Bakteriella Infektioner hos Neutropena

Mats Kalin Infektionsklinken Karolinska universitetssjukhuset, Solna mats.kalin@karolinska.se

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Non-specific defense

First line of defense Barrier function

Cytoreductive chemotherapy primarily affects cells with a high rate of division, like bone marrow cells and epithelial cells Mucous membranes are affected causing mucositis, which may be especially severe in the oral cavity, in the lower oesophagus and in the perianal region. Necrotising enterocolitis may also occur

Mucositis severely compromises the barrier function Therefore, translocation of bacteria from the entire GI canal to the blood occurs with increased frequency
Bacteria translocated to the blood stream are normally rapidly cleared by granulocytes In case of granulocytopenia bacteremia with signs and symptoms of sepsis will develop Most commonly translocated bacteria causing bacteremia in neutropenic pts - Gramneg enteric rods from the lower GI tract including - P.aeruginosa - alpha-streptococci from the oral cavity

Granulocytes

Infection Risk in Relation to Granulocyte Count

% W I T H F E V E R

100 90

H H

< 0.1

80
70

60
50 40 30 20
H

0.1 0.5
J B J J

10
0
H J B

H J B

J B

0.5 - 1

10

days

Bodey et al 1969, AAC 9:386

In addition to mucositis and granulocytopenia cancer chemotherapy will cause - T and B cell deficiencies - for long time periods implying increased risks for infection w - intracellular bacteria, herpes viruses, PCP and other fungi (T-deficiency) - pneumococci (Ig-deficiency)
CTL
Antigen presentation

P T B

Granulocytes

Macrophages

Cytokine regulation

In addition steroids and other drugs may compromise macrophage function

Blood stream Pathogens at the Center for Haematology, Karolinska hospital

Stenotrophomonas Other Gramneg maltophilia Enterobacter Pseudomonas aerugionsa CNS

1988-2001 n=1402

S.aureus
Klebsiella

Alpha-strept
E.coli
Cherif et al 2004 The Haematology J 4:240

Enterococci Other Pneumococci Grampos

Bacteria in Single Organism Bacteremia in EORTC Trials

35 30 25 20 15 10 5 0 1973-78 1980-83 1986-88

S.aureus CNS Strept E.coli P.aerug Other G-

1989-91

Course in Neutropenic Patients with Gramneg Bacteremia who did not receive Appropriate Therapy

Within 12 h 24 h 48 h

% dead 15 57 70

Bodey et al 1985, Arch Intern Med 145:1621

Infections in Neutropenic Cancer Patients

The risk for bacterial infection is related to depth and length of neutropenia
Bacteria are translocated from the GI tract

GI flora may be affected by hospitalisation and ab therapy

The course may be fulminant with septic shock Symptoms may be subtle due to lack of immune response Fever is the signal for risk of serious infection

Broad-spectrum antibiotic therapy must be started immediately when a neutropenic patient presents with fever:

- Cephalosporin with Pseudomonas activity - Carbapenem - Piperacillin/Tazobactam .

..but only after blood cultures have been obtained

before start of antibiotics 20 40 ml in 4-6 bottles - - excluding anaerobic bottles? >1 venipuncture does not facilitate interpretation

but if CVC or PAC is used a peripheral specimen should also be obtained

Time to positive results from CVC/PAC and peripheral sample, respectively, can be used to diagnose line infection

Cultures should also be obtained from urine, wounds and airways Lamy 2002, CID 35:842 Ortiz & Sande 2000, Am J Med 108:445 DesJardin 1999, Ann Intern Med 131:641

105

- Combination therapy is not superior to monotherapy - But the addition of an aminoglycoside may be of value in septic shock AG exert concentration-dependent killing Single daily dose recommended

% survival

80 70 60 50 40 30 20 10 0
Top level > 7/28 vs < 7/28 mg/L Moore 1984 Am J Med 77:756

Bact.conc cfu / ml

24 H

It is of decisive importance to follow the course closely

Therapy may have to be changed as a results of

deteriorating general condition new signs and symptoms of focal infection results of cultures, most importantly blood cultures results of chest X ray or other investigations

Pulmonary Infiltrates in Neutropenic Patients

Totally 1573 patients 1986-92
295 (17%) developed pulmonary infiltrates
- 29 % microbiologically documented

Complete Response
- 61 % in patients with pulmonary infiltrates - 83 % in other documented infections

Early deaths (<21 days): 22 %

_________________________________________
Meschmeyer et al 1994, Medizinische Klinik 89:114 Cancer 73:2296 Annals Hematol 69:231

Prospective randomized double blind study of Vancomycin vs Placebo for persistant neutropenic fever after 48-60 h of Piperacillin/tazobactam (34 C, n=165 of tot 763) Excluded: CVC-inf, Pulm inf, Gramneg and PT-Res Grampos infect

Total case fatality rate 4 Vanco vs 8 placebo

Cometta 2003, CID 37:382

Indications for Vancomycin

Clinically suspected serious CVC infection

Infection with cephalosporine resistant bacteria Blood culture reported positive for Gram-pos bacteria in a patient with deteriorating condition before final identification and susceptibility report Hypotension or other evidence of cardiovascular impairment and ??
- Severe mucositis - Quinolone prophylaxis - due to risk of infection with penicillin resistant alphastreptococci

Hughes 2002 CID 34:730 (IDSA Guidelines)

GI epithelial damage

Bacteremia
Increased GI yeast colonisation /focal infection Antibiotic therapy

Yeast translocation

Invasive yeast infection

Invasive Fungal Infections in Cancer

intensity of chemotherapy and improved antibiotic therapy

Patients

More patients surviving for longer periods with severe immune defects

(?) Invasive Candidiasis

Pneumocystis J Pneumonia (PCP)

Improved Fungal Therapy, Prophylaxis, Other factors (?)

mortality rate invasive candidiasis, especially C.albicans non-albicans Candida more patients with invasive aspergillosis more patients with uncommon fungal infections

Pneumocystis carinii

Patients with T-cell-defects primarily affected - incidence related to degree of immunosuppression

High dose (median max.dose 80 mg / d) steroid therapy for prolonged time periods (median 3 mo) is the other important predisposing factor, tapering of dose especial risk Diagnosis by - Clin presentation: dry cough, dyspnea, CXR, CT - IFL and PCR from sputum or BAL Cotrimoxazole drug of choice for therapy, very high doses

Clinical Condition after 72 h of Antibiotic Therapy Relation to Ultimate Outcome, n=1085

IMPROVING STABLE DETERIORATING

25 % 15% 46% 18% 21%

% afebrile after 5 days % ultimately surviving

65 % 10% 39% 23% 28%

10 %
FUO

20%
CDI

Gbacteremia

33%
bacteremia

25% G+

22%

100 100

33 90

5 11

De Pauw & Intercontinental Study Group, Ann Intern Med 1994

FUO 89 episodes

Afebrile after ab therapy 60 episodes

Failure 29 episodes

antibiotics stopped 48h after defervescence 31 episodes

antibiotics continued > 48h after defervescence 29 episodes

Neutropenic when ab stopped 23 episodes

Neutropenia resolved 8 episodes

Neutropenic when ab stopped 26 episodes

Neutropenia had resolved 3 episodes

Fever relapsed 3 episodes

Fever relapsed 2 episodes

Fever relapsed 6 episodes

Success 3 episodes

Success 20 episodes

Success 6 episodes

2 patients died

Cherif 2004, SJID 36:593

Success 20 episodes

Observed and Predicted Rates of Fever Resolution

- without serious complications - as a response to adequate ab therapy for neutropenic fever - in relation to points by the MASCC risk index score Characteristic Points Age < 60 y 2 No COPD 4 Solid tumour or no previous fungal dis 4 Burden of illness none or mild 5 or moderate 3 No dehydration 3 No hypotension 5 Outpatient status 3

8-16 17-18 19-20 21 n=71 67 67 172

22 52

23 102

24 25-26 127 98

Klastersky et al 2000, J Clin Oncol 18:3038

Prospective evaluation of MASCC at Hem C Karolinska

Low risk patients (105 episodes)

Ineligible for oral therapy (38 episodes)

eligible for oral therapy (67 episodes)

Excluded

Discherged with oral antibiotics 24 hours after defervescence

Infection related mortality 2 patients

Clinical assessment after 3 days

MASCC risk-index score < 21 (high risk): 176 pts (63%) w serious medical complications in 63% > 21 (low risk) 105 pts w serious medical complications in 15% - and in an additional 21% other facts precluded oral therapy

Fever relapse readmission One patient

Continued afebrile 66 episodes

Final evaluation after 4 weeks

Fever relapse 2 patients one aspergillosis one pneumocyctis

Afebrile (success) 64 patient

No mortality

Thus, a total of 24% of haematological patients with neutropenic fever could be discharged with oral therapy 24 h after Cherif et al 2006 defervescence, essentially w/o complications
Haematologica

Resistance problems according to ICU-STRAMA Gramneg enterobacteria

Quinolones ESBL

5-10 % rare findings

Enterobacter
Cephalosporin Quinolones inducable resistance in high frequency 5-10 %
25 % 12 % 10 % 17 % 100 % 30 % 10 %

Pseudomonas aeruginosa
Imipenem Quinolones Ceftazidime Piperacillin

Stenotrophomonas maltophilia
Imipenem Quinolones Ceftazidime

Hahnberger: http://e.lio.se/ivastrama/