2 Recent GuidelinesNational Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections vEuropean Society for Medical Oncology. Management of Febrile Neutropenia: ESMO Clinical Practice Guidelines 2010Infectious Disease Society of America Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer
4 ObjectivesIdentify predisposing factors and common pathogens that cause infectionsReview initial investigations that will help direct therapy
5 Objectives IICompare recommendations for empiric antibiotic selections for high risk and low risk patients.Discuss assessment of response, treatment modifications and duration of therapy.
6 Incidence of Febrile Neutropenia Induction-remission for AML 70-90% Elderly patients receiving CHOP35-45%Mortality Estimates from Febrile NeutropeniaHematological malignanciesUp to 11%Gram-positive bacteremia5%Gram-negative bacteremia18%
7 Definition of Febrile Neutropenia Fever: Single oral temperature ≥38.3°C or persistent temperature ≥38.0 °C for >1 hour.Neutropenia: ANC <0.5, or ANC <1.0 and a predicted decline to <0.5 over next 48 hrs. (ANC= absolute neutrophil count)
8 Predisposing Factors Malignancy Surgical risk Grade of neutropenia TypeAdvanced/refractoryObstructiveSurgical riskGrade of neutropeniaDisruption of mucosal barriersCorticosteroid use
15 Site-Specific Cultures Diarrhea: C.difficile assay, stool microscopy and cultureSputum microscopy and cultureAspirate/swab/biopsy of any skin lesionsViral testsVesicular or ulcerated skin/mucosal lesionsThroat or nasopharynx for respiratory symptoms (esp. during outbreaks)LP if CNS symptomsFungal cultures
16 Risk Status Assessment Low RiskHigh RiskOutpatient at time of feverInpatient at time of feverNo acute comorbid illnessesSignificant medical comorbidityAnticipated short duration of severe neutropeniaAnticipated severe or prolonged neutropeniaNo renal insufficiencyCrCL <30 ml/minNo hepatic insufficiencyTransaminases ≥5x ULNGood performance statusUncontrolled/progressive cancer,Mucositis grade 3-4MASCC Risk Index score ≥21MASCC Risk Index score <21Complex infection
17 Klastersky J,J Clin Oncol 2000; 18:3038–51. MASCC IndexMultinational Association for Supportive Care in CancerProspectively validated tool to rapidly assess risk before access to neutrophil count.Scores 21 are at low risk of complications (max score 26).MASCC scoring index:Burden of illness: no or mild symptoms 5Burden of illness: moderate symptoms 3Burden of illness: severe symptoms 0No hypotension (systolic BP >90 mmHg) 5No chronic obstructive pulmonary disease 4Solid tumour/lymphoma with no previous fungal infection 4No dehydration 3Outpatient status at onset of fever 3Age <60 years (not valid in children <18 years) 2Klastersky J,J Clin Oncol 2000; 18:3038–51.
18 Low Risk Treatment Low risk, adult patients Vigilant observation No focus of infection, hemodynamically stableNo systemic symptoms other than feverNo organ failure, pneumonia, soft tissue infectionRecovering bone marrowReliable patientVigilant observationAccess to medical care 24-7Return to clinic ifPositive culturesPersistent/recurrent fever (3-5 days)Unable to tolerate PO regimenCipro 500 mg PO Q8h + amoxicillin-clavulanate 500 mg PO Q8h
19 Principles of High Risk Treatment Inpatient treatment with IV antibiotics (60 min)Coverage for MRSA or resistant Gram-negative bacteria may be required.Monotherapy is equivalent to combinations (with few exceptions)
21 IV Monotherapy Cefepime Imipenem-cilastin Meropenem** Piperacillin-tazobactam** (NCCN)Ceftazidime** (with concerns)**Formulary (all others Non-formulary at THC)The options for IV monotherapy are consistent between guidelines and are listed here in alphabetical order except that ceftazidime is not preferred due to reduced efficacy against gram-positive and ESBL organisms.Quinolones have been evaluated as monotherapy but have shown equivocal results in clinical trials (some positive and some negative) and are not recommended in the current versions of any of the guidelines.
22 IV Combination Therapy Advantages:Synergistic effect against gram-negReduced emergence of resistanceDisadvantages:Lack of activity against gram-pos?Toxicity
23 IV Combination Therapy Aminoglycoside + (meropenem, imipenem-cilastin or piperacillin-tazobactam)Aminoglycoside + (cefepime or ceftazidime)Ciprofloxacin + (meropenem, imipenem-cilastin or piperacillin-tazobactam)Although meta-analysis found equivalent efficacy, bactericidal activity and synergistic effect of a b-lactam antibiotic in combination with an aminoglycoside is preferable to monotherapy with antipseudomonal cephalosporins in high risk patients.Although there have been many comparative trials, results have proven similar in meta-analysis when study design variations are taken into consideration.
24 IV Therapy Options: Comparison Piperacillin-tazobactamBroad spectrum gram(-), gram(+) & anaerobic coverageUse for intra-abdominal sourceNot recommended for meningitis (poor CSF penetration)Imipenem-cilastinBroad spectrum gram(-), gram(+) & anaerobic and ESBL coverageRisk of seizures in CNS malignancy or renal impairment
25 IV Therapy Options: Comparison MeropenemBroad spectrum gram(-), gram(+) & anaerobic and ESBL coverageUse for intra-abdominal sourcePreferred for meningitis/CNS infectionCeftazidimePoor gram(+) activityBreakthrough streptococcal infectionsNo activity against anaerobes, enterococcusGood CSF penetration
26 IV Treatment Options: Comparison AminoglycosidesGram(-) coverage, synergy with beta-lactams against S.aureus and EnterococcusNephrotoxicity, ototoxicityCiprofloxacinGram(-) and atypical bacterial coverageNo anaerobic coverage, less gram(+) activity than other optionsGood clinical studies as empirical PO or IV therapyAvoid in patients recently treated with quinolone prophylaxisLevofloxacin: better gram (+) coverage but limited studies available for use as empiric therapy.
27 Vancomycin Vancomycin not routinely recommended Use should be limited to specific indications:clinically suspected serious catheter-related infectionknown colonization with MRSA or pcn/ceph-resistant pneumococcigram-positive bacteremiahypotensionsoft-tissue infectionsevere mucositisReassess Vancomycin after hours
28 Antifungals as Empiric Therapy? High risk patients with prolonged neutropenia and site-specific symptoms:Oral thrush: Mucositis mouthwash, FluconazoleEsophageal lesions: FluconazoleSinus/nasal symptoms and suspicious CT/MRI: Amphotericin BPneumonia: voriconazole, amphotericin BEmpiric treatment required based on H&P as positive cultures can take several days.
29 Antifungals Added Later? IDSA recommends consider antifungal if febrile after 3-5 days and remains neutropenicAmphotericin B is preferredFluconazole may be acceptable at institutions with low rates of mold infections or drug-resistant Candida species
30 Antifungals Added Later? NCCN recommends:Add fluconazole ifno prior azole antifungal prophylaxis,low risk for invasive aspergillosis andlow rates of azole-resistant Candida.Dosing:150 mg PO x1 dose for vaginal candidiasis200 mg PO daily x14 days for candidal pyelonephritis800 mg x1 then 400 mg daily x14 days from first negative culture for candidiasis (not recommended if received prophylaxis)400 mg PO daily prophylaxis for neutropenic patients
31 Antifungals Added Later? NCCN RecommendsAdd voriconazole, liposomal amphotericin B or an echinocandin if already exposed to an azole or known to be colonized with non-albicans Candida.Voriconazole 6 mg/kg IV q12h x2 doses then 4 mg/kg IV/PO q12hAmphotericin B 3-5 mg/kg IV dailyCaspofungin 70 mg IV x1 then 50 mg IV daily; 70 mg IV daily for aspergillosisContinue until neutropenia has resolved, or for at least 14 days in patients with a demonstrated fungal infection.
32 When to Add Antiviral Therapy Oral vesicular lesions: HSVEsophageal lesions: HSV, CMVSkin lesions: VZVPneumonia: InfluenzaCNS symptoms: HSV
33 Antiviral Doses Acyclovir: Valacyclovir: Ganciclovir: Foscarnet: Mucocutaneous HSV: 5 mg/kg IV Q8hSingle dermatomal VZV: 800 mg PO 5x/day or 5 mg/kg IV Q8hDisseminated VZV or HSV: 10 mg/kg IV Q8hValacyclovir:HSV or VZV treatment: 1g PO Q8hGanciclovir:CMV treatment: 5 mg/kg IV Q12h x2 weeks then 5 mg/kg IV Q24h x2-4 weeksFoscarnet:Acyclovir-resistant HSV: 40 mg/kg IV Q8hCMV treatment: 90 mg/kg IV Q12h x2 weeks then 120 mg/kg IV Q24h x2-4 weeksOseltamivir:Influenza: 75 mg PO Q12h(reduced doses required in renal impairment)
34 Assessment of Response Daily assessment until afebrile and ANC 0.5:FeverCBCRenal functionClinical Symptoms
35 Duration of Therapy Afebrile and ANC 0.5 x48 hrs: Low risk patients, no source of infection identified: can discontinue abxHigh risk patients or with documented infection: continue tailored therapy 7 daysAfebrile but ANC <0.5 after 5-7 days:low risk: can discontinue abxhigh risk: continue abx until ANC 0.5 or 14 days in pts not expecting ANC recovery.Febrile:Neutropenic: continue abx at least 14 days, reassess for non-responseNon-neutropenic: discontinue abx 4-5 days after ANC >0.5 if no source of infection identifiedIDSA: Time to devervescence: 2-7 days, Median time to clinical response: 5-7 daysIDSA 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer
36 Follow up for Non-Responsive Patients Febrile but otherwise stableIf non-neutropenic consider stop abx 4-5 days after ANC >0.5Consider antifungal therapy with activity against mold if fever continuing ≥4-5 days.Febrile and clinically unstableBroaden coverage to include anaerobes, resistant gram negative, resistant gram positive organismsEnsure coverage of CandidaConsider antifungal therapy with activity against mold if fever continuing ≥4 days of therapyID consult
37 Duration of Therapy for Documented Infection Skin/soft tissue: 7-14 daysSinusitis: daysBacterial pneumonia: days
38 Duration of Therapy for Documented Infection Uncomplicated bacteremia:Gram negative: daysGram positive: 7-14 daysS.aureus: at least 2 weeks after first negative blood culture and normal TEEYeast: ≥2 weeks after first negative blood culture
39 Duration of Therapy for Documented Infection Aspergillus min 12 weeksViral:HSV/VZV: 7-10 daysInfluenza: ≥5 days.
40 Future directions Compare the role of oral therapy and IV monotherapy Antibiotic lock solutions for CVADsNew role for new CSFs ?
42 Pneumonia Additional Tests: If high risk consider adding sputum culturesNasal wash for respiratory virusesLegionella urine antigen testConsider BALIf high risk consider addingCT chest to define infiltratesID ConsultInclude coverage for:atypical bacteria with azithromycinP.jirovecii with SeptraMRSA with vancomycin or linezolidadding antiviral therapy (influenza outbreak)mold-active antifungal (voriconazole or liposomal amphotericin B) if high risk