Infections in Immuno-compromised Patients

mostquestionNf Infections in Immuno-compromised Patients line quid dngchoiceprophylaxis tungstic Doseforopen inte Su Lee, Pharm.D., M.S., BCIDP, BCPS Recommended Reading •National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), version 3.2024 •Freifeld AG, Bow EJ, Sepiowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious disease society of America. Clin Infect Dis. 2011;52(4):e56–e93. •Taplitz RA et al., Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: ASCO and IDSA Clinical Practice Guideline Update, Journal of Clinical Oncology, 2018; 36(14);1443-1453 a Immune System Defects Cell mediated immunity (T-lymphocyte, or Macrophages) defects caused by • corticosteroids, cyclosporine, chemo-radiotherapy • lymphoma, leukemia, AIDS, etc. jPredispose patients to: Humoral immunity (B-cells) defects caused by • Multiple myeloma, chronic lymphocytic leukemia • Splenectomy • corticosteroids, chemotherapy • chronic immunosuppression for Graft Versus Host • Bacterial infection: usual pathogens plus Disease (GVHD) in allogeneic Hematopoietic Stem Cell • Listeria, Nocardia, Legionella, Mycobacteria Transplant (HSCT) or allograft rejection in solid organ • Viral infection / reactivation / dissemination hinges transplantation (SOT) • Herpes simplex (HSV), Varicella zoster (VZV), Cytomegalovirus (CMV) Predispose patients to infection by encapsulated organisms* • Fungal infection • Strep. pneumoniae, Neisseria meningitidis, Difficult • Candida, Aspergillus, Cryptococcus Haemophilus influenzae fursus • Protozoal infection *bacteria covered with a polysaccharide capsule. Examples of such • Pneumocystis jiroveci pneumonia(PJP, PCP = bacteria include Streptococcus pneumoniae, Klebsiella, Haemophilus Pneumocystis carinii pneumonia) influenzae, Neisseria meningitidis, and Pseudomonas aeruginosa. • Toxoplasma gondii Reviews in Medical Microbiology: January 2010 - Volume 21 - Issue 1 - p 7-10 to treat Neutropenia : Definition Abnormally reduced number of neutrophils circulating in peripheral blood • Absolute neutrophil count (ANC) • [WBC x (% neutrophil segs + % bands)] / 100 • Neutropenia: ANC < 1000 cells/mm3 • defines neutropenia indicates decline sufficient to predispose patients to infection (risk) • Severe neutropenia: ANC < 500 cells/mm3 • indicates high risk for infection • Treatment guidelines use this marker as the critical value in making therapeutic decisions regarding treatment of suspected or documented infection • Profound neutropenia: ANC < 100 cells/mm3 • indicates severe risk for infection and death Additional risk factors for infection include: • Rate of neutrophil decline • Increased rate = increased risk of infection • Chemotherapy-induced neutropenia • Duration of neutropenia • Severe neutropenia > 10 days places patients at especially high risk for serious infection / poor outcome • HSCT patients may be severely neutropenic (NO detectable granulocytes) for 3-4 weeks Major factor predisposing immunocompromised patients to infection 5 Destruction of Protective Barriers • Surgery, venipuncture, IV and urinary catheters, radiation, chemotherapy • Mucositis • Erosion of mucous membranes of oropharynx and GI tract • Provides portal of entry for pathogens • Common with chemotherapy as GI tract lined with fast growing cells which chemo kills • Most common pathogens G (+) skin flora and Candida spp. Pathogens in Neutropenic Cancer Patients Bacteria • G(+) cocci: most common cause of acute infections in neutropenic pts • Potential cause of disseminated intravascular coagulation (DIC) and ARDS • S. aureus (MRSA increased morbidity and mortality), S. epidermidis, streptococci, enterococci • G(-) bacilli: slightly less common than G(+) but associated with more morbidity and mortality • E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa (failure to initiate therapy at onset of fever results in mortality 15% at 12 hrs, 70% at 48 hrs) • Increasing frequency of Stenotrophomonas maltophilia or Burkholderia cepacian • Enterobacter, Serratia, Citrobacter increasing: Beta-lactamase induction leads to more frequent development of resistance (ESBL, AmpC) • Anaerobes are infrequent cause Pathogens in Neutropenic Cancer Patients Fungus • Common in patients that are neutropenic for extended periods (>5-7 days) of time and who receive broad-spectrum antibiotics, or/and corticosteroids • Candida and Aspergillus spp. most common • Invasive Fungal Infection is associated with high morbidity and mortality • ~1/3 of febrile neutropenic pts who failed broad-spectrum Abx, have a systemic fungal infections • Up to 40% of pts with hematologic malignancies had deep fungal infections at autopsy • ~65% due to Candida spp. • C. albicans most common : Oral thrush, mucositis to invasive candidiasis (mortality 38%) • C. krusei, glabarata often resistant to azole • 30% due to Aspergillus spp. : Very serious (mortality 80% in HSCT or prolonged neutropenia) • Aspergillosis should be suspected in neutropenic cancer patients colonized with Aspergillus who remain febrile despite ≥ 7 days of broad-spectrum Abx Pathogens in Neutropenic Cancer Patients JE JE infections • Viral infections (Herpes simplex) • Parasitic • Mucous membrane damage and immunosuppression results in reactivation of HSV-1 resulting in latent viral infections • Gingivostomatitis • Often co-infection with Candida (OPC) • infection may spread to esophagus • Recurrent genital infections common as well (HSV-2) • Potential for dissemination and CNS infection (meningitis) • Pneumocystis jiroveci • Toxoplasma gondii • Less common due to routine use of trimethoprim-sulfamethoxazole (Bactrim®, Septra®, co-trimoxazole) prophylaxis Clinical Presentation Most important clinical finding in neutropenic cancer patients is FEVER! • Always consider fever to be the result of infection until proven otherwise Mata • Single temperature >101° F (> 38.3°C) orally or temp > 100.4° F (> 38.0°C) for > 1 h orally • Other possible causes of fever include blood product reactions, tumor lysis, hemolysis, underlying malignancy, reactions to drugs or biologic agents (monoclonal antibodies), or in SOT this can be allograft rejection • Treat the neutropenic fever with antibiotics first then try to rule in/out other potential causes Evaluate the patient carefully for signs and symptoms of infection • In neutropenic fever, HSCT or SOT patients signs of infection may be absent or altered • Bacteremia commonly presents only as fever! • Since there are NO WBCs there are NO WBCs in the urine and NO infiltrate on CXR • Blood cultures (2 or more sets including vascular access devices for bacteria and fungi) • Cultures of other suspected sites, aspiration, biopsy of suspected sites • CBC with differential, blood chemistries, vital signs, CXR, etc. Febrile neutropenia is a medical emergency Empiric Therapy Broad spectrum antibiotics, bactericidal, usually parenteral, should be initiated at the onset of fever • Withholding antibiotic until isolation of a pathogen results in unacceptably high mortality rate • Undiagnosed infection (inappropriately treated) can 0 30 deteriorate rapidly and result in death • Pseudomonal bacteremia in neutropenic patients coveras results in mortality rates of 15% at 12hrs and 70% at to 48hrs if untreated! move pseffofrere • If appropriately treated: • Decreases mortality by 70-90% • 7-21% mortality at 48hrs Passive Empiric Therapy Considerations • • • • at Local resistance patterns Patient risk for infection Drug allergies Concomitant nephrotoxins (platins, chemotherapy) • Previous antimicrobial exposure including prophylaxis (quinolones, azoles, TMP/SMZ) Determine patient’s risk for a severe infection Pathogens based on anticipated duration of neutropenia • LOW: Neutropenia < 7 days considered short duration • Bacteria • MODERATE: Neutropenia 7-14 days • Bacteria and fungi • HIGH: Neutropenia for > 14 days • Bacteria, fungi, viruses and parasites Risk Factors for Serious Medical Complications in Patients With FN Febrile Neutropenia (FN) Risk Factors • • • • • • • • • • • • Development of F N as inpatient Hypotension Sepsis Cardiovascular disease Pulmonary disease Leukemia or lymphoma Age > 65 years Prior fungal infection Visceral organ involvement Organ dysfunction Uncontrolled malignancy Severity and duration of neutropenia • Prior episode Febrile Neutropenia Risk Factors for Inpatient Mortality in Hospitalized Patients With FN • Comorbidities: CHF, PE, lung, renal, liver, and cerebrovascular disease no • Infectious complications: hypotension, pneumonia, bacteremia, fungal infection • Cancer type (leukemia, lung cancer) • Age > 65 years NCCN Febrile Neutropenia Guideline Fever: Single temperature > 38.3°C (101°F) orally or > 38.0°C (100.4 °F)over 1 h Neutropenia: < 500 neutrophils/mcL or < 1,000 neutrophils/mcL and a predicted decline to < 500/mcL over the next 48 h SET Comprehensive evaluation: physical examination, laboratory/radiologic assessment, cultures Determine if High Risk Determine if Low Risk 19 High risk (any factor listed below) • • • • • • • • • • Inpatient status at time of development of fever Significant medical comorbidity or clinically unstable Anticipated prolonged severe neutropenia: <100 cells/mcL for > 7days Hepatic insufficiency : 5 times ULN for aminotransferases around 20,0 Renal insufficiency : Creatinine Clearance < 30 mL/min Uncontrolled / progressive cancer Pneumonia or other complex infections at clinical presentation Allogenic stem cell transplantation Mucositis grade 3-4 (Can’t swallow solid food) MASCC Risk Index score of less than 21 (MASCC: Multinational Association of Supportive Care in Cancer) Hospital Admission required for IV therapy 20 MASCC RISK-SCORE/MODEL • Estimate the patient's burden of illness at the time of initial clinical evaluation. • Score the factors in the model and sum them. BURDEN OF ILLNESS MASCC RISK-SCORE/MODEL How sick is the patient at presentation (sign/symptoms)? Characteristic Burden of illness • No or mild symptoms • Moderate symptoms No hypotension No COPD Solid tumor or hemotologic malignancy with no previous fungal infection No dehydration Outpatient status Age <60 years No S/S Mild S/S Moderate Severe Moribund = = = = = 5 5 3 0 0 Estimate the burden of illness considering all comorbid conditions Weight 5 3 5 4 4 3 3 2 t #/26 Max number 21 NCCN Febrile Neutropenia Guideline • • • • • • • Low risk (none of the high risk factors and most of the following): Outpatient status at time of development of fever No associated acute comorbid illness, independently indicating inpatient treatment or close observation Anticipated short duration of severe neutropenia Good performance status (ECOG 0-1) No hepatic insufficiency No renal insufficiency A score of 21 or greater on the MASCC Risk Index Outpatient Therapy Ambulatory Clinic Home Care Hospital IV Therapy ? to PO Therapy 22 ECOG Performance Status Eastern cooperative oncology group Grade Description 0 Fully active, able to carry on all performance without restriction. Restricted in physically strenuous activity but ambulatory and able to do light work. Ambulatory > 50% of waking hours and capable of all selfcare but unable to carry out any work activities. 1 2 3 4 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Totally confined to bed or chair. 5 Dead 23 Empiric Therapy Oral empiric therapy may be appropriate for low-risk patients • Overall condition and other risk factors determine outpatient or inpatient therapy • Medication Compliance • Good caregiver support • Access to medical care around the clock • Patients who meet criteria achieve similar outcomes as patients who receive parenteral antibiotic • Response rates 77% - 95% • Benefits of outpatient therapy include increased quality of life and reduced exposure to multi-drug resistant institutional pathogens • Oral therapy also beneficial for moderate risk patients as a step-down from IV therapy • Response rates comparable to patients remaining on IV therapy • Inclusion criteria: • defervescence within 72 hours of initiation of parenteral therapy • Hemodynamic stability • Absence of positive cultures/site of discernable infection • Ability to take oral medications NCCN Febrile Neutropenia Guideline OUTPATIENT THERAPY Give first antibiotics and observe for 2-12 hours Oral Therapy (no N/V, tolerable to PO, no prior use of FQ Px) e Ciprofloxacin + Amoxillin/clavulanate IV Antibiotics at home Levofloxacin or Moxifloxacin Golesspreferred agent Daily follow-up exam Daily follow-up exam 25 Empiric Therapy High risk g Intravenous antibiotic monotherapy (choose one): • Cefepime (category 1) • Ceftazidime (category 2B) • Imipenem/cilastatin (category 1) • Meropenem (category 1) • Piperacillin/tazobactam (category 1) • No evidence to suggest one regimen is superior to another • Overall response rate 70% - 90% • Relatively low toxicity, ease of administration, less cost • Relatively limited G (+) activity • MRSA, PCN resistant Strep. pneumoniae, some viridans strep, VRE, MRSE (CNS) • Possibility of selection for resistance among Pseudomonas, Enterobacter, Serratia, Citrobacter Routine use of MRSA agents NOT recommended. • Because of the risk for emergence of resistant organisms (VRE, VISA) Addition of MRSA agents: • Prospective studies indicate there is no benefit in adding vancomycin to initial empiric therapy IF vancomycin is added later when needed • If preliminary lab results indicate G(+) infection, MRSA agents are appropriate empirically while susceptibility results are pending Continuation of Therapy • After empiric therapy is initiated continuous to daily assessment of the patient is essential • After 72 hours or more of therapy clinical status and C&S results need to be evaluated • Determines necessity of modification of therapy (expand/target coverage) j my • If neutropenia persists, coverage must remain broad to prevents secondary infection Continuation of Therapy Fever of Unknown Origin Management of patients who remain febrile w/o microbiologic or clinical documentation of infection OH is 5-7 days • Usual time to defervescence • Patients require careful evaluation • Fever after > 3 days due to several causes • Nonbacterial infection (~25%), resistant bacterial infection, slow response to therapy, emergence of secondary infection, inadequate drug therapy concentrations, drug fever, cell wall deficient bacteremia, infection at an avascular site such as an abscess or infected prosthesis/catheter • Patients often remain febrile until neutropenia resolves NCCN Febrile Neutropenia Guideline Evaluate overall response to empiric therapy in 3-5 days (72-120 h) RESPONDING • Decreasing fever trend • S/S stable/improving • hemodynamically stable No change in regimen Antibiotics should continue at least until ANC > 500 and increasing • • • • NON RESPONDING Persistent fever or spike S/S not improving hemodynamically unstable Persistent positive cultures Fever of Unknown Origin Documented Infection Assess ABX Consider adding CSF cerebrospinal no fluid 29 NCCN Febrile Neutropenia Guideline NON RESPONDING Fever at > 4 days Evaluation Regardless if clinically stable or not Consider antifungal therapy with activity against molds for fever continuing > 4 days of empiric antibiotic therapy Duration of therapy depends on clinical course, neutropenia recovery, toxicity, and opinions of Infectious Disease consultants 30 Continuation of Therapy • Neutropenic patients who remain febrile despite 4 or more days of broad-spectrum empiric therapy are candidates for antifungal therapy • Persistence of fever or development of new fever during treatment may be due to an invasive fungal infection • In documented fungal infection blood cultures remain negative in > 50% of cases 8 autopsies show a high incidence of invasive fungal infections despite no • Post-mortem evidence of a fungal infection before death • Lack of availability of rapid sensitive diagnostic tests (PNA—FISH) • Empiric antifungal therapy is justified • Empiric therapy to cover of both Candida and Aspergillus as > 90% of fungal infections due to these Invasive Candidiasis Therapy • For febrile neutropenic patients with prolonged fever despite 4-6 days of empirical antibiotic therapy • Voriconazole or fluconazole (low risk for aspergillosis or azole resistant Candida) MOREsage • Echinocandin (caspo- mica- or anadula- fungin) nephrotoxity• Amphotericin B or Liposomal Amphotericin B Chydrophin • Adjust therapy based on culture results if a fungus identification is made (see prior lecture) • Duration of Therapy • Until resolution of neutropenia and S/S of infection (if no fungus isolated) • Two weeks after resolution of symptoms and last positive culture when a fungal pathogen is identified 32 Antifungal Therapy • Antifungal therapy may be discontinued when neutropenia has resolved in a clinically stable patient with NO evidence of fungal infection • In prolonged neutropenia antifungals are • continued at least 2 weeks after cultures are negative and symptoms resolve in a fungal infection • continued at least 12 weeks in an Aspergillus infection • Persistent fever may be due to non-bacterial non-fungal infection • Viral, mycobacterial, protozoal infection • Administration of blood products • Tissue necrosis of solid tumor as a result of chemotherapy NCCN Febrile Neutropenia Guideline Fever Unknown Origin Clinically Stable Duration of Therapy ANC ≥500 for ≥ 2 days Discontinue Continue current regimen until neutropenia resolves Switch to oral antibiotics until neutropenia resolves Neutrophils so < 500 sage Consider discontinuation of antibiotics after 7-14 days if pt remains stable 7-14 days if patient remains stable (category 2B) 34 NCCN Febrile Neutropenia Guideline DOCUMENTED INFECTION Duration of Treatment go o Initial antibiotics continued until ANC is > 500 cells/mcL and increasing o Duration of antibiotics individualized based upon: o Neutrophil recovery o Rapidity of defervescence o Specific site of infection o Infecting pathogen o Patient's underlying illness Treat the infection usually for 7-14 days: o SSTI (5-14 days)Sinusitis (7-14 days) or Pneumonia (5-14 days) o Blood stream infection (7-14 days) o Yeast >2wks after 1st negative blood culture + s/s resolution o Aspergillus > 12 weeks o HSV/VZV (7-10 days) o Influenza (5 days) talk and days wositeofon feeti 35 AE1 • Summary • ANC • Fever • NCCN Febrile neutropenia guidelines • High risk • Empiric regimen • Abx • Antifungals Prolonged Immune Suppression Duration of immune suppression covered from this point forward in months to years Hematopoietic Stem Cell Transplant (HSCT, HCT) patients Solid Organ Transplant (SOT) Patients Human Immunodeficiency Virus (HIV) infected patients (AIDS): Reviewed by Dr. Morataya HSCT Infection Risk • High-Dose Chemotherapy/Radiation Therapy • Increased risk because of prolonged periods of profound neutropenia (ANC = 0 for 3-4 weeks) • Allogeneic (Matched Unrelated Donor transplants) receive prolonged immunosuppressive therapy for the prevention/treatment of graft vs. host disease • All these (Chemo/RT) results in disruption of protective barriers (mucous membranes, skin, GI tract) • Predisposed to earlier severe infections (i.e.) • Fungal infections are often fatal • Aspergillosis mortality rates ~90% • Similar risks in Solid Organ Transplantation (SOT) SOT Infections • Infection is the most frequently encountered complication associated with immunosuppression in the first transplant year • Infection can be a life-threatening complication following transplantation • Twice as many patients are admitted to hospitals with infections than for acute graft rejections • Infection is the second leading cause of death after cardiovascular disease in SOT patients • Transplant recipients are unique hosts because • impaired state of health pre-transplant • undergo technically complex procedure • post-operative immunosuppression • Early diagnosis/treatment of infections are essential to reduce morbidity/mortality Overview of SOT Infections • The type of bacterial infections in transplant patient are similar to other patients and HSCT in the first month post transplant • Surgery exposes otherwise sterile tissue to bacteria • Antibiotic selection and use same as non-transplant host • Immunosuppression makes one rely more on the antibiotic than the patient to fight the infection • Immunosuppression predisposes transplant recipient to virus and fungus infections that would be controlled in a non-transplant host with a competent immune system • Take precautions to control exposures to viruses and fungi Risk Factors for SOT Infection Pre-transplant Medical Condition Heart disease Diabetes Chronic lung disease Latent infections Chronic hepatitis Cytomegalovirus Herpes simplex virus Varicella-zoster virus Tuberculosis Colonization Preop antibiotics alter normal flora Preop hospitalization nosocomial exposure Emmanuolides, Holt 1996 Transplant Surgery Prolonged procedure Multiple transfusions Graft ischemia Graft Injury Bowel leak Graft Hepatitis viruses Cytomegalovirus HIV Post-transplant Hospital Flora Resistant bacteria Aspergillus Legionella Post-op management Catheter TPN, neutropenia Prolonged intubation Prolonged antibiotics Repeat laparotomy Immunosuppression Cyclosporine Azathioprine/MMF Tacrolimus Corticosteroids Muromonab CD3, ATG Incidence of Infection in SOT Based on Organ Type % Infection Liver Kidney Heart Lung Pancreas Bacterial 33-68 47 21-30 54 35 Viral Cytomegalovirus - CMV Herpes simplex v - HSV Varicella zoster v - VZV 22-29 3-44 5-10 8-32 53 4-12 9-35 1-42 1-12 39-41 10-18 8-15 50 6 9 Fungus Candida sp Mycelial fungi 1-26 2-4 2 1-2 1-5 3-6 10-16 3-19 32 3 Pneumocystis jiroveci 4-11 5-10 1-8 15 na Type of infection Don’t memorize the numbers – Know the pathogens cell my Candida Fungal Infection in SOT • Cause of high morbidity and mortality • Most fungal infections are an overgrowth of Candida from bowel • Broad-spectrum antibiotics kill bacteria that control candida overgrowth • Mortality 30-70% with Invasive Fungal infections • Other fungal infections reflect exposure to the fungal source • Recent or remote environmental exposures (soil, air) Aspergillosis Cryptococcus Blastomycosis Murcormycosis Dermatophytes • Aggressive diagnosis, prevention, and treatment needed • Fungal infection is usually well established at diagnosis • Success of treatment usually poor in transplant patients • Ampho-B, Echinocandins, Azoles HCST / SOT Infection Timeline Conventional → Nosocomial → Opportunistic → Persistent Bacterial: wounds, UTI, IV catheter, pneumonia, CDI Listeria, Tuberculosis Viral Infections Herpes simplex virus , Hepatitis B, Hepatitis C reactivation / new exposure Influenzae, Parainfluenza, Respiratory syncitial virus Cytomegalovirus (CMV) retinitis/colitis Epstein-Barr virus Varicella zoster Papillomavirus Fungal Candida spp. Aspergillus spp. Cryptoccus neoformans, Endemic fungi Miscellaneous opportunistic infections Nocardia asteroides Pneumocystis jiroveci Toxoplasma gondii, Mycobacterium tuberculosis 0 1 2 3 4 Months After Treatment 5 6 HCST / SOT Infection Timeline HSCT /SOT patients: >100 days post transplant and AIDS 1st Early in the month • Suspect normal bacteria in region of surgery (SOT) or patient’s own flora and colonizers (FN) • > 50% of pathogens infecting neutropenic patients are acquired in the hospital • Infection control is essential • Proper, meticulous HAND WASHING • Alcohol based hand cleansers • Reverse isolation “Neutropenic precautions” • Laminar airflow rooms not proven to decrease mortality • Suspect opportunistic infections, latent reactivation of viral/fungal pathogens • SOT/HSCT Late post-engraftment / allogeneic transplant period associated with Rejection and aggressive immunosuppression • HSCT - VZV in 50% of patients with GVHD / rejection by 10 months • 30-45% are disseminated • 50% of disseminated result in death • CMV – cytomegalovirus • Pneumocystis jiroveci pneumonia (PJP / PCP) • If bacteria: encapsulated bacteria (Haemophilus influenzae, Neisseria, Strep. pneumoniae) Antibiotic Px Antibacterial prophylaxis is controversial • In allogeneic HSCT with GVHD ~20% develop G(-) bacteremia with a 25% mortality in these patients • Development of / selection for resistant bacteria • Fungal overgrowth • Lack of impact on patient survival • Delayed marrow recovery (TMP/SMZ, co-trimoxazole) • High cost • Adverse effects: GI, NVD, other • Decreased infection rates (febrile neutropenia) • TMP/SMX better than placebo • Fluoroquinolones more effective than TMP/SMX • Ciprofloxacin • Olfloxacin (Levofloxacin) • Add G (+) coverage (PCN, macrolide, rifampin) Antifungal Px Fluconazole prevention of invasive fungal infections • Meta analysis of 7000 cancer patients • Decreased use of parenteral antifungal therapy • Decreased superficial and invasive fungal infections • Decreased fungal infection related mortality rates • Dose: Fluconazole 400mg/day until marrow recovery • Recommended during high-risk periods • HSCT/SOT/AIDS patients – risk persists • ~ 1-2 yrs in allogeneic HSCT • Lifetime in SOT/AIDS • Cancer regimens with prolonged neutropenia (months) to ~ 1-2 yrs years in Leukemia patients • Risk of emerging azole resistance (C. krusei, C. glabrata) • Does not protect against Aspergillus • Use amphotericin B, Echinocandin, Posaconazole HSCT - HSV Infection HSCT – VSV Infection • HSV Infections: Gingivostomatitis, esophagitis, genital lesions, pneumonia • Usually in the first month after transplant • Most common in patients with serologic evidence of prior exposure • Reactivation of latent HSV disease • 80% of seropositive patients experience mucocutaneous disease after intensive therapy • <25% of seronegative patients acquire HSV infections • Must know HSV serologic status prior to transplant • HSV prophylaxis recommended for all seropositive HSCT patients • 0-10% reactivation with prophylaxis vs. 60-80% without prophylaxis • Acyclovir 5mg/kg IV q 12 hrs or 200mg PO TID • Valacyclovir 500-1,000mg PO daily • Up to half of allogeneic HSCT patients surviving up to 10 months develop an infection caused by VZV • Acute or chronic GVHD predisposes to VZV infections • Both primary (varicella) or recurrent disease (herpes zoster) present as skin lesions which usually remain contained to local areas • 30-45% of these disseminate to other body organs causing mortality as high as 50% r HSCT - Antiviral Treatment no IBI • HSV or VZV Infections: • Acyclovir 5-10mg/kg IV Q8H • Adjust for renal insufficiency • Foscarnet for Acyclovir resistant disease • VZV exposure • Prophylaxis recommended for allogeneic HSCT patients with GVHD lasting more than 24 months • Varicella immune globulin 625 IU IM within 48-96 hours after close contact with persons with chickenpox or shingles for prevention of VZV related disease SOT Viral Infections • Active infections documented in nearly half of SOT transplant recipients • Affects patient and graft survival • Associated with higher rate of rejection • Immune system activated to fight infection • Immune system sees transplanted organ as another “infecting object” • Aggressive diagnostic and therapeutic intervention required • Viruses - Herpes family • Cytomegalovirus (CMV) 50-60% of population positive • Herpes simplex virus (HSV) 90% of population positive • Varicella zoster virus (VZV) 90% of population positive • Epstein-Barr virus (EBV) 95% of population positive SOT - Herpes Simplex Virus (HSV) • Many recipients are HSV antibody (+) • Incidence: 3-53% can reactivate posttransplant • Reactivation occurs within the first 6 weeks post-transplant • Disease presentation: • mucosal outbreak, • dissemination to visceral organs (liver, lungs, CNS) • Diagnosis • direct immunofluorescence • tissue culture/body fluid culture • serologies: (+) for IgM or 4-fold increase in IgG • Treatment (mucocutaneous) • Acyclovir (Zovirax®) • IV 5 mg/kg q 8h x 1 week (lesions must crust over) • PO 200 mg 5 times/day or 400 mg TID x 5-7 days • Alternatives: • Valacyclovir (Valtrex®) 1 Gm PO Q12H • Famciclovir (Famvir®) 0.5-1 Gm PO Q12H • Treatment (encephalitis / disseminated) • acyclovir 10mg/kg IV q 8h x 10 days asprevent urine • Hydrate well to crystallization and renal failure • Adjust dose in renal insufficiency • Prophylaxis • Acyclovir 400mg PO BID • Valacyclovir 1Gm PO qday Varicella Zoster Virus (VZV) • Also called Herpes Zoster • Varicella zoster is initial infection (chicken pox) • Shingles is a re-activation infection • Disease presentation: rash, pneumonia, encephalitis, graft dysfunction In SOT: • Active disease (VZV) is less common than HSV in transplant patients • 90% of transplant recipients are VZV sero-positive prior to transplant • 10% are at risk to acquire primary VZV infection • Typically occurs within first 6 months post-transplant In HSCT: • See prior section on HSCT-VSV • Treatment (pneumonia / encephalitis) • IV: acyclovir (Zovirax®)10-20 mg/kg q 8h x 7-10 days • Treatment (dermal) • PO: acyclovir 800 mg 5 times/day x 7 days • PO: famciclovir (Famvir®) 500 mg tid x 7 days • PO: valacyclovir (Valtrex®) 1000 mg tid x 7 days • Prophylaxis (exposure significant) within 4 days • Varicella Zoster Immune Globulin – (VZIG, VariZIG®) • 0-10kg 125 units IM • 10.1-20kg 250 units IM • 20.1-30kg 375 units IM • 30.1-40kg 500 units IM • > 40kg 625 units IM • Adverse effects: pain on injection site, malaise, headache, anaphylaxis SOT - CMV Clinical Manifestations • Flu-like syndrome: fever, malaise, arthralgias, nausea, vomiting • Hematologic changes: leukopenia, atypical lymphocytosis, thrombocytopenia • Effect on allograft: chronic rejection or injury • Specific organ involvement lung transplant – CMV pneumonitis heart transplant – CMV pneumonitis kidney transplant – CMV nephritis liver transplant – CMV gastritis, hepatitis, colitis Risk Factors for Developing CMV • Source of acute infection • Donor (+) to host (-): primary infection 40-60% • Donor (+) to host (+): acute infection 5-22% • Donor (-) to host (+): latent-secondary infection 510% • Donor (-) to host (-): primary infection 5-15% • Corresponding medical conditions that increase CMV risk • Net state of immunosuppression • Type of organ transplanted (kidney, lung, pancreas) • Immunomodulatory Events (acute rejection episodes) • HLA mismatching (increased immunosuppression) • Cadaveric transplantation • Re-transplantation • Blood products CMV Prophylaxis (SOT) Regimen Dose High dose acyclovir 3200 mg/day PO Pre-emptive ganciclovir IV 2.5-10 mg/kg/day then PO 1500-3000 mg/day Ganciclovir followed by acyclovir IV ganciclovir 2.5-10mg/kg/day then PO acyclovir 3200mg/day Valganciclovir 900mg daily PO CMV Immune globulin CMV IgG every 2-4 weeks 150 mg/kg/dose tapering to 50mg/kg/dose at week 12 Treatment For active Infections (HSCT, SOT): • Ganciclovir (Cytovene®) 1st choice • Foscarnet (Foscavir®) 2nd choice • Valganciclovir (Valcyte®) • Cidofovir (Vistide®) • Resistance develops to all of these and combination therapy is often required • In HSCT, SOT treat until PCR CMV viral load is undetectable and resolution of signs and symptoms. • Consider chronic maintenance therapy after relapse CMV Treatment : Ganciclovir Valganciclovir • Acyclic nucleoside • Must be taken into cells and phosphorylated then binds to DNA • IV and Intra-ocular implant • IV dose: • Induction dose 5mg/kg q 12h x 14-21 days • Bone marrow suppression with neutropenia 50% • Also thrombocytopenia • Monitor ANC and PLT • CSF may be given • Oral prodrug hydrolyzed to ganciclovir e • 900 mg dose orally gives similar levels to ganciclovir 5mg/kg IV • Equally effective to ganciclovir • Similar ADRs • More convenient route 53 CMV Treatment : Cidofovir Foscarnet • Also a nucleotide analog • Most potent of all the CMV treatments • Inhibits viral DNA polymerase and reverse transcriptase • 60mg/kg IV Q 8 hours or 90 mg/kg IV Q 12 hours • Dose limiting toxicity is nephrotoxicity • Also active vs. HSV and VZV • Used for those that have failed ganciclovir • Poorly absorbed but long half life • Once weekly induction therapy and every other week maintenance therapy • ADRs • Nephrotoxic (filtration and active secretion) • Prehydrate with 1L NS before and 1L NS during or after • Probenecid blocks tubular secretion and decreases nephrotoxicity • Monitor renal function • Crystalizes in nephrons • Hydrate prior to infusion • Electrolyte imbalance including hypocalcemia • Neutropenia 20%, monitor CBC • Hypotony (decreased intra-ocular pressure), uveitis 54 Pneumocystis jiroveci Pneumonia (PJP) to • Reclassified from protozoa to fungus based on RNA • Cyst form and trophozoite form • Clinical Presentation • • • • Fever, shortness of breath, and nonproductive cough Increased lactate dehydrogenase In general, with CD4 counts < 200/mm3 Hypoxemia with increased alveolar-arterial (A-a) gradient and decreased partial pressure of oxygen 56 Pneumocystis jiroveci Pneumonia (PJP/PCP) • X-ray of PCP pneumonia • increased opacification (whiteness) in the lower lungs on both sides, characteristic of PCP pneumonia http://upload.wikimedia.org/wikipedia/commons/thum b/7/74/PCPxray.jpg/220px-PCPxray.jpg Accessed on 4/8/14 Diagnosis • Induced sputum or bronchoalveolar lavage (BAL) or transbronchial biopsy as • Silver stain of sputum sample http://upload.wikimedia.org/wikipedia/commons/thumb/ 5/59/Pneumocystisjiroveci.jpg/220px57 Pneumocystisjiroveci.jpg Accessed on 4/8/14 Pneumocystis jiroveci Pneumonia Treatment • depends on: • Severity • Mild: Alveolar-arterial oxygen gradient (A-a gradient) < 35 or PaO2 > 70 mm Hg • Can be treated as an outpatient • Moderate or Severe: A-a gradient > 35 or PaO2 < 70 mm Hg • Initial episode of PCP • Need for parenteral therapy • Prior adverse reactions or hypersensitivity 58 PJP Treatment/Preferred Tx : TMP/SMX • Drug of choice unless history of LIFE THREATENING intolerance • Severe to moderate • 15-20 mg/kg IV or PO of TMP component divided q 6 or q 8 hours for 21 days • Mild to moderate • 2 DS TID for outpatient Tx (1DS TMP/SMX=160/800 mg) • A good response in up to 70% of patients • Also effective to Toxoplasma gondii • 25-50% of patients intolerant • Rashes, severe urticaria, exfoliative dermatitis, SJS • GI intolerance (Not give PO Q6 H), abdominal pain • Hematologic – leukopenia, anemia, thrombocytopenia • Also: neurologic toxicities, Hyperkalemia, hepatitis • Mild reactions (rashes) treat with antihistamines • Severe reactions switch to another drug 59 4819 no 61 PJP Treatment : Alternatives Atovaquone suspension • Mild to moderate disease • Also effective to Toxoplasma gondii • Well tolerated vs. other agents • Rash, fever, elevated LFT’s, and emesis possible • Safer but less effective than TMP/SMX • Fatty foods increase absorption TMP-dapsone • Not for those with Type 1 hypersensitivity to sulfa • Co-administration increases blood levels of both • Synergistic inhibition of folate cycle • Dapsone associated with hematologic toxicity • Hemolytic anemia, methemoglobinemia, neutropenia, thrombocytopenia • Test for G6PD deficiency 62 PJP Treatment : Alternatives Clindamycin + Primaquine • Skin rashes common but they subside • Some toxicities • Fever, rash, granulocytopenia, methemaglobinemia • Test for G6PD deficiency IV Pentamidine • More toxic than TMP/SMX • Nephrotoxicity, glucose intorelance, hepatotoxicity, hyperkalemia, hyperamylasemia • Drug discontinuation in 18% • Monitor closely • Renal toxicity can be reduced with reduction in dose • Discontinue if signs of pancreatitis 63 severe More no PJP Treatment : Corticosteroids • Acute severe PJP with PaO2 <70 mm Hg or A-a gradient > 35 (Not in TB, if use→ disseminated TB) • Treat acute inflammatory reaction due to Pneumocystis • Can prevent fatal deterioration (Motality 90 %→40%) • Prednisone • 40 mg bid x 5 days, 40mg daily x 5 days, 20 mg daily x 11 days (21 days total) • Benefits greater than risks 64 Pneumocystis jiroveci Pneumonia • Primary Prophylaxis • TMP/SMX 1 DS daily is most efficacious (or 1SS daily) • If rash, rechallenge is worth risk • Desensitize vs. changing agents • • • • DAPSONE Atovaquone Dapsone + pyrimethamine (with leukovorin) Nebulized pentamidine *G6PD deficient Pt: Atovaquone or Pentamidine -avoid TMP/SMX, Dapsone, and Primaquine –hemolytic anemia 65 Toxoplasmosis • Toxoplasma gondii is found worldwide • Seropositivity in US ranges from 5-40% • SOT: High risk seropositive donor to seronegative recipient - 80% transmission • Infection can be severe in immunocompromised patients 65-83% mortality rate post transplant • Myocarditis, encephalitis, pneumonitis, chorioretinitis or disseminated infections • Tissue biopsy necessary to make the diagnosis • Diagnosis often made at autopsy • In SOT Prophylaxis (seropositive donor /recipient): • pyrimethamine + TMP/SMX x 3 months • then a lifetime of TMP/SMX DS tablet daily • In SOT Treatment: 6 weeks or longer • pyrimethamine + leucovorin + sulfadiazine • pyrimethamine + leucovorin + ( clindamycin OR clarithromycin OR azithromycin OR atovaquone) cannothavelive vaccineto 3yrs immuno Infections are common in immune suppressed patients Immune Compromised Patients’ Infection Summary Multiple host factors place immune suppressed patients at risk for infection Identification of these risk factors may minimize morbidity/mortality Prophylaxis for bacterial, fungal, viral, and protozoal infections are important during periods of high immunosuppression Rapid diagnosis and treatment are essential for eradication/suppressing infection