[CIS-PAGID] a question on CGD baby_Tb meds + antifungal prophylaxis

[Sergio Rosenzweig]

Hi YaeJean,
Attached below is a very comprehensive response from Tim Jancel, our
Pharmacist at NIH, about CGD, RIF and azoles (bottom line, Rifampin will
make all your azoles levels almost undetectable). As a side note, Itra
levels when given at prophylaxis dose and measured at trough are usually
undetectable (Gallin et al, NEJM, 2003). 
Sergio

I would call the RIF interaction with Itra/Posa/Vori as absolutely
contraindicated due to subtherapeutic concentrations of the azoles due
to RIF.  It would be incredibly difficult to overcome this interaction,
even with dose increases with the azoles.  I remember at least 2 pts in
which we could not overcome the RIF induction of metabolism even with
incredibly large doses of IV Vori and we ended up discontinuing the RIF.

Azole (Fluconazole, Voriconazole, Itraconazole, and Posaconazole)
concentrations will all be reduced by Rifampin, but the extent of this
reduction will vary based on the specific azole.  Fluconazole should be
the least affected azole, but reduced Fluconazole concentrations will
still be seen when given concomitantly with Rifampin — see below.  In
addition, Fluconazole does not cover molds such as Aspergillus, so is
not usually a therapeutiv option for CGD.

Rifampin is an inducer of all the significant CYP450 isoenzymes (1A2,
2C9, 2C19, 2D6, 3A4), P-glycoprotein and UGT enzymes.

Typically we would suggest discontinuation of RIF if the azole is
indicated.

Voriconazole
Voriconazole is a substrate of 2C9, 2C19* and 3A4, so the interaction
with Rifampin is quite significant.
Prescribing information: Rifampin (600 mg once daily) decreased the
steady state Cmax and AUC of voriconazole (200 mg every 12 hours for 7
days) by an average of 93% and 96%.  We have tried this on a handful of
patients, and similar to the prescribing information, Vori
concentrations decreased to subtherapeutic concentrations.

Posaconazole
One would expect that the extent of this interaction would be less for
Posaconazole since it is NOT a substrate of CYP450.  However,
posaconazole is a substrate for the efflux transporter P-glycoprotein.
Rifampin is an inducer of CYP450, P-glycoprotein, and UGT enzymes.  
We published a case in CID last year regarding subtherapeutic
Posaconazole concentrations in a CGD patient:
http://www.ncbi.nlm.nih.gov/pubmed/20166829
I have also found another NIAID patient on Posa/Rif in 2007 on a recent
retrospective review and found his Posaconazole concentrations were 0.0
ng/mL and 70 ng/mL while on Rifampin (undetectable and sub-therapeutic,
respectively)                                             

Fluconazole
Fluconazole is primarily renally eliminated, not a substrate if CYP450,
and only ~10% of Fluconazole undergoes hepatic metabolism.
 
The data below suggest Fluconazole exposure will be reduced by Rifampin.


Posaconazole/Rifampin
Clin Infect Dis.   2010 Mar 15;50(6):939-40.
Rifampin and posaconazole coadministration leads to decreased serum
posaconazole concentrations.
Hohmann C  Kang EM , Jancel T 


Voriconazole/Rifampin
Antimicrob Agents Chemother.  2007 Sep;51(9):3455-6. Epub 2007 Jul 2.
Induction of voriconazole metabolism by rifampin in a patient with acute
myeloid leukemia: importance of interdisciplinary communication to
prevent treatment errors with complex medications.


Sergio D. Rosenzweig, MD, PhD
Chief, Infectious Diseases Susceptibility Unit
Laboratory of Host Defenses, NIAID, NIH
10 Center Dr., Bldg. 10, CRC 5W-3888
Bethesda, MD 20892-1456
Phone (301) 451 8971
Fax (301) 451 7901
Cell (240) 361 7617
Pager 102 10678
srosenzweig at niaid.nih.gov
 
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>>> YaeJean Kim <yaejeankim at skku.edu> 06/13/11 12:23 AM >>>

Dear all,


Thanks to you all, I could save the 4 month old boy with CGD early this
year. (I diagnosed CGD because of a hx of liver abscess due to Serratia
when
HO people was suspecting hepatoblastoma).
He is doing well now but I have additional question.

He has had inflammation/abscess like lesions at the BCG site and neck
LN...I
continued Tb meds (which I started in Feb when he developed ADRS, at
that
time we did not have any evidence)
Now since last month, the LN got inflammed more and pus from the
operated LN
is AFB positive...we are culturing the organism now.

So, I think this child has Mycobacterium bovis infection due to BCG
immunization and I will continue current meds (INH, Rifampin,
Ethambutol)..
 It seems that the response is slow...but IFN-r is not available in
Korea so
I can't use it.

I initially started ampho when his condition was serious but then
switched
to itraconzole prophylaxis.
But there is a significant drug infection between Tb meds and
itraconazole...the level of itraconazole is undetectable...I currenly
discontinued itraconzole.
My worry at this moment is that I am not giving him any antifungal
prophylaxis.

I think he may need stem cell transplant since he is suffering from
serious
infections since young ages (2 months) but his conidtion would be only
ready
when I control this mycobacterium infection and protect him from any
serious fungal infection...

 I would appreciate any suggestion regarding this situation.

Thanks.

YaeJean



-- 
Yae-Jean Kim, MD
Assistant Professor
Division of Infectious Diseases
Department of Pediatrics
Sungkyunkwan University School of Medicine
Samsung Medical Center
50 Irwon-dong Gangnam-gu
Seoul, Korea
Tel)  +82-2-3410-0987  Fax) +82-2-3410-0043
yaejeankim at skku.edu