Antimicrobial part 3 Flashcards
Mycobacteria are rod-shaped background
• aerobic bacteria that
grow slowly—their cell walls contain mycolic acids
•These pathogens produce lipophilic cell walls that
stain poorly with a Gram stain—once stained, these
bacilli do not lose color when made acidic—thus the
name Acid Fast Bacilli
•These infections cause slow-growing granulomatous
lesions—and can occur anywhere in the body
Drugs used for Myobacteria
Ethambutol Isoniazid [INH]—prototype drug Pyrazinamide Rifabutin Rifampin Rifapentine
Second line drugs for TB
Aminosalicylic acid Bedaquiline Capreomycin Cycloserine Ethionamide Aminoglycosides/Fluroquinolones/Macrolides
Chemo for TB
-M. tuberculosis is slow growing and requires treatment for months –years -LTBI can be treated for 9 months with INH or 12 once a week higher doses of INH + Rifapentine -Active TB has to be treated with several drugs for several months -Multi-drug resistant TB is typically treated for 2 years
EXTREMELY DRUG
RESISTANT [XDR]
TUBERCULOSIS
• This is a bacilli that is resistant to INH and Rifampin and is resistant to any fluoroquinolone and at least 1 of 3 injectable 2nd line agents— Amikacin, Kanamycin or Capreomycin
HOW DO WE
DEAL WITH
DRUG
RESISTANCE??
Resistance in M. tuberculosis, when it is treated with one drug—so multiple drug therapy is used to suppress resistant strains
⬇️
1st line agents—INH, Rifampin, Ethambutol and Pyrazinamide are the DOC and highly efficacious with tolerable SE profilesRifabutin or Rifapentine can replace Rifampin in certain scenarios
⬇️
Active disease ALWAYS requires multiple drugs—3 or more with proven in vitro activity against the isolate
⬇️
Clinical improvement occurs quickly—weeks, but therapy is continued much longer to kill persistent organisms and
prevent relapse
⬇️
Standard therapy is INH, Rifampin, Ethambutol and Pyrazinamide for 8 weeks, then INH and Rifampin for 16
more weeks
What is 2nd line therapy for MDR-TB—disease resistant to
INH and Rifampin—
is treated with an aminoglycoside [Streptomycin, Kanamycin or Amikacin] or Capreomycin [all of these are
injectables], a quinolone [Levofloxacin or Moxifloxacin], Ethambutol and Pyrazinamide [if sensitive to these] and one or more of these—Cycloserine, Ethionamide or PAS
Isoniazid: MOA
• Prodrug—activated by mycobacterial catalase
peroxidase [KatG]
• Target enzymes that are essential for the synthesis
of mycolic acid
• Inhibiting this acid leads to destruction of the tubercular cell wall
Isoniazid: Antibacterial spectrum
• Specific to M. tuberculosis
• M. kansasii may be susceptible at higher drug
dosages
• Most nontubercular Mycobacteria are resistant to INH
• Drug works well on rapidly growing bacilli and intracellular organisms
Isoniazid: Resistance
• Resistance follows chromosomal mutations
incapable of prodrug activation
• Acyl carrier mutated proteins
• Over expression of the target enzyme InhA
• Cross resistance can occur between INH and Ethionamide
Isoniazid: Pharmacokinetics
• Readily absorbed after oral dose
• Food impairs absorption—especially high fat foods
• Drug diffuses into all body fluids, cell and caseous
materials [necrotic tissue that looks lie cheese produced
in the tubercular lesions]
• Drug levels in CSF is the same as in the serum
• INH undergoes N-acetylation and hydrolysis
• INH acetylation is genetically regulated, with fast
acetylators having a 90” serum ½ life, while slow
acetylators have a 3-4° serum ½ life
• Excretion is from glomerular filtration and secretion as
metabolites
• Slow acetylators excrete more of the parent compound
Isoniazid: ADEs
• Hepatitis
• If hepatitis is not recognized and INH is continued, death
can be the result
• Chance of hepatitis increases with age, in those who are
also on Rifampin and in those who drink ETOH daily
• Peripheral neuropathy—paresthesias of hands and
feet—due to a relative Pyridoxine deficiency—daily
supplementation with B6 is mandatory
• Convulsions—in those prone to seizures
• Rash and fever signal hypersensitivity
• INH inhibits breakdown of Carbamazepine and
Phenytoin—so SE of these drugs of these can be
amplified
RIFAMYCINS—
RIFAMPIN,
RIFABUTIN,
RIFAPENTINE
🟣Group of similar macrocyclic antibiotics that are considered 1st line for TB
🟣Rifampin has broader coverage than does INH and can be used for several bacterial infections
🟣Resistant strains can occur rapidly—so it is never given as monotherapy for TB
Rifampin: MOA
• Blocks RNA transcription by interfering with the
ß subunit of mycobacterial DNA-dependent RNA
polymerase
Rifampin: Antimicrobial spectrum
- Bactericidal for intracellular and extracellular mycobacteria, including M. tuberculosis, M. kansasii and M. avium complex [MAC]
- Effective for many Gram + and Gram –pathogens and is used to prevent meningitis in those exposed to Meningococci or H. influenzae
- Highly active against M. leprae
Rifampin: Resistance
• Caused by mutations in affinity for the bacterial DNA-dependent RNA polymerase gene for the drug
Rifampin: Pharmacokinetics
- Absorption is adequate after oral dose
- Distribution occurs in all body fluids and organs
- Concentrations attained in the CSF are variable—10 to 20 percent of blood concentrations
- Taken up by the liver and undergoes enterohepatic recycling
- Can induce liver CYP 450 enzymes and transporters—causing many drug interactions
- Rifampin undergoes autoinduction—causing shortened elimination ½ life over the 1st 2 weeks of dosing
- Elimination of the drug and its metabolites is via the bile and feces—a small amount is excreted in the urine
- Urine/feces/other secretions will become orange-red in color; contact lens will be stained
Rifampin: ADEs
- Nausea
- Vomiting
- Rash
- Hepatitis and death from liver failure [rare]
- Use cautiously in alcoholics, older patients and in those with chronic liver disease
- Modest increase in chance of liver dysfunction when given with INH and Pyrazinamide
- When dosed intermittently at high dose, flu-like syndrome can occur—fever, chills, muscle aches that can progress to ARF, hemolytic anemia and shock
Rifampin: Drug Interactions
- Induces phase I CYP 450 enzymes and phase II enzymes—it can decrease the ½ life of co-administered drugs that are metabolized by these enzymes
- HIV PIs
- Methadone
- OCP
- Prednisone
- Propranolol
- Quinidine
- Sulfonylureas
- Voriconazole
- Warfarin
- This decreased ½ life may mean increasing the dose of the other drug, switch to a drug not affected by Rifampin or change Rifampin to Rifabutin
RIFABUTIN
🟣Derivative of Rifampin—preferred to treat TB in those that are HIV + on PIs or several NNRTIs
🟣It is less potent inducer of CYP 450 enzymes, thus less drug interactions
🟣ADEs similar to Rifampin, but can also cause uveitis, hyperpigmentation and neutropenia
RIFAPENTINE
🟣Has a longer ½ life than Rifampin
🟣With INH, can be used weekly in those with LTBI and in
selected HIV negative patients with minimal pulmonary TB
PYRAZINAMIDE
🟣Synthetic, oral agent used short-term with INH, Rifampin and Ethambutol
🟣MOA is unknown
🟣Must be hydrolyzed by pyrazinamidase to pyrazinoic acid
🟣Active against TB in acidic lesions and
in macrophages
🟣Distributes throughout body, penetrates CSF
🟣Can contribute to liver dysfunction
🟣Causes uric acid retention [but gout uncommon]
🟣Most benefit occurs early in treatment—so agent is only used 8 weeks in a 24
week regimen
ETHAMBUTOL
• Bacteriostatic and first line for mycobacteria
• Inhibits arabinosyl transferase—an enzyme important for the synthesis of mycobacterial cell wall
• Used with INH, Pyrazinamide and Rifampin pending cultures and susceptibility
• Distributes well throughout body, but CSF penetration is variable—question if it is adequate for TB meningitis
•Parent drug and metabolites are excreted in the urine
•ADEs—optic neuritis—which affects vision and ability
to see red and green
• Risk increases with higher doses and in those with CKD
• Visual acuity and color discrimination should be checked
before prescribing and periodically during therapy
•Uric acid excretion is decreased—caution in those
with a history of gout
Ethambutal: ADE
Optic neuritis with blurred vision, red-green color blindess
– est baseline visual acuity and color vision; test monthly
Isoniazid: ADE
Hepatic enzyme elevation, hepatitis, peripheral neuropahy
–take baseline hepatic enzyme measurements; repeat if abnormal or pt at risk or symptomatic. Clinically significant interaction with phenytoin and carbamazepine
Pyrazinamide: ADE
Nausea, hepatitis, hyperuricemia, rash, joint ache, gout (rare)
–take baseline hepatic enzymes and uric acid measurements; repeat if abnormal or patient is at risk or symptomatic
Rifampin: ADE
Hepatitis, GI upset, rash, flu lie syndrome, significant interaction with several drugs
–take baseline hepatic enzyme measurements and CBC; repeat if abnormal or patient is at risk or symptomatic. warn pt that urine and tears may turn red-orange in color
ALTERNATIVE SECOND LINE DRUGS
These agents are less effective and more toxic than 1st line agents**
Streptomycin Para-Aminosalicylic Acid Capreomycin
🟣Streptomycin 🟣Para-Aminosalicylic Acid 🟣Capreomycin 🟣Cycloserine 🟣Ethionamide 🟣Fluoroquinolones 🟣Macrolides 🟣Bedaquiline
Streptomycin
• Aminoglycoside
• One of 1st TB drugs
• Action greatest for extracellular organisms
• If isolate is resistant to Streptomycin—can be treated with Kanamycin or Amikacin [bacilli remain sensitive to
these agents
Para-Aminosalicylic Acid
- Works by folic acid inhibition
* Largely replaced by Ethambutol, but remains important part of many MDR-TB regimens
Capreomycin
- Parenterally administered polypeptide that inhibits protein synthesis very much like aminoglycosides
- Reserved to treat MDR-TB
- Careful monitoring of renal function and hearing is needed
Cycloserine
• Oral TB drug that disrupts D-alanine incorporation into
bacterial cell wall
• Distributes well throughout body fluids and CSF
• Excreted unchanged in the urine
• Accumulation in those with CKD
• ADEs—CNS disturbances [lethargy, difficulty concentrating, anxiety, SI] and seizures have been seen
Ethionamide
- Structural analog of INH—disrupts mycolic acid synthesis
- MOA is not identical to INH, but some overlap in resistance patterns
- Widely distributed throughout the body and CSF
- Metabolism is in the liver to active and inactive metabolites
- ADEs limit its use—nausea, vomiting, hepatoxicity, hypothyroidism, gynecomastia, alopecia, impotence and CNS have been reported
Fluoroquinolones
- Moxifloxacin and levofloxacin have a role in MDR-TB
* Some NTM are also susceptible
Macrolides
- Azithromycin and Clarithromycin are used in regimens for several NTM—including MAC
- Azithromycin may be preferred for those at risk for drug interactions as Clarithromycin is both a substrate and an inhibitor of CP 450 enzymes
Bedaquiline
• ATP synthase inhibitor
• Approved to treat MDR-TB
• Given orally
• Active against many types of mycobacteria
• BB warning for QTc prolongation, monitoring of EKG is necessary
• Elevated LFTs has been seen, so these must be monitored
• Metabolized by CYP 450 3A4
• Administration with strong CYP 450
3A4 inducers [such as Rifampin] should be avoided
Leprosy
HANSEN DISEASE
•Skin infection with M. leprae
•Uncommon in US—but still a
major problem world wide
DAPSONE
- Structurally related to sulfonamides; inhibits dihydropteroate synthase in the folate synthesis pathway
- Bacteriostatic for M. leprae; some resistant strains can be seen
- Also used to treat pneumonia from Pneumocystis jirovecii in the immunosuppressed
- Well absorbed from the GI tract
- Distributed throughout the body, with high concentrations in the skin
- Hepatic acetylation
- Parent drug and metabolites are eliminated in the urine
- ADEs—hemolysis, methemoglobulinemia [highest risk in those with G6PD deficiency] and peripheral neuropathy
CLOFAZIMINE
• Phenazine dye
• MOA involves binding to DNA; its redox properties causes formation of cytotoxic O2 radicals that are toxic to the bacilli
• Bactericidal
• Potentially useful to treat M. tuberculosis and NTM
• Recommended by WHO as part of a shorter
regimen [9-12 months] for MDR-TB
• Given orally; accumulates in the tissues, allowing
intermittent therapy—does not enter the CNS
• Pink to brownish-black discoloration of the skin
occurs—tell patient in advance
• Eosinophilic enteritis [requiring surgery] has
occurred
• Has anti-inflammatory and anti-immune properties
• Erythema nodosum may not develop in patients on
this drug
Anitfungal drugs
• Infections from fungus are called mycoses
• May involve the skin only—cutaneous mycoses extending into the epidermis or may be subcutaneous or systemic
• Fungi have rigid cell walls composed of chitin rather than peptidoglycan [what is seen in bacteria]
• Fungal cell membrane contains ergosterol rather than cholesterol
• Fungi are generally resistant to antibiotics, and bacteria are resistant to antifungal agents
•Incidence of candidemia has been on the rise in the
last decade—this is thought to be related to the
increased number of patients with chronic
immunosuppression—organ transplant patients,
chemotherapy, biologics to treat autoimmune and/or
HIV infection
• Candidiasis is treated with ___
olyenes, azoles, nucleoside analogs, echinocandins and allylamines—depending on infection site and severity
Candida has 20 different species—
it is a yeast that is considered part of our normal flora—overgrowth occurs in diabetics, those on long-term antibiotics and in those that are immunosuppressed
_________are preferred for invasive Candidiasis, candidemia and esophageal candidiasis
Echinocandins
In order to identify this strain of yeast—one of two
methods of fungal testing must be ordered
matrix assisted laser desorption/ionization time of flight
[MALDI-TOF] or Bruker MALDI Biotyper
[preferred—100% accurate]—these compare
ionized microorganisms from the patient samples to
a reference database
AMPHOTERICIN B: MOA
- Naturally occurring polyene antifungal produced from Streptomyces nodosus
- DOC for several life-threatening mycoses
- Binds to ergosterol in the plasma of the fungus—it forms pores that require hydrophobic interactions between the lipophilic segment of the polyene antifungal and the sterol—the pores disrupt the membrane function and call cell death
AMPHOTERICIN B: Antifungal spectrum
- Ether fungicidal or fungistatic—depending on the organism and concentration given
- Covers C. albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis and many strains of Aspergillus
- Can be used to treat Leishmaniasis
AMPHOTERICIN B: Resistance
• Infrequent, but is from decreased ergosterol content of the fungal membrane
AMPHOTERICIN B: Pharmacokinetics
• Given slow IV infusion
• Insoluble in water and must be co-formulated with Na+
deoxycholate or artificial lipids to form liposomes [the liposomal preps are associated with less renal and infusion toxicities, but are more expensive]
• Extensively bound to plasma proteins and is distributed
throughout the body
• Inflammation favors penetration into body fluids, but little is found in CSF, vitreous humor, peritoneal or synovial fluid
• Low levels of drug and its metabolites are excreted mainly in the urine over a long period
• The drug has a LOW therapeutic index
AMPHOTERICIN B: ADEs fever and chills
- Occur 1-3 hours after IV infusion started; less with repeated infusions
- Premedication with APAP or a low dose of a steroid helps to prevent
AMPHOTERICIN B: ADE: renal impairent
• Even though only a small amount is excreted in
the urine, patients can have a decrease in their
GFR and decrease in their renal tubular
functioning
• Renal function usually returns to baseline
when drug is stopped, but residual damage can
persist if high doses were needed
• Azotemia is made worse if patient is on other
nephrotoxic drugs—aminoglycosides,
Cyclosporine, Vancomycin—good hydration can
reduce azotemia
• Loading patient with NS infusion before
Amphotericin dose or use of the liposomal
Amphotericin B minimizes risk of renal damage
AMPHOTERICIN B: ADE Hypotension
• Shock-like fall in BP accompanied by low K+ can
occur—potassium supplement is required
• Be careful in those on Digoxin and other agents that
can cause K+ fluctuations
AMPHOTERICIN B: ADE thrombophlebitis
• Adding heparin to the infusion prevents this ADE
ANTIMETABOLITE ANTIFUNGALS: MOA
• Enters fungal cell through cytosine specific
permease; it is converted to a series of compounds that disrupt nucleic acid and protein synthesis
• Amphotericin B increases cell permeability, allowing more 5FC to penetrate the leading to synergistic benefits
ANTIMETABOLITE ANTIFUNGALS: ANTIFUNGAL SPECTRUM
- Fungistatic
- Effective with Itraconazole to treatChromoblastomycosis
- Used with Amphotericin B to treat systemic mycosis and meningitis from C. neoformans and C. albicans
- Can be used for CandidaUTIs when fluconazole is not appropriate [resistance can occur with repeated courses]
ANTIMETABOLITE ANTIFUNGALS: RESISTANCE
• May occur from decreased levels of enzymes in the
conversion of 5-FC to 5-FU and other metabolites
• Resistance is less with a combination of %-FC + a 2nd antifungal agent
• Not used as a single agent
ANTIMETABOLITE ANTIFUNGALS: PHARMACOKINETICS
- Well absorbed after oral dose
- Distributes throughout body water and penetrates well into CSF
- 5 –FU is detectable in patient and is likely the result of the metabolism of 5-FC by intestinal bacteria
- Excretion of parent drug and metabolites is via glomerular filtration—dose must be reduced in those with renal disease
ANTIMETABOLITE ANTIFUNGALS: ADEs
- Reversible neutropenia
- Thrombocytopenia
- Dose related bone marrow depression
- Reversible hepatic dysfunction and elevated LFTs has been seen
- Nausea
- Vomiting
- Diarrhea
- Severe endocarditis has been reported
Example of AZOLE ANTIFUNGALS
Fluconazole [Diflucan]—prototype drug Itraconazole [Sporanox] Posaconazole [Noxafil] Voriconazole [Vfend] Isavuconazole [Cresemba]
AZOLE ANTIFUNGALS
🟣Azoles are made up of 2 different classes of drugs—
the Imidazoles and the Triazoles
🟣They have similar MOA and spectra, but the
pharmacokinetics and therapeutic uses vary
🟣In general—the Imidazoles are used topical for
cutaneous infections while the Triazoles are given
systemically for treatment or prevention of cutaneous
and systemic mycoses
🟣Most of the Imidazoles are discussed under
dermatologic drugs
AZOLE ANTIFUNGALS: MOA
• Fungistatic
• Inhibit 14-a demethylase and
block demethylation of lanosterol to ergosterol
• Inhibiting ergosterol biosynthesis disrupts fungal
membrane structure and function
AZOLE ANTIFUNGALS: RESISTANCE
• Is becoming common, especially when prolonged
therapy is needed in immunosuppressed patients
• Mechanism of resistance—mutations in 14-a
demethylase gene that leads to decreased azole
binding and efficacy
• Some fungi develop efflux pumps that pump the drug
out of the cell or have reduced ergosterol in the cell wall
AZOLE ANTIFUNGALS: DRUG INTERACTIONS
• All azoles inhibit CYP 450 3A4 to some degree
• Patients on other meds that are substrates for this isoenzyme can have increased concentrations and
toxicity
• Itraconazole, Voriconazole are metabolized by CYP 450 3A4 and other CYP 450 isoenzymes—so, concomitant use of potent CYP 450 inhibitors [Ritonavir] and inducers [Rifampin, Phenytoin] can lead to increased ADEs or clinical failure of the these [2] azoles
AZOLE ANTIFUNGALS: CONTRAINDICATIONS
- All oral azoles are teratogenic
* Avoid in pregnancy unless the potential benefit outweighs the risk
FLUCONAZOLE
🟣1st triazole antifungal—Diflucan
🟣It is the least active of all triazoles—spectrum
limited to yeast and some dimorphic fungi
🟣No role in treating Aspergillus or Zygomycosis
🟣Very active against Cryptococcus neoformans,
C. albicans and C. parapsilosis
🟣Resistance is a concern with C. krusei and C.
glabrata
🟣Used to prevent invasive fungal infections in BMT
patients
🟣DOC for Cryptococcus neoformans after induction
therapy with Amphotericin B and Flucytosine, and is
used for treatment of Candidemia and Coccidioidomycosis
🟣Effective against most forms of mucocutaneous
Candidiasis
🟣Can be used as single dose treatment for vulvovaginitis
PEARLS OF FLUCONAZOLE
🟣Available oral and IV
🟣Absorbed well after oral dose
🟣Distributes widely to body fluids and tissues
🟣Majority of the drug is excreted unchanged via the
urine
🟣Doses must be reduced in those with renal disease
🟣ADEs—nausea, vomiting, headache and skin rashes
ITRACONAZOLE
🟣Synthetic triazole with broad antifungal spectrum compared to Fluconazole
🟣DOC in Blastomycosis, Sporotrichosis,
Paracoccidioidomycosis, Histoplasmosis
🟣Rarely used for Candida or Aspergillus—because of more effective agents
🟣Available as capsules, tablets and solution
🟣Sporanox distributes well in tissues—including bone and adipose
🟣Extensively metabolized by the liver; drug and
its metabolized are excreted in the urine and feces
🟣ADEs—nausea, vomiting, rash, low K+, HTN,
edema, headache; liver toxicity can occur when given with other liver toxic drugs
🟣It is a negative inotropic effect—avoid in those with ventricular dysfunction or HF
POSACONAZOLE
• Synthetic triazole—broad spectrum antifungal similar to Itraconazole
• Noxafil comes in oral suspension, tablets or IV
• Used for treating and prevention of invasive Candida and Aspergillus in the immunocompromised
• Used in invasive fungal infections from Scedosporium and Zygomycetes
• Low bioavailability and should be given with food
• Not metabolized by CYP 450—eliminated by
glucuronidation
• Drugs that increase gastric pH [PPIs] can
decrease the absorption of oral Posaconazole,
and should be avoided
• Due to potent inhibition of CYP 450 3A4,
concomitant used of Ergots, Atorvastatin,
Citalopram and Risperidone are contraindicated
VORICONAZOLE
🟣Synthetic triazole related to Fluconazole—broad
spectrum antifungal available orally and IV
🟣Has replaced Amphotericin B as the DOC for
invasive Aspergillus
🟣Approved to treat invasive candidiasis, as well as
Scedosporium and Fusarium
🟣High oral bioavailability and penetrates into
tissues well
🟣Extensively metabolized by CYP 450 2C19, 2C9,
3A4 and metabolites are excreted in the urine
🟣Inhibitors and inducers of these isoenzymes can affect levels of Vfend—causing toxicity or clinical failure
🟣This drug displays non-linear kinetics—which can be affected by drug interactions and pharmacogenetic variability—CYP 450 2C19 polymorphisms
🟣High trough levels are associated with visual and auditory hallucinations and an increased risk of liver damage
🟣It is also an inhibitor of CYP 450 2C19, 2C( and 3A4—drugs that are substrates of these isoenzymes are impacted by this drug
🟣Contraindicated with Rifampin, Rifabutin, Carbamazepine and St. John’s wort
ISAVUCONAZOLE
- Cresemba is broad spectrum antifungal which is supplied as the prodrug Isavuconazonium in oral and IV forms
- The prodrug is rapidly hydrolyzed by esterases in the blood to Isavuconazole
- Coverage similar to Voriconazole—approved for invasive Aspergillus and invasive mucormycosis
- High bioavailability after oral dose; distributes well into the tissues
- Metabolized by CYP 450 3A4/5 and uridine diphosphate-glucoronosyltransfereases
- Co-administration with other potent CYP 450 3A4 inhibitors and inducers is contraindication
- Cresemba is also an inhibitor of CYP 450 3A4 isoenzyme, thus increasing the concentration of drugs that are substrates of CYP 450 3A4
- ADEs—nausea, vomiting, diarrhea, hypokalemia
FLUCONAZOLE SUMMARY
Spectrum activity: + Routes of admin: oral/IV Oral Bioavailability:95 Drug level affected by food or gastric pH: no Protein binding% :10 Primary rout of elimination: renal Cytochrome P450 enzymes inhibited: CPY3A4, 2C9, 2C19 Half-life: 25 HOURS CSF penetration: yes Renal excretion of active drug: >90 TDM recommended (rationale): No
ITRACONAZOLE SUMMARY
Spectrum activity: ++
Routes of admin: oral
Oral Bioavailability: 55 (solution)
Drug level affected by food or gastric pH: yes
Protein binding% : 99
Primary rout of elimination: hepatic, CYP3A4
Cytochrome P450 enzymes inhibited: CYP3A4, 2C9
Half-life: 30-40HR
CSF penetration: NO
Renal excretion of active drug: <2
TDM recommended (rationale): YES (EFFICACY)
ISAVUONAZOLE SUMMARY
Spectrum activity: +++
Routes of admin: ORAL, IV
Oral Bioavailability: 98
Drug level affected by food or gastric pH: NO
Protein binding% : 99
Primary rout of elimination: HEPATIC, CYP3A4, UGT
Cytochrome P450 enzymes inhibited: CYP3A4
Half-life: 130HR
CSF penetration: YES
Renal excretion of active drug: 45
TDM recommended (rationale): UNKNOWN (THERAPEUTIC LEVELS NOT YET DETERMIED)
VORICONAZOLE SUMMARY
Spectrum activity: +++
Routes of admin: ORAL, IV
Oral Bioavailability: 96
Drug level affected by food or gastric pH: NI
Protein binding%: 58
Primary rout of elimination: HEPATIC, CYP2C19, 2C9, 3Z4
Cytochrome P450 enzymes inhibited:CYP2C19, 2C9, 3A4
Half-life: DOSE DEPENDENT
CSF penetration: YES
Renal excretion of active drug: <2
TDM recommended (rationale): YES(EFFICACY AND SAFETY)
POSACONAZOLE SUMMARY
Spectrum activity: ++++
Routes of admin:ORAL, IV
Oral Bioavailability: VARIABLE
Drug level affected by food or gastric pH: YES
Protein binding%: 99
Primary rout of elimination: HEPATIC, GLUCURONIDATION
Cytochrome P450 enzymes inhibited: CYP3A4
Half-life: 20-66 HR
CSF penetration: YES
Renal excretion of active drug: <2
TDM recommended (rationale): YES (EFFICAY)
THE NEW KIDS ON THE BLOCK—THE ECHINOCANDINS EXAMPLES
- Capsofungin—Cancidas
- Micafungin—Mycamine
- Anidulafungin—Eraxis
•These drugs interfere with the synthesis of the fungal
cell wall and inhibit the synthesis of ß [1,3] D-glucan,
leading to lysis and cell death
•All of these agents are given IV once daily
PEARLS OF ECHINOCANDINS
Micafungin is the only agent that does not require
a loading dose
Potent against Aspergillus and most Candida ssp.—
including those resistance to azoles
Minimal activity against other fungi
ADEs—fever, rash, nausea, phlebitis
Must be given by slow IV infusion to prevent a
histamine induced flushing seen with rapid infusion
CAPSOFUNGIN
- Cancidas—prototype drug
- 1st line for those with invasive Candida—including candidemia
- 2nd line for invasive Aspergillosis in those who have failed or cannot take Amphotericin B or an azole
- Co-administration with CYP 450 enzyme inducers [Rifampin] mandates an increase in Capsofungin dose
- Should not be given with Cyclosporine—due to elevation of LFTs
MICAFUNGIN AND ANIDULAFUNGIN
1st line options for invasive Candidiasis, including candidemia Micafungin is also indicated for prevention of invasive Candida infections in those undergoing stem cell transplants These drugs are not substrates for CYP 450 enzymes and not have any associated drug interactions
DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS
•Mold-like fungi that cause cutaneous infections are called dermatophytes—or tinea •Tinea is classified by the part of the body affected •3 fungi cause the majority of these infections—Trichophyton, Microsporum and Epidermophyton
EXAMPLE OF DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS
Squalene Epoxidase Inhibitors Griseofulvin Nystatin Imidazoles Tolnaftate
Squalene Epoxidase Inhibitors
• Act by inhibiting squalene epoxidase; blocking the biosynthesis of ergosterol, essential part of the fungus cell wall • Terbinafine [Lamisil]
Griseofulvin
• Disrupts mitotic spindle and inhibits fungal mitosiS
Nystatin
• Polyene antifungal and its MOA is similar to
Amphotericin B
Imidazoles
- Butoconazole [Gynazole]
- Clotrimazole [Desenex; Lotrim AF]
- Econazole [Spectazole]
- Ketoconazole [Nizoral]
- Miconazole [Zeasorb]
- Oxiconazole [Oxistat]
- Sertaconazole [Ertaczo]
- Sulconazole [Exelderm]
- Terconazole [Terazol]
- Tioconazole [Monistat]
Tolnaftate
- Topical thiocarbamate that distorts hyphae and stunts mycelial growth in susceptible fungi
- Tinactin
DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS
Efinaconazole
Ciclopirox
Tavaborole
Efinaconazole
• Topical triazole antifungal used to treat onychomycosis
of toenails from Trichophyton rubrum and Trichophyton
mentagrophytes
• Requires 48 weeks of therapy
• Effective against Candida albicans
• Jublia
Ciclopirox
- Pyridine antimycotic, inhibits the transport of essential parts of the fungal cell, and interferes with DNA/RNA and proteins
- Effective against Epidermophyton, Microsporum, Candida ssp. and Malassezia
- The shampoo can be used for seborrheic dermatitis
- Comes in cream, gel, suspension and nail lacquer
- Loprox / PenLac
Tavaborole
• Inhibits aminoacyl-transfer ribonucleic acid synthetase,
preventing fungal protein synthesis
• Active against Trichophyton rubrum, Trichophyton
mentagrophytes and Candida albicans
• Topical solution to treat toenail fungus—48 weeks of treatment required
• Kerydin
Which of the following antifungal
agents is most likely to cause renal
damage?
Amphotericin B
Voriconazole is the DOC for _____
Aspergillosis
