infection control strategies

4. Principles of Empiric Antibiotic Therapy 1.Recognition of commonly occurring pathogens, link between specific pathogens and specific sites, drug and/or tumor, tumor-related barrier breakdown 2.Broad coverage directed against the most common pathogenic organisms

5. Principles of Empiric Antibiotic Therapy 3.Prevention of development of multi-resistant organisms 4.Hold the fort until the underlying lesion is corrected by the return of neutrophils

6. Definitions Fever: single oral temperature of > 38.3 °C (101 °F) or > 38 °C (100.4 °F) for more than 1 hour. Neutropenia: ANC <500cells/mm3 or ANC <1000 cells/mm3 with a predicted decrease to <500 cells/mm3 CID 2002, 34:730-751

7. Recognition of potential pathogens Evaluation of the host Diminished inflammatory response alters usual signs and symptoms of infection Fever may be the earliest warning sign Absence of fever in patient with localizing signs, even if subtle, may point to infection

8. Cancer Treatment Nutritional status Microbial flora Humoral + cellular immunity Phagocytic defenses RE system Skin + mucosal barriers

9. Recognition of potential pathogens Mouth: gingiva, dentition, buccal mucosa--gram+ anaerobes/HSV/ Candida Skin: BMA/B, LP, venipuncture sites, tissue around nails - gram+/ fungal / Pseudomonas/VZV Abdomen/perianal area: enterococci/gram-/anaerobes Central Catheter: gram+/- Pulmonary: bacteria, PCP, virus, fungi Diarrhea: C. difficile Even with a comprehensive evaluation, an infectious etiology is demonstrated in 50 to 70% of cases

10. Recognition of potential pathogens All efforts should be made in order to identify a pathogen Focal findings should be investigated + cultures should be sent when possible If no focus send BC/UC Determine whether vancomycin is needed Evaluation of the host

11. Blood Cultures If CVC is present culture all ports - 33% of times only one port is positive Peripheral blood cultures when CVC is present is controversial and may not contribute to the management of the pediatric patient Blood cultures should be sent at least daily if patient remains febrile

12. Broad coverage against the most common organisms 85-90% of isolated pathogens during new fever in a neutropenic patient are bacteria Gram + and Gram - bacteria. Endogenous flora / nosocomial flora The relative distribution of these organisms vary among institutions Antibiotic sensitivity patterns vary among institutions

13. Bacterial Causes during F/N

14. Use of central vascular devices Nutritional status Intestinal Parasitosis Infection control strategies 60 % of hospital-acquired infections are caused by drug resistant microbes in industrialized countries this is many times unknown in developing countries Disparities between Nations: potential explanations

15. Emergence of Antimicrobial Resistant Bacteria Hospital-acquired Community-acquired 1950 1960 1970 1980 1990 S. aureus Gram - rods Enterococcus spp S pneumoniae H. influenzae N. gonorrhoeae M. catarrhalis Shigella spp

16. Emergence of Antimicrobial Resistant Bacteria Gram-positive cocci The most recent of which are VRE MRSA are no longer confined to hospital wards 90 % of strains of S.aureus are resistant to penicillin Prevalence of DRSP shows geographic variation 30- 40%

17. Emergence of Antimicrobial Resistant Bacteria Gram-negative bacilli ESBL are enzymes that mediate resistance to third generation cephalosporins and monobactams but do not affect cephamycins or carbapenems Common ESBL producers are E. coli, Klebsiella spp, P.aeruginosa and enterobacteria

18. Cause more indolent infections The most common isolates (CNS, VRE, Corynebacterium jk) Cause acute infections that progress rapidly S.aureus, S.viridans, pneumococcus also Cause usually superinfections

19. Reassess after 3-5 days BC gram + cocci in clusters Known MRSA colonization CVL tunnel infection Suspected sepsis Substantial mucosal damage Prophylaxis with quinolones Sudden increase in temp >40°C Selection of initial antibiotic therapy

20. AntibioticEnteric Gram – P. Aeruginosa CPS/ CNS Entero cocci Strepto- cocci Anaerobes Ceftazidime Cefoperazone +++ ++/- --- Cefepime +++++/- - + + Imipenem Meropenem ++++++/++++ Quinolones ++++++/+++++ Aztreonam Aminoglycoside +++-/---- Ticar/Tazo Piper/clavul ++++++/+++++

21. AntibioticEnteric Gram – P. Aeruginosa CPS/ CNS Entero cocci Strepto- cocci Anaerobes Ceftazidime Cefoperazone +++ ++/- --- Cefepime +++++/- - + + Imipenem Meropenem ++++++/++++ Quinolones ++++++/+++++ Aztreonam Aminoglycoside +++-/---- Ticar/Tazo Piper/clavul Higher incidence of C. diff colitis/ N+V/ seizures Good efficacy More gram positive infections detected Good efficacy and tolerance Usually in prophylaxis during neutropenia in high risk patients Use in lactams allergy – only in combination Toxicity – use only in combination Limited experience – interfere with Aspergillus antigen detection

22. Reassessment – Afebrile patient

23. Sequential Oral antibiotics Limited experience Significant cost reduction Only for low-risk patients Less tolerance (GI toxicity) Antibiotic Regimens: Ciprofloxacin Cipro + amoxi-clavulanic

24. Factors that favor a Low Risk for severe infections during Neutropenia ANC > 100 cells/mm3 AMC >100 cells/mm3 Normal CXR Nearly normal renal and lever function tests Duration of neutropenia < 10 days No CVL infection Malignancy in remission Peak temperature <39 °C No neurological or mental status changes No abdominal pain No appearance of illness No co-morbidity complications Laboratory Clinical

25. Reassessment – Febrile Patient Review all cultures Meticulous Physical exam CXR- Image any organ suspected of having infection (CT/US) Status of CVL/PIV or venipuncture site Pursue biopsy / culture of affected areas / BAL Send Aspergillus galactomannan

26. Approach to the febrile neutropenic patient Summary History - Physical exam CXR-UC-BC bp + cx of suspicious lesions Empiric broad spectrum antibiotics Documented infection Fever unknown origin { {

27. Factors involved in decreasing mortality Supportive care strategies Infection control strategies