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Influenza-associated aspergillosis in

critically ill patients

Prof. Dr. Paul Verweij, medical microbiologist

Dr. Frank L. van de Veerdonk, infectious disease physicianDr. Roger Brüggemann, hospital pharmacist- clinical pharmacologist

A retrospective multicentreobservational cohort study

Motive: 38 year old female admitted to the ICU

Collaborators: 8 ICU

AMCW. Freudenberg – de GraafC. HodiamontJ. WieringaN. RoescherC .van der Berg

VuMCK. van DijkW. Ang

LUMCM. van de BeekJ. van Paassen

ErasmusMCB. RijndersA. VonkB. van der HovenC. van Tienen

MUMCA. Oude Lashof

D. Bergmans

UMCUPJ Haas

LPG Derde

RadboudumcF. van de Veerdonk

E. KolwijckP. Lestrade

J. Ramahat-LangendoenH. van der Hoeven

P. Verweijet al…

UMCGC. Oliviera dos Santos

G. KampingaC. van Leer-Butter

H. Aardema144 influenza

23 IAA

Am J Resp Crit Care Med 2017; in press

microbiology symptoms

risk factors outcome

23 IAA

Characteristics

Am J Resp Crit Care Med 2017; in press

microbiology

23 IAA

Influenza: A – 21 (H1N1 - 11)B - 2

BAL – 18 patients: GM+ 17 (94%)Culture+ 14 (78%)

Serum GM – 14 patients: GM+ 10 (71%)

MIC test – 14 patients: AzoleR 4 (29%)

Microbiology

Am J Resp Crit Care Med 2017; in press

symptoms

23 IAA

Symptoms

Am J Resp Crit Care Med 2017; in press

Aspergillus tracheobronchitis……..

Lesions not typical for invasive aspergillosis…..

Aspergillus tracheobronchitis……..

Aspergillus tracheobronchitis……..inside the bronchi

23 IAA

NO UNDERLYING DISEASE 7

RISK

Risk groups

J Antimicrob Chemother 2011; 66 Suppl 1: i5-14.

risk factors HIGH 2Hematol. malignancy

INTERMEDIATE 4COPD

LOW 6KidneyTX, FSGS, Chron immunol disease

NO 4Arthrosis, hypertension

outcome

23 IAA

Outcome

LOW

NO

INTERMEDIATE

HIGH 2

4

6

4

NO UNDERLYING DISEASE 7

14 of 23 (61%)

Am J Resp Crit Care Med 2017; in press

outcome

23 IAA LOW

NO

INTERMEDIATE

HIGH 2

4

6

4

NO UNDERLYING DISEASE 7

9 of 16 (56%)Outcome

Am J Resp Crit Care Med 2017; in press

outcome

23 IAA LOW

NO

INTERMEDIATE

HIGH 2

4

6

4

NO UNDERLYING DISEASE 7

5 of 7 (71%)Outcome

Am J Resp Crit Care Med 2017; in press

Survivors compared with Non-survivors

* p=0.06

**

Opname op de IC met respiratoire insufficiëntie

Influenza PCR-test +

BronchoscopieAanwezigheid plaques

GM in BALGM in serum

Aspergillus kweek BAL

Tenminste 1 +

Start antifungale therapie:Voriconazol + echinocandine of

Liposomaal AmB ofVoriconazol+liposomaal AmB

Na 2 weken bij klinische verbetering en geen resistentie aangetoond:

VoriconazolIntensief klinische opvolging

TDM

Afwachten

-

NB•IAA kan voorkomen bij patiënten zonder bestaande risicofactoren•IAA kan voorkomen bij patiënten zonder kenmerkende CT afwijkingen zoals halo-teken•Menginfecties van azool-gevoeligeen azool-resistente A. fumigatuskomen voor•Behandeling met corticosteroïden is niet geïndiceerd

Directe Aspergillus resistentie

test(ESRC)

Influenza geassocieerde aspergillose (IAA)

Expertisecentrum Schimmelinfecties Radboudumc/CWZ (ESRC)

Respiratoire verslechtering of + aspergillus kweek uit respiratoire

materiaal

Why does this happen in influenza?

Another case... (2 months ago)

Patient 49 yr male

Spondylodiscitis

Another case...

Patient 49 yr male

Spondylodiscitis

Biopsy

Aspergillus fumigatus

Unexpected...

Story?

No medical history of any significant infections

Admitted march 2016 with H1N1

Diagnosis of S. aureus pneumonia

BAL:

S. aureus

Aspergillus fumigatus

Aspergillus nidulans

Serum GM positive

Treated with Flucloxacillin

and voriconazol

CGD phenotype

Does this make any sense?

Chronic granulomatous disease

Generation ofreactive oxygen species (ROS)

NADPH oxidase

Aspergillus nidulansAspergillus fumigatus

S. aureus Hyperinflammation

Increased IL-1

Influenza and NADPH-oxidase

Sun et al. Journal of Immunology 2014

Influenza and NADPH-oxidase

Sun et al. Journal of Immunology 2014

Hypothesis

Influenza induces a transient CGD phenotype

Influenza and neutrophils

Live influenza did not supress

ROS in neutrophils

Influenza and macrophages

Live influenza supressed ROS

Influenza and monocytes

Live influenza supressed ROS

while inactivated inflenza did not

Heat-inactivated

LC3 associated phagocytosis

Hyperinflammatory response

Inflammasome and IL-1 in CGD

Hyperinflammation

Increased IL-1

Macrophage activation syndrome

Hemophagocytosis in influenza

Hemophagocytosis in influenza

Macrophage activation syndrome

Anakinra and MAS

Why anakinra for MAS/rHLH?

HLH-94 protocol

Pandemic...

Are we prepared?

Still need to increase awareness

Early diagnosis/treatment > prophylaxis?

MAS/HLH > HLH protocol no option anakinra

Avoid corticosteroids?

Interferon gamma treatment?

Why H1N1?

Flucloxacilline– an innocent bystander

Pharmacology:Voriconazole Posaconazole Isavuconazole

Bioavailability >90% (but lower in children) OS: Variable, saturable oral

absorption; food intake, especially

with high fat content, increases oral

bioavailability; gastric acid inhibitors

decrease drug absorption

Delayed release tablet: less impact

of PPI.

>95% (no significant foodeffect has been found withoral administration). Isavuconazonium sulfate, a water-soluble prodrug that is rapidly and almost completely (99%) convertedto isavuconazole via plasma esterases

Protein binding 58% >98% >98%

Volume of distribution 4.6L/kg 5-25 L/kg 4.4 – 7.7 L/kg

Time to reach steady state 2 days 7-10 days 14 days

Tissue penetration

- Lung tissue

- Cerebrospinal fluid

- Vitreous humor

- Urine

GoodGood (CSF – plasma ratio 0.3 – 0.6)

Good (around 60%)<2%

Good / excellent

Poor (CSF - plasma ratio 0 – 2.4)

Limited (around 21%)

< 0.1%

Good

Poor in CSF, good in brain

Good

ND

Metabolism Hepatic via CYP2C19, 2C9 and CYP3A4

Hepatic by UGT1A4 Hepatic via CYP3A4

Half-life 6 hours (but non linear PK) 30-35 hours 56-104 hours

Primary route of elimination Renal (all metabolites) Feces Feces

Activity of antifungal agents

AmB

5FC

FCZ

ITZ

VCZ

PCZ

ISA

CAS

ANF

MIC

Slide fom Paul Verweij; with permission

Especially the class of azole drugs cause interactions

R.J.M. Bruggemann, J.W. Alffenaar, N.M.A Blijlevens, E.M. Billaud, J.G. Kosterink, P.E Verweij; D.M. Burger. Clinical relevance of pharmacokinetic drug interactions with antifungal azole drugsClin Infect Dis. 2009 May 15;48(10):1441-58

Two–way interactions: voriconazole as example

• Effect on voriconazole by:• CYP2C19 inhibition: omeprazole

• CYP3A inhibition: HIV-PIs

• CYP3A / 2C19 inducers: phenytoin, rifampin, St Johns wort

• Effect of voriconazole (inhibition) on:

• CYP3A substrates: tacrolimus, CsA, Ca-antagonist, statins, benzodiazepines,

macrolides, etc.

• CYP2C9 substrates: acenocoumarol, sulfonylureum derivatives, omeprazole,

ibuprofen

• Can lead to:

• Toxicity

• Reduced effectivity

• Difference between oral versus IV• Dose dependent R.J.M. Bruggemann, J.W. Alffenaar, N.M.A Blijlevens, E.M. Billaud, J.G. Kosterink, P.E

Verweij; D.M. Burger. Clinical relevance of pharmacokinetic drug interactions with antifungal azole drugsClin Infect Dis. 2009 May 15;48(10):1441-58

We perform therapeutic drug monitoring to optimize exposure

Case A

• MUMC+ (Maastricht), 65 year old women

• Cerebral aspergillosis (biopsy proven) ; on 200 mg BID voriconazole. • Results voriconazole 0.8 mg/L (target 2.0 mg/L) • - > increase dose to 300 mg BID IV and repeat measurement

• On 300 mg BID again low exposure • -> further increase on 30-06 to 400 mg BID PO

-> adequate concentration (4 mg/L)

• Because we had access we determined drug concentrations in liquor

• Results was 2.0 mg/L (while on 400 mg BID PO )-> average ratio is 0.3 – 0.6 ; now 0.5)

Data with permission from Dr. A. Oude-Lashof, MUMC, Maastricht

Unknow cause of subtherapeutic concentrations

• Patient deteriorates and is again treated with voriconazole IV 400 mg BID

• No interacting drugs

• Contraintuitive: Switch to oral as oral therapy gave good exposure

• Meanwhile: investigate the cause of low concentrations on IV

(reconstitution problems, incompatibilities etc) • Analytical : no mistakes identified• Transport: voriconazole is stable for 14 days at ambient temp

• Drug administration was correct• Sampling appeared correct – no tubes switched• All nursing documentations were very adequate!

Case B

• 12-year old female with ALL (March 2015)

• Disseminated S aureus with large abcesses• Proven invasive pulmonary aspergillosis

• Cerebral leasions (dd aspergillus, S aureus, leukemia?

• First assessment of voriconazole drug concentrations: 0.1 mg/L

• No interacting drugs!• Pediatric patients have more rapid metabolism - causal relation?

Case B

• Increase dose to 16 mg/kg/day IV:

• Trough 0.14 mg/L ; Peak 1.7 mg/L• Clearance? Increased volume of distribution (capillairy leakage)?

• Advice: increase again to 3dd 8mg/kg IV

• Unexplainable low drug concentrations of voriconazole on intravenousdosing

• Check preparation and administration; • Can PF be the cause? Or recently started flucloxaciline?

v\

v\

Interaction between voriconazole and flucloxacillin during treatment of disseminated Scedosporium apiospermum infection. Kennedy B, Larcombe R, Chaptini C, Gordon DL. J Antimicrob Chemother. 2015 Jul;70(7):2171-3.

Data with permission from Dr. A. Oude-Lashof, MUMC, Maastricht

Data with permission from Dr. B Witjes, VUMc, Amsterdam

Flucloxacilline and voriconazole

Hesitation ?

• Flucloxacilline activates Pregnane X receptor upregulation of CYP3A4

and to a lesser extent CYP2C8/9• Same mechanism as reduction in clearance due to inflammation

• Voriconazole is metabolized primarily by CYP2C19 and to a lesser extend CYP2C9 and CYP3A4

Flucloxacilline - voriconazole

• A combination quite often seen in CGD patients

• Likely to occur in patients with H1N1 and both bacterial as well as fungal complications

• 20 patients in the past 2 years in Radboud had this combination

• 10 experienced low or undetectable drug concentrations

• Hypothesis on the cause of the interaction is still under investigation

• In the meanwhile…........? ? • Cephalosporins for S aureus infections?

• Other azole drugs for IAA / IPA ?

Center of Expertise in Mycology Radboudumc / CWZo Dr. Roger Brüggemann (pharmacy/pharmacology)o Dr. Frank van de Veerdonk (infectious diseases)o Prof. Dr. Paul Verweij (medical mycology)

Dutch / Belgium Mycosis Study Group (DB-MSG)o AMC (Amsterdam)o ErasmusMC (Rotterdam)o LUMC (Leiden)o MUMC+ (Maastricht)o Radboudumc (Nijmegen)o UMCG (Groningen)o UMCU (Utrecht)o VUmc (Amsterdam)

o UZ Gasthuis (Leuven)o UZ Gent (Gent)o AZ St Jan (Brugge)