Terug naar de toekomst Intensivistendagen 9 - 10 februari Influenza-associated aspergillosis in critically ill patients Prof. Dr. Paul Verweij, medical microbiologist Dr. Frank L. van de Veerdonk, infectious disease physician Dr. Roger Brüggemann, hospital pharmacist- clinical pharmacologist
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Influenza-associated aspergillosis in critically ill patients · Collaborators: 8 ICU AMC ... Opname op de IC met respiratoire insufficiëntie Influenza PCR-test + Bronchoscopie Aanwezigheid
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Terug naar de toekomstIntensivistendagen 9 - 10 februari
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
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
• 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)