Thread by @nihardesai7, Antifungals have come a LOOOONGGG way but we still lose many battles [...]

nihardesai7

Antifungals have come a LOOOONGGG way but we still lose many battles against these stubborn bugs

Let's focus on 𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞 today !!

A short thread.

#antifungals #IDTwitter #oncology #MedTwitter #MedStudentTwitter #hematology

For years AmpB was the go to agent for invasive #fungal infections. Plagued by infusion reactions & nephrotoxicity we desperately needed newer agents

𝐀𝐳𝐨𝐥𝐞𝐬 𝐰𝐞𝐫𝐞 𝐭𝐡𝐞 𝐚𝐧𝐬𝐰𝐞𝐫.

𝐈𝐦𝐢𝐝𝐚𝐳𝐨𝐥𝐞𝐬 like ketoconazole were the 1st on the scene. FDA approved :1981

𝐓𝐫𝐢𝐚𝐳𝐨𝐥𝐞𝐬 were next in line. The 1st generation flucon and itraconazole and the 2nd generation 𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞

The FDA approved it in May 2002 for the Rx on invasive aspergillosis

It acts by

14 α lanosterol demethylase which l/t

Ergosterol synthesis

𝐓𝐫𝐢𝐚𝐳𝐨𝐥𝐞𝐬 were next in line. The 1st generation flucon and itraconazole and the 2nd generation 𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞The FDA approved it in May 2002 for the Rx on invasive aspergillosisIt acts by 14 α lanosterol demethylase which l/tErgosterol synthesis

It reaches max plasma concentration 1-2hrs after an oral dose

Extensively hepatically metabolized to N-Oxide metabolite by the CYP 450 system

In poor metabolizers the AUC is

It reaches max plasma concentration 1-2hrs after an oral doseExtensively hepatically metabolized to N-Oxide metabolite by the CYP 450 systemIn poor metabolizers the AUC is 4x

𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞 𝐃𝐨𝐬𝐢𝐧𝐠:
𝟔𝐦𝐠/𝐤𝐠 q12h for 2 doses

𝟒𝐦𝐠/𝐤𝐠 q12h thereafter.

Adults <40kg :

maintenance dose by 50%
CTP A & B CLD:

maintenance dose by 50%
CTP C CLD: No data

𝐀𝐯𝐨𝐢𝐝 𝐦𝐞𝐚𝐥𝐬 𝟏𝐡𝐫 𝐛𝐞𝐟𝐨𝐫𝐞 𝐚𝐧𝐝 𝐚𝐟𝐭𝐞𝐫 𝐨𝐫𝐚𝐥 𝐝𝐨𝐬𝐞

𝐀𝐝𝐯𝐞𝐫𝐬𝐞 𝐑𝐞𝐚𝐜𝐭𝐢𝐨𝐧𝐬:

Visual Disturbances(~30%) Blurred vision, photophobia etc. Occurs within 1/2hr of dosing & lasts for abt 1/2hr MC during 1st week of therapy. Reversible

Transaminitis(15%) including cases of ALF.

Skin Reactions(5%) rarely need Rx discont

𝐀𝐝𝐯𝐞𝐫𝐬𝐞 𝐑𝐞𝐚𝐜𝐭𝐢𝐨𝐧𝐬:Visual Disturbances(~30%) Blurred vision, photophobia etc. Occurs within 1/2hr of dosing & lasts for abt 1/2hr MC during 1st week of therapy. ReversibleTransaminitis(15%) including cases of ALF.Skin Reactions(5%) rarely need Rx discont

𝐎𝐫𝐚𝐥 Voriconazole can be safely given to all CKD patients.

𝐈𝐕 to be avoided at CrCl<50ml/min d/t accumulation of SBECD vehicle.

Voriconazole is a 𝐂𝐘𝐏𝟑𝐀𝟒 𝐢𝐧𝐡𝐢𝐛𝐢𝐭𝐨𝐫 & drug interactions must always be kept in mind when prescribing.

𝐎𝐫𝐚𝐥 Voriconazole can be safely given to all CKD patients.𝐈𝐕 to be avoided at CrCl<50ml/min d/t accumulation of SBECD vehicle.Voriconazole is a 𝐂𝐘𝐏𝟑𝐀𝟒 𝐢𝐧𝐡𝐢𝐛𝐢𝐭𝐨𝐫 & drug interactions must always be kept in mind when prescribing.

𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞 𝐫𝐞𝐬𝐢𝐬𝐭𝐚𝐧𝐜𝐞 is an emerging problem. It ranges from 10-35% in various reports.

The figure below highlights the MC mech of resistance acquisition. Mutations in the 𝐂𝐘𝐏𝟓𝟏𝐀 𝐠𝐞𝐧𝐞 are an important cause.

𝐕𝐨𝐫𝐢𝐜𝐨𝐧𝐚𝐳𝐨𝐥𝐞 𝐫𝐞𝐬𝐢𝐬𝐭𝐚𝐧𝐜𝐞 is an emerging problem. It ranges from 10-35% in various reports.The figure below highlights the MC mech of resistance acquisition. Mutations in the 𝐂𝐘𝐏𝟓𝟏𝐀 𝐠𝐞𝐧𝐞 are an important cause.

This thread is a recapitulation of the basics. Important for beginners like myself, might not interest the seniors in the field.

References:
doi:10.1111/j.1470-9465.2004.00841.x
doi:10.1080/08998280.2003.11927910
http://doi.org/10.1007/s00210-020-01950-x

@sujeethemat @MedTweetorials @SChellapuram @ID_fellows @IJMPOofficial @med_to_bed @DrESHAJ9 @Gurleenoberoi18 @docsamdeshmukh @DigambarPanchal @SujayRainchwar @NutanJoshi27 plz add more to this thread.

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