Klinik für Infektiologie und Institut für Infektionskranhkeiten

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1 Klinik und Poliklinik für Kinderchirurgie Infektiöse Komplikationen der Neutropenie Prof. Martin Täuber Klinik für Infektiologie und Institut für Infektionskranhkeiten

2 This patient has most likely bacteremia with Gramnegative rods??? Microbiologically documented 32.5% Bacteremia 24% Bacteria-non-bacteremic 5% Viral 1% Fungi 2% Mixed 0.5% Clinical infection 26% No etiology 38% Non-infectious causes 3.5% (EORTC-IATCC Trials VIII and IX; Klastersky et al. 1997; n = 1290) Infektionen Neutropenie / mgt Dies ist Blindtext 2

3 This patient has most likely bacteremia with Gramnegative rods??? Gram-positive: Staphylococci (S. aureus, CNS) Streptococci (viridans) Gram-negative: Enterobacteriaceae (E. coli, Klebsiella, Proteus, Serratia) Pseudomonas aeruginosa Infektionen Neutropenie / mgt Dies ist Blindtext 3

4 There is no time for blood cultures before starting antibiotics???? Approach to patients with neutropenic fever Treat it as an emergency (hours count!!) Physical exam oral cavity, anal region, lungs, vascular catheter sites Blood cultures 2 cultures, in stable patient 30 min apart (including from catheter); no more than 3 cultures per day, repeat after 2-3 days if clinically not improved Urine analysis Electrolytes, creatinine, LFT, CRP; Hämatology, if no recent values Chest radiogram (HR CT) Infektionen Neutropenie / mgt Dies ist Blindtext 4

5 Physical exam: Sources of neutropenic fever Neutropenic Normal Oropharynx, gingiva Respiratory tract Skin, soft tissue, catheters ++ + Perianal ++ (+) Oesophagus + + Gastrointestinal Urinary tract + ++ Infektionen Neutropenie / mgt Dies ist Blindtext 5

6 The lethality without appropriate antibiotic therapy in this patient is >90%?? Total 55/230 (24%) 24/475 (5%) Infections 35/55 (64%) 12/475 (2.5%) ( 1 Klastersky, Institute Brodet, Brussels; 2 EORTC 1995) Infektionen Neutropenie / mgt Dies ist Blindtext 6

7 Treatment should be initiated with at least 2 antibiotics, including an aminoglycoside?? Hughes et al. CID 2002:34: Infektionen Neutropenie / mgt Dies ist Blindtext 7

8 Empirical therapy: Importance of local epidemiology Primary modality: Single drug Senitivities Insel 2000 P. aeruginosa E. coli Klebsiellen Ceftazidime (3 x 2 gm/d) 93.7% 98.8% 100% Cefepime (2-3 x 2 gm/d) 96 % 100% 100% Imipenem (3 x 0.5 gm/d) 91% 100% 100% Meropenem (3 x 1 gm/d) 93.5% 100% 100% Piperacillin/Tazobactam 94.6% 93% 91% (4 x 4.5 gm/d) BERN Infektionen Neutropenie / mgt Dies ist Blindtext 8

9 Use of vancomycin in neutropenic fever Do not use vancomycin routinely (resistance development - VRE) Consider use if: - Catheter related infection - Blood cultures grow gram-positive organisms - Patient in shock, developing ARDS - Severe mucositis (?) - High likelihood of MRSA or penicillin-resistant viridans streptococci (not (yet) a problem in Bern Infektionen Neutropenie / mgt Dies ist Blindtext 9

10 Indications for Removal of Catheter Clinically obvious subcutaneous tunnel infection Sepsis Septic emboli Loss of function Lack of response to antibiotic therapy Infection with difficult to treat organisms: Ps. aeruginosa, multiresistant gram-negative rods, S. maltophilia, atypical mycobacteria, fungi If the catheter can be removed easily, it is always better to remove it in cases of proven catheter infection Infektionen Neutropenie / mgt Dies ist Blindtext 10

11 The patient needs an urgent HR-CT scan of the chest??? Hughes et al. CID 2002:34: Infektionen Neutropenie / mgt Dies ist Blindtext 11

12 Opportunistic invasive fungal infections Neutropenia: Mold infections (Aspergillus, Mucorales, andere); Candida ICU/Catheter associated: Candida CMI/Transplantation: Aspergillus, Cryptococcus, Mucorales Infektionen Neutropenie / mgt Dies ist Blindtext 12

13 Diagnosis of invasive Aspergillosis Microspopy/culture Low sensitivity in BAL; important in tissue HR-CT Screening method if fever >5 d on antibiotics High sensitivity; specificity? latency? (focal infiltrates; halo- and crescent moon sign) Galaktomannan antigen (ELISA, others) Some false positives (low specificity); high sensitivity; clinical utility not clear PCR In general high sensitivity; practical relevance for management not established Infektionen Neutropenie / mgt Dies ist Blindtext 13

14 Antifungal drugs for invasive fungal infections Amphotericin B ( mg/kg/d) (AND LIPID FORMULATIONS) First line for all serious infections, including disseminated severe infection with Candida, or Candida infection after prophylaxis with Azoles Fluconazole ( mg/d) Infections due to sensitive Candida, including immunocompromised patients Itraconazole ( mg/d; p.o., i.v.: check levels) Second line and f/u therapy for Aspergillus and other sensitive fungi Seems effective for invasive pulmonaly aspergillosis (CID 2001;33:e83) Caspofungin (Cancidas ) (70 mg / 50 mg/d i.v.) Alternative to AmpB for Aspergillus; fungicidal against most Candida Voriconazole (4-6 mg/kg bid i.v.; 200 mg bid p.o.; check levels!) +/- equivalent to AmBisome for empiric therapy of neutropenic fever (NEJM 2002;346, 225); superior to Ampho B for invasive aspergillosis in neutropenic patients (NEJM 2002;347, 408) Posaconazole (4 x 200 mg / 2 x 400 mg p.o.) Active against Aspergillus and non Aspergillus molds (v.a. Mucorales). Only orale therapy. Controlled data mostly for prophylaxis in patients with AML induction chemotherapy. Infektionen Neutropenie / mgt Dies ist Blindtext 14

15 Schema zur Therapie von invasiven Pilzinfektionen Candidämie oder invasive Candidiasis bei nicht-neutropenischen Patienten Candidämie oder invasive Candidiasis bei Neutropenie Persistierendes Fieber in Neutropenie Invasive Aspergillose (hoch-verdächtiges HR-CT; Galactomannan; Kultur) Nicht-Aspergillus Schimmelpilze; Salvage 1. Wahl 2. Wahl 3. Wahl Diflucan Fungizone Cancidas (plus Diflucan ) Fungizone Cancidas Diflucan (bei unkomplizierter Candidämie) Fungizone Cancidas AmBisome oder Vfend Vfend Fungizone Cancidas Fungizone Ambisome Noxafil Kombinationen??? (Cancidas plus AmphoB oder Azole) Infektionen Neutropenie / mgt Dies ist Blindtext 15

16 Risk categories for adverse outcome in neutropenic patients Risk factors High risk Intermediate Risk Malignancy AML BMT Solid tumors Autologous SCT Chemotherapy intensive intensive; with radiotherapy Low risk Solid tumors conventional Duration of neutropenia Complicating Faktors* > 14 d 7 14 d < 7d Present Absent Absent * Schock; localized infection (i.e., catheter); respiratory or renal insufficiency; epilepsy; nausea, vomiting, diarrhoe; severe thrombocytopenia; severe mucositis Infektionen Neutropenie / mgt Dies ist Blindtext 16

17 Low Risk Score: Guide to oral therapy from Klastersky et al., J Clin Onco 2000;18: Infektionen Neutropenie / mgt Dies ist Blindtext 17

18 Therapy of neutropenic fever: Low risk patients Oral therapy (2 controlled studies)* Ciprofloxacin 2 (- 3) x 750 mg/d plus Amoxicillin-Clavulanate 3 x (500 -) 625 mg/d Patients: Solide tumors ~70% High-dose chemo with SCT: 14% Outpatient therapy? Few controlled data (Malik et al. Am J Med, 98, 1995) Needs infrastructure, expertise * Kern et al; Freifeld et al. NEJM 341; 1999 Infektionen Neutropenie / mgt Dies ist Blindtext 18

19 Adverse effects of antibiotic therapy for neutropenic fever Freifeld et al. NEJM 341; 1999 Infektionen Neutropenie / mgt Dies ist Blindtext 19

20 Opportunistic infections in BMT Pneumonia Bacteria non-bacterial (interstitial) Virus HSV CMV Adeno VZV Fungi Candida Aspergillus Bacteria G+ Cocci/ G- rods Encapsulated (Pneumococci) Riskfactors Neutropenia Acute GVHD + Therapy Chronic GVHD 0 d 50 d 100 d months Transplantation Infektionen Neutropenie / mgt Dies ist Blindtext 20

21 Prevention of Bacterial Infections Selective bowel decontamination Efficacy suboptimal, resistance development TMP/SMX Indicated for PCP prophylaxis (Lymphomas, ALL, BMT, SOT) Can reduce infection rate, no effect on febrile episodes and mortality; adverse events (myelosuppression), resistance Quinolones (Levofloxacin) Equally or more effective than TMP/SMX; prevent documented gramneg. infections. May increase gram+ infection. Some studies suggest benefit on morbidity (fever, infections, duration of hospital stay); Important: - Results in placebo control group - Resistenzen - Cost / Benefit analysis In Bern not used routinely! Infektionen Neutropenie / mgt Dies ist Blindtext 21

22 Prophylaxis against fungal infections Options Fluconazole Prevents superficial and invasive infections due to sensitive Candida albicans and C. tropicalis; can select azole-resistant Candida (C. krusei, C. glabrata) Voriconazole Less systemic infections in patients with severe neutropenia; more effective than fluconzole or itraconazole; drug of choice for Aspergillus Posaconazole More effective than fluconazole and itraconazole in preventing all fungal infections and invasive fungal infections. Also improved survival. (Cornely, NEJM 2007;356:348) Infektionen Neutropenie / mgt Dies ist Blindtext 22

23 Prevention of viral infections HSV Serology and history (recurrent H.); use prophylaxis (valciclovir, vamciclovir, aciclovir i.v.) in seropositives during BMT and SCT. Prophylaxis not routinely recommended in other situations CMV In all transplants (except autologous stem cells) stratify according to D/R sero-status; use prophylaxis or pre-emptive therapy VZV Risk increased throughout first year after transplant; outcome good, if treated early. Prophylaxis not routinely recommended Infektionen Neutropenie / mgt Dies ist Blindtext 23

24 Take home messages Aggressive, rapid management of neutropenic fever with appropriate antibiotics important Use of vancomycin only in selected situations Prolonged fever despite antibiotics: Fungal infection? Check for invasive fungal infections by HR-CT and GM (only Aspergillus); implement anti-fungal therapy Low risk patients can be treated orally Prophylaxis strategies (antibacterial, antifungal) must be implemented locally based on local empidemiology and standard of care Infektionen Neutropenie / mgt Dies ist Blindtext 24