Comparison of oral antifungals

Availability in Hospital Keningau

• Cap Fluconazole 50mg & 200mg
• Tab Griseofulvin 125mg
• Cap Itraconazole 100mg
• Tab Ketoconazole 200mg 
• Suspension Nystatin 100 000 units/ml

Comparison of Oral Antifungals

Antifungal	Indication (FUKKM)	Pharmacokinetics
Ketoconazole 200mg (B)	Pityriasis Versicolor Systemic Mycoses (other skin mycosis) Nail infection	Absorption can be increased by administration with a cola beverage (requires acidic condition) Half life elimination is biphasic (initial 2 hours and terminal 8 hours)
Fluconazole 50mg Fluconazole 100mg (A)	Oropharyngeal candidiasis, atrophic oral candidiasis Tinea Pedis, corporis, cruris, versicolor and dermal candidiasis Invasive candida & cryptocococcal infections (includes meningitis) Prevention of relapse cryptococcal meningitis in AIDS after completion of primary therapy Prevention of fungal infections in immunocompromised patients	Oral bioavailability > 90% The long serum half-life (approximately 24 hours) allows once-daily dosing Good penetration into CSF Absorption is not affected by the presence of food or gastric pH.
Itraconazole 100mg (A/KK)	Dermatomycosis including pityriasis versicolor Oral candidiasis Palmar tinea manus and plantar tinea pedis Fingernail onychomycosis Toenail onychomycosis Vulvovaginal candidiasis	Capsule bioavailability of approximately 55% Relatively long half-life, approaching 25 to 50 hours thus allows OD dosing Absorption increased by concurrent ingestion of cola or cranberry juice
Voriconazole 200mg Voriconazole 50mg (A*)	Treatment of immunocompromised patients with progressive, possibly life-threatening infections such as invasive aspergillosis, fluconazole-resistant serious invasive candidiasis, candidiasis of the oesophagus, serious fungal infections caused by Scedosporium species and Fusarium species Prevention of breakthrough fungal infections in febrile high risk neutropenic patients	Oral biovailability >90% in adult and may vary with <12 year old Ability to penetrate CSF
Syr. Nystatin 500 000 (B)	Prevention and treatment of candidiasis of the skin and mucous membranes Protection against candidas overgrowth during antimicrobial /corticosteroid therapy and as selective decontamination regimens	Poorly absorbed Excreted unchanged at feces  Should be swished about the mouth and retained in the mouth for as long as possible (several minutes) before swallowing.
Griseofulvin (B)	Dermatophyte infection of the skin, scalp, hair and nails, where topical therapy has failed or inappropriate	Absorption is almost complete (ultramicrosize) Half life elimination is 9-24 hours
Flucytosine 500mg (A*)	Only for the treatment of fungal meningitis	Ability to penetrate CSF Bioavailability 78%-89% (decreased in neonates

Spectrum of activity

Imidazole (Ketoconazole)

• Ketoconazole causes more gastrointestinal disturbances compared to other azoles.
• Has been largely replaced by other triazoles due to favourable pharmacokinetic and safety profile
• Should not be used as first-line treatment for any fungal infection.
• It should be used for the treatment of endemic mycoses (eg, histoplasmosis, blastomycosis) only when alternative antifungal therapies are not available or tolerated.
• Contraindicated in acute or chronic liver disease.

Triazole (Itraconazole, Fluconazole, Voriconazole)

• The drugs in this class offer activity against many fungal pathogens without the serious nephrotoxic effects observed with amphotericin B 
• Due to its inotropic effects, itraconazole’s labeling includes a black box warning in patients with heart failure, particularly in patients receiving a total daily oral dose of 400 mg

Pyrimidine (Flucytosine)

• Flucytosine has limited clinical indication and is used primarily in combination with Amphotericin B as combination therapy for cryptococcal meningitis and selected life threatening Candida syndromes                 

References

• Uptodate
• https://mycology.adelaide.edu.au/docs/antifungals.pdf 
• https://www.uspharmacist.com/article/the-fungus-among-us-an-antifungal-review 
• Lexicomp 
• FUKKM 

Statins - Induced Transaminitis

Introduction 

• The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated (transient) in the absence of proven hepatotoxicity and commonly occurs in the first 12 weeks of therapy.  
• This class effect is usually asymptomatic, reversible, and dose-related.
• There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders.

Effects of Statins on The Liver

• Statins exert a potent inhibition of hepatic 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which accounts for the reduction in LDL cholesterol observed with these drugs.
• Although the underlying mechanism remains unclear, hepatotoxicity may result from changes in the lipid components of the hepatocyte membrane, leading to an increase in its permeability with a subsequent “leakage” of liver enzymes.
• This is supported by the observation that elevations in aminotransferase levels.

Incidence of Elevation of Liver Enzymes During Statin Treatment

• The incidence of elevated aminotransferase levels with different types of statins generally did not exceed 3% of the studied patients' sample. 
• There seems to be a direct relationship between the statin dose and the incidence of transaminitis. 
• The reported average incidence of elevations in serum aminotransferase levels to >3x ULN was < 1% in patients receiving low to moderate doses.
• Similarly, the incidence of transaminitis increases up to 2% to 3% in those receiving high doses of statins.
• The incidence of transaminase elevations is similar among all statins, despite their different pharmacokinetic characteristics
• Most cases of transaminitis exhibit spontaneous improvement without the need for drug discontinuation, probably a result of the development of adaptation or tolerance.

Management and Monitoring

Algorithm for Management of Abnormal Liver Enzymes Before and During Statin Treatment

Statins in Preexisting Liver Dysfunction

• US FDA continues to recommend that statins be contraindicated in patients with chronic liver disease; however, several authors have recommended starting low-dose statin treatment (because of the possible greater incidence of liver enzyme elevations with higher doses) and having levels rechecked 2 weeks later.
• LFT monitoring should be performed every month for the first 3 to 4 months and 4 times a year thereafter.
•   If the levels of transaminases increase to > 3X baseline values, discontinuation of the drug should be considered.
• Clinical correlation with worsening of underlying disease, as well as exclusion of alcohol abuse and drug interactions, should be done before attempting permanent discontinuation of the drug. 
• Once levels return to baseline, rechallenge can be considered. 

Conclusion

• The latest reviewed data indicate or support the recommendation from US FDA that “all currently marketed statins appear to be associated with a very low risk of serious liver injury.”
• Clinicians should not withhold statin therapy for patients whose transaminase elevations have no clinical relevance or are attributable to known stable chronic conditions. Evaluating other causes for alteration in LFTs should be made before establishing a causal relationship with a statin agent.
• Statin use need not be avoided in patients with preexisting liver dysfunction if its use is clearly indicated.
• However, as reported in literature, potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice

References 

1. Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD, and Eugene R. Schiff, MD. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clinic Proceedings 2010 Apr; 85(4): 349–356.
2. Jimmy Jose. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharm Bioallied Sci. 2016 Jan-Mar; 8(1): 23–28.
3. Edward Onusko MD. Statins and elevated liver tests: What’s the fuss?.J Fam Pract 2008 July;57(7):449-452.
4. US Food and Drug Administration (FDA) PhRMA/FDA/ASSLD drug induced hepatotoxicity white paper post marketing considerations: November 2000.
5. US Department of Health and Human Services. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Guidance for industry: drug-induced liver injury: premarketing clinical evaluation Published July 2009

Cefuroxime Tablet & Suspension

Pharmacokinetic of Cefuroxime Axetil (Tablet)

Pharmacokinetic of Cefuroxime Axetil (Suspension)

Suspension –Tablet Conclusion

• The absorption of cefuroxime from the suspension is more prolonged compared to tablets, leading to later, lower peak serum levels and slightly reduced systemic bioavailability (4-17% less) .
• Cefuroxime axetil for oral suspension was not bioequivalent to cefuroxime axetil tablets when tested in healthy adults. 
• The tablet and powder for oral suspension formulations are NOT substitutable on a milligram-per-milligram basis. 
• The area under the curve for the suspension averaged 91% of that for the tablet, and the peak plasma concentration for the suspension averaged 71% of the peak plasma concentration of the tablets.