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Infections in Immunocompromised Host A focus on Febrile Neutropenia Historical Background First description around 1900 Rare until development of chemotherapy In the 1960s: mainly in acute leukemia with profound neutropenia G-ve sepsis most common with mortality = 90% Empirical therapy with synergistic combinations of antibiotics reduced mortality to + 10 % In the1980s: development of chemotherapy for solid tumors leading to less severe and less protracted neutropenias For multiple reasons, replacement of G-ve infections by G+ve →severity of infections decreases FN becomes a heterogeneous syndrome Risk-stratification models allow for identification of low risk patients with additional treatment options Increase of fungal sepsis in specific groups of neutropenic patients leads to widespread use of empirical antifungal agents Introduction Immunocompromised Host: Patient with intrinsic or acquired defects in host defenses Increased risk of infection Incidence is increasing – HIV/AIDS, organ transplant, and cancer pts Infection remains the leading cause of autopsydetermined death in neutropenic cancer patients Introduction Infectious complications are a major cause of morbidity and mortality in cancer patients due to advances in therapeutics of the malignancy. Cytotoxic chemotherapeutic agents, immunotherapy, and bone marrow transplant almost invariably affect bone marrow function. Introduction The normal kinetics of blood cell turnover influence the sequence and sensitivity of each of the formed elements. Polymorphonuclear leukocytes (PMNs; T1/2 = 6 to 8 h) platelets (T1/2 = 5 to 7 days) red blood cells (RBC; T1/2 ~ 120 days) have most, less, and least susceptibility to usually administered cytotoxic agents, respectively. The Causes and Consequences of Neutropenic Complications Chemotherapy Radiation Neutropenia Disease Process FEBRILE NEUTROPENIA Complicated Infections Prolonged Hospitalization DEATH Adapted from Lyman GH. Oncology. 2003:17(suppl):8-13. Introduction Infections are the most common complication of neutropenia Febrile neutropenia is a MEDICAL EMERGENCY!!! Typically occurs 7-10d post chemo Timely/Thorough assessment and antibiotics are life saving Introduction Risk of infection is proportional to severity and duration of neutropenia Recovery of ANC is the most important factor determining the outcome of infectious complications Definitions ANC = (% segs or PMNS + % Bands) x WBC/100 • Neutropenia – ANC <1000 – ANC <500 – what most treatment guidelines consider critical – ANC <100 – risk of infection and death is greatest • Fever – Single oral temp > 38.3° C (101° F) – Temp > 38.0° for > 1 hour (100.4° F) NCCN Definitions of Neutropenia and Febrile Neutropenia Neutropenia Fever ANC <500/μL or ANC <1000/μL and a predicted decline to ≤500/μL over the next 48 h Oral temperature >38.3°C (single reading) or >38.0°C (>1 h) fever + neutropenia = febrile neutropenia ANC example Example 1 – WBC = 3.6 – 45% Segs – 10% Bands ANC = 55% (3600)/100 OR = 0.55 (3600) = 1980 Example 2 – WBC 3.0 – 38% Neutrophils ANC = 0.38 (3000) = 1140 Risk Factors for FN Patient-related Comorbidities Age (>65 y) Chronic obstructive pulmonary disease Female gender Cardiovascular disease Poor performance status Liver disease Poor nutritional status Kidney disease Decreased immune function Diabetes mellitus Conditions associated with Low baseline serum risk of serious infection hemoglobin level Open wounds Active tissue infection NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005. Risk Factors for FN Treatment-related Cancer-related Type of chemotherapy (high Hematologic dose cyclophosphamides, malignancies anthracyclines) Bone marrow History of severe neutropenia involvement with tumor with similar chemotherapy Advanced or Preexisting neutropenia or uncontrolled cancer lymphocytopenia Elevated serum LDH Extensive prior chemotherapy (lymphoma) Concurrent or prior radiation therapy to marrow-containing LDH = lactate dehydrogenase; RDI = relative dose-intensity. bone NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005. Risk Factors for FN Altered skin defenses / foreign body CVC Urinary / Foley catheter Radiation induced skin damage / cellulitis Surgery Mechanical ventilation Mucositis / Stomatitis Colonization Recovery of an organism without clinical signs of infection Most infection are from bacteria that colonized the GIT, URT, and Skin Incidence of Neutropenia and FN per Tumor Type and Regimen Neutropenia Risk Regimen FN Other Docetaxel, doxorubicin 33% Grade 3 or 4 neutropenia: 97% Docetaxel, doxorubicin, cyclophosphamide 25% Grade 4 neutropenia: 88% Doxorubicin, paclitaxel 32% Grade 4 neutropenia: 89% MVAC 26% Grade 3 or 4 leukopenia: 62% Paclitaxel, carboplatin 21% Grade 3 or 4 neutropenia: 39% Breast Bladder Regimen Small Cell Lung Etoposide, cisplatin Topotecan, paclitaxel Non–Small Cell Lung Carboplatin, paclitaxel Cisplatin, paclitaxel Colorectal Irinotecan Non-Hodgkin’s Lymphoma CHOP Neutropenia Risk FN Other Fever: 18% 21% Grade 3 or 4 neutropenia: 85% Grade 4 neutropenia: 96% 4% 16% Grade 3 or 4 neutropenia: 63% Grade 3 or 4 neutropenia: 75% 14% Grade 3 or 4 neutropenia: 47%48% Hospitalization: <age 65: 7.9% ≥age 65: 13.8%5 Grade 3 or 4 leukopenia: 34%-72% Other immune system defects T-lymphocyte and macrophage function (cellmediated immunity) Transplant patients receiving immunosuppressive drugs, HD, HIV B-cell function (humoral immunity) Underlying disease such as multiple myeloma or CLL Etiology of Infection Primary site often includes alimentary tract and where there has been damage to integument – Site of infection can be documented in only 30% to 40% of febrile episodes Bacterial infections most common (fungal infections increasing) Gram - replaced by Gram + organisms (often methicillin resistant) Etiology of Infection Check for other causes of fever Reaction to blood products chemotherapy cell lyses and the underlying malignancy Etiology of Infection Timeline helps narrow the differential Early: Bacterial Gram Positives (staph, strep …) Gram Negatives (e.coli, klebsiella, Pseudomonas..) Mixed in 25% Infrequently anerobes Etiology of Infection Late Candida Aspergillosis PCP (if on steroids) Varied Viral Herpes family( HSV, EBV, CMV, RSV, Paraflu etc… Most Common Organisms Gram-Positive Cocci and Bacilli Most likely if infected catheter 60-70% of documented infections, WHY? Staphylococcus species Streptococcus species Enterococcus faecalis / faecium Corynebacterium species Most Common Organisms Gram-negative Bacilli and Cocci E. coli Klebsiella sp. Pseudomonas aeruginosa Fungal infections: usually super infections Candida sp or other fungi can cause primary infections In BMT patients and prolonged N > 7 days Most Common Organisms Viral Mostly a reactivation of latent infections Herpes Simplex, Varicella Zoster CMV in Stem Cell Transplant Clinical Presentation Fever is the most important presenting symptom in a neutropenic patient 60% of neutropenic patients who become febrile have an established / occult infection 40% of patients based on a documented microbiological origin 20% of patients based on clinical findings alone Clinical Presentation Many normal signs and symptoms of infection may be absent, WHY? Inflammation may be minimal ⇓ or absent indurations, erythema, and postulation normally seen in bacterial skin infections Pneumonia without infiltrate, infiltrates may not develop until ANC > 500 Meningitis without UTI without pyuria WBCs in CSF Clinical Presentation Most common sites of infection lung→only fever and dry cough Skin cellulitis → no pain, heat , erythema, swelling Clinical Presentation Search should be undertaken for subtle signs and symptoms PAIN at most commonly infected sites Periodontium Pharynx Lower esophagus Lung Perineum Skin Bone marrow aspiration site Catheter access sites Evaluation Thorough Physical Exam Cultures > 2 sets of blood cultures; 1 set from a central venous access site and a peripheral vein Any lesions suspected of being infected Urine if any S&S of UTI, presence of catheter, or abnormal U/A Stool cultures if diarrhea present Evaluation CXR if s/s of respiratory tract infection or if outpatient therapy is planned CBC What would you expect? SrCr, BUN, and transaminases Determine high and low risk patients (see algorithm) Evaluation: Low/High risk neutropenia algorithm Scores >= 21 considered low risk Other algorithms available Factors that favor low risk ANC > 100 Duration of neutropenia < 7 days Resolution of neutropenia expected in < 10 days Normal CXR No IV catheter site infection Normal hepatic and renal function No appearance of illness Treatment Algorithm Outpatient Inpatient Treatment Empiric antibiotic therapy should be administered promptly if afebrile, but signs and symptoms of infection present If febrile with ANC< 500 or > 500 and predicted to < 500 Gm –ve infections have a 91% mortality in the 1st 24-48 hrs Remove any sources of infection if possible Treatment Initial antibiotics Must consider site of infection/ likely pathogen Frequency of isolation Antibiogram of hospital Allergies Concomitant Organ Must treatments dysfunction have bactericidal activity Treatment Optimal antibacterial spectrum Cover gm-ve bacilli : E.coli, K.pneumonia, P.aeruginosa + staphylococci, streptococci Optimal regimen remains controversial Proposed Classification/Management for FN Patients High Risk: Prolonged Neutropenia ( > 14 d), Heme CA or allo BMT, substantial comorbidity, unstable Admit, IV therapy (usually combination Rx) for duration of neutropenia; Ampho B empiric Rx for continued fever Proposed Classification/Management for FN Patients Moderate Risk: Neutropenia 7-14 d, auto BMT, stable, minimal comorbidity Initial IV Rx (monotherapy OK), early discharge with po if response; Ampho B for cont’d fever (especially if azole prophy) Low Risk: < 7d neutropenia, solid tumor, stable Outpatient IV or po therapy; azole Rx ok for cont’d fever Candidates for Outpatient Therapy Appears stable < 60 years ANC > 100 No source identified Responsive tumor No comorbidity bleeding, BP, CA++, respiratory failure, altered MS Suspected duration of neutropenia is not a determining factor (can’t predict at time of febrile presentation) Oral antibiotics As initial therapy or as follow up therapy Oral ciprofloxacin + amoxicillin-clavulanate May use clindamycin in allergic patients Monotherapy Monotherapy does not cover Coagulase-negative staphylococci MRSA Enterococcus (except imipenem covers faecalis) Monotherapy Ceftazidime 3rd generation cephalosporin/ antipseudomonal covers only some gram + organisms May improve staphylococcal cover with vancomycin Increasing lactamases resistance ( K.pneumonia produce β- Monotherapy Cefepime 4th generation cephalosporin FDA approved as monotherpay for FN Low affinity for β-lactamases more potent than Ceftazidime against gram + organisms ( ↓ need for vancomycin) Above advantage is lost when high rate of MRSA Monotherapy Carbapenems Imipenem+ Cilastatin or meropenem Broad spectrum against gm+ve and gm-ve + anerobes Evidence Higher More support efficacy incidence of N/V expensive Monotherapy- Summary Monotherapy is appropriate as initial empiric TX No evidence to support superiority of one agent Carbapenems are usually not used due to cost and potential of resistance of Acinetobacter Carbapenems reserved who failed initial empiric TX or have Hx of infection with resistant organisms Monotherapy- Summary Ineffective monotherapy Monobactams→lacks gm+ve activity Fluoroquinolones →variable gm+ve activity, used for prophylaxis B-lactam/b-lactamase inhibitor combinations Two Drug Therapy Advantages Broad spectrum activity Potential synergy Minimal emergence of drug-resistant strains Disadvantages Lack of G + activity when AG + ceftaz is used Additive toxicities when AGs are added Empiric Combinations Anti-Pseudomonal PCN or 3rd G Cephalosporin + aminoglycoside Most established combination response no rates all around 70%, advantage of one b-lactam over another Disadvantage; nephrotoxicity, TDM Empiric Combinations Double β-lactam; Anti-Pseudomonal PCN + 3rd G Cephalosporin or Moxalactam Similar response rates Limited experience Poorer less response in documented P. aeruginosa nephrotoxic, high cost Empiric Combinations Ciprofloxacin + AG or B-lactam Associated with ↑ gm +ve infections Cipro activity against P. aeruginosa has ↓ (<70%) Empiric Vancomycin Rationale Previous combinations lack activity against MRSA Increasing gm+ve pathogens Should be D/C after 3-5 days if G+ve infection not identified Disadvantages Excessive use → Vanco resistant organisms VRE/VRSA ↑ AG nephrotoxicity Mortality from staphylococcal infections is < 4% in 1st 48 hrs → can delay adding until pathogen is confirmed. Indications for Vancomycin Clinically suspected catheter/Skin related infection Known colonization with resistant G+ve organism/MRSA Positive blood culture for G+ve bacteria Hypotension / CV impairment Severe mucositis in hospitals with high MRSA (HD-Ara-C) Quinolone prophylaxis Severe Sepsis In institution frequently isolating viridans streptococci Vancomycin Up Front? PRO change in most common isolates in F/N ? Less febrile days overall, and perhaps less ampho B use viridans streptococci may be fatal; particular problem with quinolone prophylaxis and regimens that induce severe mucositis CON overall mortality from documented gm(+) bacteremia only 5% vast majority of patients with gm(+) survive and respond to addition of Vanco VRE Alternatives to Vancomycin Linezolid Oxazolidione IV or oral Thrombocytopenia Quinupristin-dalfopristin IV High side effect profile High potential for DI Drug Allergy Need to assess type of allergy and determine risk versus benefit Know the organisms you need to cover If unable to use β-lactam Vanc + Cipro Vanc + Aztreonam Modifying Initial Empiric Regimen Reassess after 3 days to determine efficacy of regimen Fever status Clinical condition improved or deteriorated Changes made sooner if condition deteriorates Etiologic pathogen identified Afebrile within 3-5 days No Etiology Identified Continue empiric TX for 7 d If ANC> 500 for 2 days→ may D/C Abs D/C Abs after 14 days in prolonged neutropenia without evidence of infection ANC< 500 at 7 d with initial ANC< 100 or mucositis or unstable → continue ABs Afebrile within 3-5 days Etiology Identified Additional antimicrobial or AB dosage adjustment based on susceptibility tests and serum conc. If persistently neutropenic→Maintain broadspectrum antibacterial coverage. If neutropenia resolved →narrow therapy against organism for appropriate duration Persistent Fever during 3-5 days No Etiology Identified Check for other causes of fever Tumor lyses Nonbacterial infection Resistant bacterial infection Inadequate serum and tissue levels of antibiotics Slow response to therapy Drug related fever Emergence of a second infection/super infection Infection at avascular site Persistent Fever during 3-5 days No Etiology Identified RE-ASSESS patient! If re-assessment reveals no new cause: 3 options 1) Continue current therapy 2) Change or add antibiotics 3) Add anti-fungal drug with or without antibiotic change Persistent Fever during 3-5 days No Etiology Identified 1.Continue current therapy Pt remains stable, not deteriorate Neutropenia expected to resolve within 5 d Continue Abs 4-5d after recovery of neutropenia Continue Abs for 14 days with continued neutropenia and reassess. Persistent Fever during 3-5 days No Etiology Identified 2.Modify initial Abs If there is evidence of disease progression Catheter site drainage, abdominal pain, pulm. Infilt Add or change ABs Persistent Fever during 3-5 days No Etiology Identified 3. Add antifungal In pts with hematological CA, persistent fever, neutropenia > 5d of Abs Up to 1/3 of febrile neutropenic patients who do not respond to a 1-week course of abx have systemic fungal infections Generally must cover Candida and Aspergillus Adding Amphotericin B Reliable activity against Candida and Aspergillus addition of AmphoB appears to improve outcome Considered DOC for empiric antifungal Tx Continue until resolution of neutropenia Persistent neutropenia→ 2 wk course Documented infection → variable depending on diagnosis Amphotericin B 0.7 mg/kg IV qd is the dose used in severe infections Rapid titration up to 0.7 mg/kg over 3 days is used if infection is less severe Amphotericin B - Toxicities Infusion Related F/C, N/V, HA, thrombophlebitis, myalgias and arthralgias Premeditation may reduce these symptoms (Tylenol, Benadryl) Meperidine can be given for rigors Amphotericin B - Toxicities Nephrotoxicity 80% of patients develop some type of impairment Dose related Potentiated by other nephrotoxins Electrolyte Imbalances ⇓ K, ⇓ Mg, ⇓ Ca Lipid formulations of Ampho B Similar efficacy Decreased side effects (infusion related and nephrotoxicity) Consider in patients at risk for nephrotoxicity or with underlying renal dysfunction. Expensive Specific criteria for liposomal Ampho B Initial Creat > 2.0 and not on dialysis (long-term) A doubling of serum creatinine and > 2.0 mg/dL refractory disease after 10 days (or 500 mg) of AmphoB High risk patients (i.e. on CsA, tacrolimus, AG, foscarnet, cis-platinum, ifosfamide;) severe or persistent infusional AE to AmphoB Other Agents Fluconazole May be used if mold infections (aspergillus sp) and drug resistant candida sp are uncommon Not for suspected aspergillus or who used FLZ prophylaxis Itraconazole When FLZ is not indicated Lower toxicity than AmphoB Other Agents Voriconazole Increased activity against aspergillus and nonalbicans candida Alternative Less to AmphoB toxic, easier to administer Bottom Line, Empiric Therapy IV lipo-amphotericin and itraconazole FDA approved, Ampho-B is a standard of care and has most clinical experience Caspofungin likely to be approved in near future Data suggest adding ONLY after 96 hours of antibacterials AND either persistent or recurrent fever at that time Bottom Line, Empiric Therapy Ampho B > Caspofungin > L-Ampho B > Itraconazole as empiric Rx in patients previously receiving fluconazole prophylaxis Voriconazole may have a role in high risk, long-term prophylaxis (e.g. Allo BMT with GvHD), or as empiric therapy in high aspergillus risk patient after initial blood Cxs (-), but not drug of choice for empiric Rx of Fever/Neutropenia Antivirals Empiric use not indicated without evidence of viral disease Indicated if clinical or laboratory evidence of viral disease Skin lesions due to herpes simplex or varicellazoster Heal the lesions to decrease potential portals of entry for bacteria and fungi Case 1 A 66-y.o. woman presents to her physician with fever, malaise, sore throat, and easy bruisability. She is diagnosed to have AML. Following induction chemotherapy, the patient becomes profoundly neutropenic (ANC≤ 100/mm3). She is asymptomatic but develops a fever on the 3rd day of neutropenia. Her PE, which includes oral mucosa, indwelling vascular catheter site, heart, lungs, abdomen, and perianal region, is normal except for an oral temperature of 39°C. A CXR is normal, and blood cultures are obtained. Case 1 1. Which one of the following measures is most appropriate? A) Obtain additional tests including sputum, throat, and urine cultures; then initiate treatment with appropriate empiric antimicrobial therapy B) Await results of blood cultures and initiate empiric antimicrobial therapy if clinical deterioration occurs C) Initiate empiric therapy with imipenem and vancomycin D) Initiate empiric therapy with cefepime E) Initiate empiric therapy with ceftazidime and tobramycin Case 1 2.Two sets of blood cultures grow gram-positive cocci in clusters. The patient appears clinically stable except for continued fever. What is the most appropriate next step? A) Await identification and antibiotic susceptibility of the organism before modifying antimicrobial therapy B) Remove the indwelling intravascular catheter C) Initiate therapy with vancomycin D) Obtain additional blood cultures via catheter and peripheral vein Case 1 3.The gm-+ve cocci in the blood are identified as MRSA. Despite appropriate management for the next 6 days, fever persists. Again, the patient appears stable with no other symptoms or signs of infection. Repeat blood cultures and CXR are negative. Which of the following is the best next step? A) Change the patient’s antibacterial regimen B) Continue the same antimicrobial therapy C) Test for Clostridium difficile toxin in stool and perform urinalysis and urine culture D) Administer empiric antifungal therapy Duration of Therapy Neutrophil count is determinant of discontinuation Afebrile by days 3 to 5 AND no infection identified ANC > 500 x 2 d, stop abx 48 h after afebrile AND ANC > 500 If ANC < 500 by day 7 If low risk and doing well, stop antibiotics when afebrile x 5 to 7 days If initially high risk, continue antibiotics If an infection documented then titrate abx according and continue a full course Duration of Therapy Persistent Fever ANC > 500: Stop 4 to 5 days after ANC > 500 and reassess (if no infection ID’d) ANC < 500: Continue for 2 weeks, reassess. If no disease present and patient stable, discontinue Transfusion of granulocytes has no role in the management of febrile neutropenia their exceedingly short half-life mechanical fragility clinical syndromes of pulmonary compromise with leukostasis after their use. Instead, colony stimulating factors (CSFs) are used to augment bone marrow production of PMNs. Use of CSF Can significantly shorten the duration of neutropenia Has not consistently reduced other measures of febrile morbidity Not routinely recommended May be indicated when a worsening course is predicted and there is an expected long delay in recovery of marrow Mechanism Of Action Granulocyte colony-stimulating factor (G-CSF), is one of 5 "classic" hematopoietic growth factors that are involved in the development and functional activation of hematopoietic elements These glycoproteins are produced naturally in lymphocytes and monocytes, and have been demonstrated to stimulate progenitor cells of different hematopoietic cell lineages The 4 other classes of CSFs granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) macrophage colony-stimulating factor (MCSF), interleukin-3 erythropoietin Available Myeloid Growth Factors Filgrastim Recombinant methionyl human G-CSF 175 amino acids Half-life SC = 3.5 hours Primarily renal clearance Pegfilgrastim Covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol 175 amino acids Half-life SC = 15-80 hours Limited renal clearance; primarily neutrophilmediated clearance Available Myeloid Growth Factors Sargramostim Recombinant yeast-expressed human GM-CSF 127 amino acids Half-life = 60 minutes Indicated only for use following induction chemotherapy in older adult patients with AML, for myeloid reconstitution after BMT, and for mobilization of peripheral blood stem cells for harvest Administration do not administer within 24 hrs of chemotherapy G-CSF or GM-CSF is conventionally started 24 to 72 hrs after completion of chemotherapy and continued until a PMN count of 1000 is achieved CSF Prophylaxis for First and All Subsequent Cycles: NCCN Guidelines If the patient is receiving: If the patient’s risk for FN* is: Treatment with curative intent or adjuvant therapy Treatment to prolong survival or improve QOL Palliative therapy to manage symptoms or improve QOL >20% (high) Use CSF Use CSF Consider CSF (discuss high-risk chemotherapy with patient) 10%-20% (intermediat e) Consider CSF Consider CSF Consider CSF (discuss (discuss high-risk high-risk chemotherapy chemotherapy with with patient) patient) <10% (low) CSF is not recommended for most patients† CSF is not recommended CSF is not recommended CSF Prophylaxis for FN Maintenance of Scheduled Dose Delivery Filgrastim Daily dose of 5 µg/kg until post-nadir ANC recovery to normal or near-normal levels Start 1-3 days after completion of chemotherapy and treat through postnadir recovery Pegfilgrastim One dose of 6 mg per cycle of treatment Start 1-3 days after completion of chemotherapy There is evidence to support use for chemotherapy regimens given every 3 weeks Phase 2 studies demonstrate efficacy in chemotherapy regimens given every 2neutrophil weeks count. ANC = absolute NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005. Prophylaxis against Infection Non-Pharmacologic therapy Reverse isolation Infection control guidelines Avoid fresh fruits and vegetables Personal hygiene Prophylaxis against Infection Antimicrobial Prophylaxis Data supports efficacy of TMP-SMX, FQs, fluconazole, and intraconazole to reduce # of infectious episodes Prophylaxis against Infection Antimicrobial No Prophylaxis absorbable antibacterial Theorized to reduce GI colonization have not showmen consistent efficacy Lack of compliance Induce resistance Prophylaxis against Infection Antimicrobial Prophylaxis TMP-SMX showen consistent benefit in reducing bacterial infections in FN patients Effect on mortality less clear Benefit must be weighed against risk of bone marrow suppression, hypersensitivity, and emergence of resistance/ super infection Should be strongly considered for patients at risk of PCP; ALL receiving intensive chemo, AIDS, Allogenic BMT. Prophylaxis against Infection Antimicrobial Prophylaxis Fluoroquinolones Equal or superior to TMP-SMX in preventing gmve infections in FN Disadvantages ↑ gm +ve in patients receiving prophylaxis Emergences of resistant gm-ve bacilli Does not reduce mortality Prophylaxis against Infection Antimicrobial Prophylaxis A. Antifungal In pts receiving chemo for solid tumors antifungal prophylaxis may not be beneficial and may ↑ risk of super infection with resistant fungi Pts with hematological malignancy and BMT may benefit more due to longer duration of neutropenia No absorbable antifungal Some have role in oropharayngeal candidiasis but not invasive fungal infections Prophylaxis against Infection Antifungals B. Systemic antifungals Itraconazole →efficacy in reducing systemic candida Fluconazole → ↓ superficial and systemic fungal infections in BMT only Limited spectrum Inferior to Itraconazole Amphotericin Effective but more toxic Prophylaxis against Infection Antivirals Pts seropostive for HS and receiving BMT, Acute leukemia, or past history of infection→acyclovir prophylaxis during neutropenia Pts seropostive for varicella and receiving BMT→acyclovir prophylaxis during neutropenia BMT→ganciclovir prophylaxis against CMV during neutropenia. Prophylaxis against Infection Antimicrobial Prophylaxis Recommendation: Routine prophylaxis controversial May not reduce the need for empiric antimicrobials Concern about emerging drug-resistant bacteria and fungi No consistent reduction in mortality