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Cancer, Infection & Palliative Medicine Dr Tim Collyns Consultant Microbiologist LTHT Overview “Febrile neutropenia” Site specific infections In era of increasing antimicrobial resistance Urinary tract Respiratory tract Skin / soft tissue Clostridium difficile Fungal Overview Presenter ignorance,…sucking eggs Hospice: “between” hospital & community Risk of “healthcare associated infections” Meticillin resistant Staphylococcus aureus (MRSA) Clostridium difficile {Meticillin sensitive S aureus (MSSA)} {Escherichia coli} Multi-resistant Gram-negative bacilli Extended spectrum β-lactamase (ESBL) producers Plasmid: other antimicrobial classes. Antimicrobial stewardship: 1o compared to 2o care 1o care: Judicious w.r.t starting antibiotics “Viral” / (non-infectious) aetiology “Simple” (if likely to be effective), short courses Resisting patient pressure for “positive” action 2o care “Start Smart – then Focus” (DH ARHAI, 2011) ..Right drug, right dose, right time, right duration…every patient. Start smart Don’t start antibiotics in absence of clinical evidence of bacterial infection. If evidence: use local guidelines to initiate prompt effective antibiotic therapy. Document on drug chart & in medical notes: clinical indication, duration or review date, route & dose Obtain cultures first Then Focus: Review clinical diagnosis & continuing need for antibiotics by 48 hrs & make a clear plan of action – the “Antimicrobial Prescribing Decision” [APD] The 5 APD options are Stop Switch iv to oral Change Continue Outpatient Parenteral Antibiotic Therapy (OPAT) Clearly document the review & subsequent APD in medical notes. Hospice / palliative medicine setting “Specific” challenges, include Preceding Acquisition of multi-resistant pathogens Debilitated of intravenous option (Efficacy of enteral vs parenteral route) Limited choice (if any) - MR GNBs. Clinical infection as the “terminal” event Infection / immunocompromised More prone to clinical infection post acquisition Lack / ongoing hospital involvement prevention in end-of-life care Visitors, staff, Guidelines Source “International” National – Yorkshire Cancer Network LTHT / NHS Leeds – Leeds Health Pathways Regional What Cancer-related Site-specific e.g. vascular catheter, urinary tract, pneumonia Organism specific e.g. MRSA, C difficile, Candidiasis, Aspergillosis (Setting: 1o or 2o care) Guidelines: NCCN: Prevention and treatment of cancer related infections - V.1.2012 NCCN Clinical Practice Guidelines in Oncology www.nccn.org More traditional – “febrile neutropenia” IDSA: Clinical Practice Guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by [IDSA]. Freifeld A, Clin Inf Dis 2011:52:e56-e93. NICE: Neutropenic sepsis: prevention & management…in cancer patients guidance.nice.org.uk/cg 151 [issued Sep 2012] 1960s: Increased sepsis risk with falling neutrophil count – risk of bacteraemia: Gram negative bacilli, esp Pseudomonas aeruginosa High mortality rate: > 50% < 48hrs 1970s: Empiric early iv therapy Schimpf 1971: carbenicillin + gentamicin 1980s: Broader spectrum β - lactams Option: Monotherapy vs “dual” therapy 1990s: Risk stratification w.r.t oral / out patient Mx 000s: Emerging infections / new agents.. 010s: (..too early ?: more emergence…& fewer new agents) NICE (2012): Treat neutropenic sepsis [NS] (2o / 3o care) as acute medical emergency, offer empiric antibiotic therapy immediately Offer β-lactam monotherapy with piperacillintazobactam initially to patients who need intravenous treatment – unless there are patient specific or local microbiological contraindications Do not offer an aminoglycoside, either as monotherapy or dual therapy, for initial empiric treatment of [NS] unless patient specific or local microbiological indications. Diagnosis of neutropenic sepsis in patients having anticancer treatment with neutrophil count < 0.5 x109 / L, & Temperature > 380 C or Other signs / symptoms consistent with clinically significant sepsis. …”Getting it right first time” Kumar 2006: Septic shock patients, duration of hypotension prior to initiation of effective antimicrobial therapy – link to survival. Within first hour: Survival 79.9% Each subsequent hour delay: average drop in survival 7.6% “Low risk” of complications Oral therapy. (Initial / sequential) Oral vs intravenous Meta-analysis: Vidal 2004 15 trials, mortality rate: 0 – 8.8% RR: 0.91 (95% CI 0.51 – 1.62) Treatment failure rates: Initial; or sequential (iv then PO) Overall: RR 0.94 (0.84-1.05) Initial oral: 0.89 (0.77 – 1.03) Sequential: 1.03 (0.86 – 1.24) Adverse events No death / permanent damage attributed to oral Rx. Higher rate of GI side effects in oral regime. MASCC risk index score (Klastersky 2000) Characteristic Extent of illness No symptoms Mild Moderate No hypotension No COPD Solid tumour or no IFI No dehydration Outpatient at onset of fever Age < 60 [>16] Score 5 5 3 5 4 4 3 3 2 >/ 21 = low risk complications / morbidity PPV 91%, specificity 68%, sensitivity 71% Commonest: Quinolone + co-amoxiclav 6 trials: quinolone alone (No difference shown between above – ‘post – protocol’ analysis). Oral antibiotic therapy : safely offered to neutropenic children / adults, haemodynamically stable, have no organ failure, can take PO medications, Do not have pneumonia, central line infection, severe SSTI Not acute leukaemics (Or use MASCC scoring system). Prudent: FQ + 2nd drug active vs G+ve: eg co-amoxiclav. Japanese guidelines: Quinolone alone Unless mucositis / skin lesions: then eg with co-amoxiclav Ciprofloxacin susceptibilities (bacteraemias, Haematology) Organism Ciprofloxacin resistant (Total) % All Gram negative bacilli 31 (132) 24 “Coliforms” 8 (70) E coli 5 11 NLFs, incl P aeruginosa 7 (45) P aer: 2 16 S maltophilia 16 (17) 94 …potential fly in the ointment – prophylactic strategy Antibiotic prophylaxis Afebrile neutropenic patients Reduce frequency of febrile episodes by administration of (broad spectrum) Ax: But potential deleterious effects: Toxicity Emergence of antibiotic resistant bacteria (FQ) Fungal overgrowth Bucaneve NEJM 2005 353:977-87 760 adult patients 500 mg Levofloxacin vs placebo for neutropenia Febrile episode All treated: 65 vs 85% (ADR -0.20; -0.26 to -0.14) Acute leukaemia: 67 vs 85% (ADR -0.19; -0.27 to -0.10) Solid tumours / lymphoma: 62 vs 84%, (-0.22, -0.29 to -0.12) Death All treated: 3 vs 5 % (ADR -0.02, -0.05 to 0.005) Acute leukaemia: 5 vs 7% (ADR -0.02, -0.07 to 0.02) Solid tumours / lymphoma: 1 vs 3%, (-0.02; -0.05 to 0.004) Cullen 2005 NEJM 2005 353:988-98 1565 patients, cyclic chemotherapy for solid tumours / lymphoma (13%) 500 mg Levofloxacin vs placebo for 7 days Febrile episode first cycle: 3.5% vs 7.5% (p<0.001) Over entire course: 10.8 % vs 15.2% (p=0.01) Hospitalisation 15.7 vs 21.6% (p=0.004) Severe infection 1 vs 2.0 % (NS) Each group: four infection related deaths. Gafter-Gvili 2006, Cochrane review 101 trials, 12599 patients: 1973-2005 Infection related deaths RR 0.59 (0.47-0.75) Fever occurrence RR 0.77 (0.74 – 0.81) All cause mortality (quinolone) RR 0.52 (0.37 – 0.74) Antibiotic resistance Infecting organisms Individual patient Unit / Hospital Community “Collateral” MRSA, C difficile (Reduced use of other antibiotics) (Cost) Treatment strategy: oral regimens MRSA Risk with fluoroquinolones. MRSA usually resistant to fluoroquinolones Good skin tissue penetration / excreted in human sweat: Loss of colonisation resistance by normal skin flora In vitro: of fibronectin – binding proteins Increased adhesion by quinolone resistant S aureus Induction Bisognano 2000, Paterson 2004, Multiple logistic regression analysis, factors associated with MRSA infection Graffunder 2002 Risk factor OR 95% CIs P value Levofloxacin 8.01 3.15, 20.3 <0.001 Macrolides 4.06 1.15, 14.4 0.03 Enteral feeding 2.55 1.37, 4.72 0.003 Surgery 2.24 1.19, 4.22 0.01 Previous hospitalisation 1.95 1.02, 3.76 0.04 LOS before culture 1.03 1.0, 1.07 0.05 NCCN 2012: Fever & Neutropenic risk category: LOW Standard chemotherapy regimens for most solid tumours Anticipated neutropenia less than 7 days Prophylaxis: Bacterial: NONE Fungal: None Viral: None unless prior HSV episode Fever & Neutropenic risk category: Intermediate / High Prophylaxis: Bacterial: Consider FQ prophylaxis CG151: Adult patients with acute leukaemias, stem cell transplants or solid tumours in whom significant neutropenia (\< 0.5x109 /L) is an anticipated consequence of chemotherapy Offer prophylaxis with fluoroquinolone during expected period of neutropenia only. [No mention of any different action if known FQ resistant, or FQ contra-indicated]. [No mention of specific oral options for FNE whilst on FQ prophylaxis – initial or s/down] …CG151 still being assessed LTHT / YCN β-lactam resistance in Enterobacteriaceae: Enzyme mediated: β-lactamases (Ancient Serine residue active site; or metalloenzymes (Zinc ion) Inherent heritage: > 2 billion years old) – gene carried on bacterial chromosome “De-repressed”: e.g. Enterobacter, Citrobacter species Acquired – transmissible genetic elements: plasmids E.g. Klebsiella pneumoniae, E coli Vary in ability to hydrolyse different β-lactams: Some drug structures more resilient than others. Some blocked by β-lactamase inhibitors clavulanic acid (co-amoxiclav), tazobactam (with piperacillin) Various classifications / name derivations 3 letter monikers for families: SHV (>50): Variable response to sulfhydryl inhibitors TEM (>130): After patient (Temoneira) CTX-M (>40), OXA, IMP: Ability to hydrolyse cefotaxime, oxacillin, imipenem VIM: Verona integron encoded metallo-β-lactamase KPC: Klebsiella pneumoniae carbapenemase New York / US. NDM: New Delhi metallo-β-lactamase Jacoby 2005; NDM-1: First detected United Kingdom January 2008. Now predominant carbapenem-hydrolysing enzyme in Enterobacteriaceae in UK (44% 2009) 2008 – 2009: 37 isolates K pneumoniae (21), E coli (7), Enterobacter spp (5), Citrobacter freundii (2), Morganella (1), Providencia (1) 29 patients – 15 in urine ESBLs widespread in India, NDM-1 also in isolates in north & south India Links between many of the UK patients and India Kumaraswamy 2010; HPA ESBLs: carbapenem Carbapenemase producing Tigecycline Polymyxin (colistin) ? Possible local choices outside the box Yorkshire & Humber: E coli surveillance data, 2010 -2012 792 isolates, 14 hospital trusts (courtesy of HPA) 8% = ESβL producers 0.1% = carbapenemase producer “Other” options (Co-trimoxazole) Intramuscular gentamicin Urinary catheter change “usually” sensitive in vitro: Nitrofurantoin Pivmecillinam (lower UTI, eGFR > 60ml/m) Mecillinam Beta lactam (6-β-amidinopenicillanic acid) Pivmecillinam Pivaloyloxymethyl ester: Much more active vs Gram negatives (Enterococci resistant, S saprophyticus may be inhibited) Enterobacteriaceae Usual suspects more tricky: P aeruginosa, Acinetobacter spp, anaerobes: resistant Serratia marcescens: usually resistant M morganii, Providencia spp may be sensitive (Paradoxical effect with P stuartii) P mirabilis, P vulgaris: usually sensitive Uses: Urinary tract infections Advantages: Lower (Upper – step down oral therapy). ((Other MDR coliforms: e.g. Biliary)) High % still susceptible (> 90% global) Low C difficile propensity “Avoid” if penicillin allergy (tho’ hypersensitivity reactions uncommon) …NB: Avoid treating “asymptomatic bacteriuria” (catheterised or noncatheterised) in adults. Increase resistance Loss of oral options. “Good” bacteria Enterococci Respiratory tract bacterial pathogens AWARE surveillance, US, 2008-10 Adapted from Pfaller 2012 % susceptible S pneumoniae H influenzae M catarrhalis Amoxicillin 83 73 Co-amoxiclav 83 99.9 100 Erythro/clarithro 60 76 99.5 Tetracycline 75 99 99.8 Co-trimoxazole 66 77 94.4 Levofloxacin 99 100 100 Linezolid >99.9 N/A N/A ..?.. Doxycycline may also protect against development of C difficile infection US study comparing ceftriaxone +/- doxycycline > 2300 patients studied 1.67 / 10000 patient days vs 8.11 / 10000 Rate of CDI 27% lower for each day of receipt HR 0.73, 95% CI 0.56 – 0-.96 Doernberg 2012 ..NB these organisms (and S aureus et al) can be normal upper respiratory tract commensal flora. Adjudge “positive” microbiology results in conjunction with current clinical / radiological findings. S aureus, AWARE surveillance, US, 2008-10 Adapted from Farrell 2012 % susceptible MSSA MRSA Penicillin (amoxicillin) 23 (0) Flucloxacillin (100) (0) Erythromycin 66 8 Clindamycin 94 66 Tetracycline 96 95 Co-trimoxazole 99 99 Levofloxacin 89 29 Linezolid 100 99.8 Long-term intravascular catheters Long term catheters should be removed for patients with CRBSI associated with: Severe sepsis Suppurative thrombophlebitis Endocarditis BSI that continues despite > 72 hours suitable antimicrobial therapy Infections due to S. aureus, P aeruginosa, fungi or mycobacteria IDSA, Mermel 2009 S aureus ; removal, unless major contraindications; e.g. No alternative venous access Significant bleeding diathesis Quality of life issues take priority over need for re-insertion of a new catheter at a different site If retain: four weeks therapy, systemic + lock therapy. Uncomplicated CRBSI involving longterm catheters due to [other] pathogens Attempt treatment without catheter removal: Systemic and antimicrobial lock therapy Administer both for 7 – 14 days ..If multiple positive catheter-drawn blood cultures with coagulase – negative staphylococci or Gram – negative bacilli, but concurrent negative peripheral blood cultures: can give lock therapy without systemic therapy for 10 – 14 days. Vancomycin: at least 1000x higher than organism MIC (e.g. 5 mg/ml) Other locks Gentamicin Taurolidine (TauroLock®) Broad spectrum antimicrobial Unique site of action / no cross resistance Spontaneously breaks down. Lock therapy: 14 days in total ?Alternating lumens 24 hourly in hospital & access needed Dwell time up to one week Repeat luminal blood cultures post completion 48 – 72 hours Clostridium difficile Diagnosis Now two stage testing process: Initial: GDH If positive: toxin test. Treatment (..if indicated; also review PPIs) Metronidazole: “non-severe” Vancomycin: “severe”: colitis; WCC >15, AKI (Fidaxomycin) Infection Prevention: Hand washing with soap & water ..Improve speeds of other diagnoses Aetiology; in vitro susceptibilities Bacteriological methods long-standing, but: Direct to specimens: PCR / NAAT blood, sterile sites Organism identification: MALDI-TOF Matrix-Assisted Laser Desorption Ionisation Time of Flight Mass Spectroscopy: bacteria / yeasts …expect more “unheard of” species names Rapid automated sensitivity testing (< 12 hours), [EUCAST]. Fungal: Prophylaxis Empiric Fever in neutropenic patient unresponsive to broad spectrum antibiotics “Pre-emptive”: suspicion of IFI Targeted treatment – proven / probable Candida Candida albicans Non C albicans: C krusei C glabrata Aspergillus spp Aspergillus fumigatus Zygomycetes Mucor, Rhizopus, Amphotericin B Azoles Lipid formulations – ambisome, (abelcet, amphocil) Fluconazole Itraconazole Voriconazole Posaconazole Echinocandins Caspofungin Micafungin Anidulafungin Changing criteria for diagnosis De Pauw 2008: EORTC / MSG revised definitions of Invasive Fungal Disease [for trial use] Host factors: Recent neutropaenia (<0.5 for > 10 days) Allogeneic stem cell transplant receipt Prolonged use corticosteroid (mean minimum: equivalent 0.3mg/kg/d, > 3 weeks) Other recognised T cell immunosuppressants: Clinical criteria Lower respiratory tract disease: 1 out of 3 defined HRCT signs. Sinonasal infection Sinusitis on imaging + > 1 sign of eg acute localised pain, nasal ulcer + black eshar Mycological criteria: eg cyclosporin, alemtuzumab (CamPath) Direct tests: microscopy / culture, Indirect tests: Aspergillus antigen “Proven”, “probable”, “possible” Pre-emptive (“Suggestive”) Evidence of IFI: Galactomannan Blood BAL. Β – glucan High - Aspergillus Resolution chest CT Dense, well-circumscribed lesion(s) +/- halo sign Air-crescent sign Cavity. Halo sign Air crescent sign Aspergillus microscopy Colonies of Aspergillus fumigatus Treatment – ongoing – azoles Aspergillosis: voriconazole More exotic moulds: posaconazole …trough levels. Conclusions: Antimicrobial stewardship Start Smart – then Focus. Increasing antimicrobial resistance – Gram negatives. Review Microbiology results in conjunction with other current information. Antimicrobial guidelines on intranet individual cases - Microbiology advice.