pharmacology of antimicrobial and antifungal agents pt III

lecture given 4/7/2026, does NOT include cases from the end of the ppxt so review those on your own time

*what are the first line agents of antimycobacterials?

rifampin, isoniazid, pyrazinamide, ethambutol

what is active TB treatment?

initial treatment for 2 months with RIPE, continuation treatment for 4 months with rifampin and isoniazid

mutli-drug resistant TB (MDR)

m. tuberculosis isolate resistant to at least isoniazid and rifampin

extensively drug resistant TB (XDR)

m. tuberculosis isolate resistant to at least isoniazid, rifampin, a quniolone, and an injectible second line agent like aminoglycoside

what is the mechanism of action of rifampin?

binds to bacterial RNA polymerase, inhibiting RNA synthesis

bactericidal, concentration dependent

what is the spectrum of activity of rifampin?

mycobacteria, G+ organisms (never used as monotherapy)

what are the uses of rifampin?

mycobacterial infections, G+ bacterial infections involving prosthetic material in combination due to development of resistance with monotherapy

what are the pharmacokinetics of rifampin?

good oral absorption- take on an empty stomach

widely distributed

liver metabolism

eliminated in the bile

what interactions can rifampin have?

CYP450 enzyme inducer (CYP3A4/1A2/2C9/2C19/2D6), reduces levels of many drugs like protease inhibitors, NNRTIs, azole antifungals, anti-arrhythmic agents, warfarin, digoxin, calcium channel blockers, corticosteroids, clopidogrel, ect

what are the adverse effects of rifampin?

orange discoloration of body fluids (tears, urine)

rash (5-10%)- self limiting, <0.3% true hypersensitivity)

hepatotoxicity (<3%)

GI disturbances

flu like syndrome is rare

what is the mechanism of action of isoniazid (INH)?

inhibits cell wall mycolic acid synthesis, which is specific for mycobacteria

bactericidal against actively growing organisms

what is the spectrum of activity of isoniazid (INH)?

mycobacteria

what are the pharmacokinetics of isoniazid (INH)?

good oral absorption

widely distributed, including CNS

liver metabolism (acetylation)

renal excretion

what drug interactions can isoniazid (INH) have?

CYP3A4 and CYP2C19 inhibitor- increases levels of phenytoin and others

what are adverse effects of isoniazid (INH)?

hepatoxicity (<3%)- typically 1-2 months after initiation, risk increases with age/underlying liver disease/alcohol consumption, asymptomatic elevation of AST in 10-20% of patients

peripheral neuropathy (<1%)- supplement with vitamin B6

skin reactions, urticaria (<1%)

what are the categories of systemic antifungals?

azole antifungals, polyene antifungals, echinocandins

what drugs fall into azole antifungals?

fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole

what drugs fall into polyene antifungals?

amphotericin B, nystatin

what drugs fall into echinocandins?

caspofungin, micafungin, anidulafungin

what is the mechanism of action of azole antifungals?

inhibits fungal enzymes responsible for converting ianosterol to ergosterol

fungistatic

all azoles are metabolized to an extent in the liver- potential drug interactions and hepatotoxicity

what are the pharmacokinetics of flucaonazole?

IV or PO, good oral absorption

widely distributed, including CNS

liver metabolism, CYP450 inhibitor (less than other azoles)

what are the adverse effects of fluconazole?

generally well tolerated

GI effects, elevations in LFTs, has been associated with reversible alopecia, QTc prolongation

amphotericin B

first available in 1960, only systemic antifungal until 1980

what is the mechanism of action of amphotericin B?

insertion of fungal cell wall, binds ergosterol (fungal membranes only), increases membrane permeability

fungicidal, concentration dependent

what are the formulations of amphotericin B?

conventional (deoxycholate) and 2 lipid formulations (preferred, liposomal or lipid complex)

what is the spectrum of activity of amphotericin B?

yeasts- candida, crytococcus, histoplasma

molds- aspergillus, mucormycoses

what are the clinical uses of amphotericin B?

first line for cryptococcal meningitis and mucormycoses

alternative for invasive candida and mold infections

what are the pharmacokinetics of amphotericin B?

poor oral absorption, widely distributed

what are the adverse effects of amphotericin B?

adverse effects limit its use

nephrotoxicity- glomerular or tubular (~40-50%)

infusion related reactions- chills, fever, tachypnea

electrolyte disturbances- K and Mg wasting

hematologic disturbances

hepatotoxicity

nystatin

polyene antifungal agent

high toxicity limits its systemic use (but can be local/topical)

not absorbed in GI tract- oral solutions, creams, powders

what are the uses of nystatin?

oral candidiasis, topical fungal infections

what are adverse effects of nystatin?

bitter taste, nausea, vomiting

t/f fluconazole is better tolerated but amphotericin B is more effective

true