Antimicrobial part 3 Flashcards

Question

Isoniazid: ADE

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

``` 🟣Streptomycin 🟣Para-Aminosalicylic Acid 🟣Capreomycin 🟣Cycloserine 🟣Ethionamide 🟣Fluoroquinolones 🟣Macrolides 🟣Bedaquiline ```

Answer 5

• 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

Answer 6

* Works by folic acid inhibition | * Largely replaced by Ethambutol, but remains important part of many MDR-TB regimens

Answer 7

* 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

Answer 8

• 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

Answer 9

* 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

Answer 10

* Moxifloxacin and levofloxacin have a role in MDR-TB | * Some NTM are also susceptible

Answer 11

* 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

Answer 12

• 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

Answer 13

HANSEN DISEASE •Skin infection with M. leprae •Uncommon in US—but still a major problem world wide

Answer 14

* 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

Answer 15

• 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

Answer 16

• 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

Answer 17

olyenes, azoles, nucleoside analogs, echinocandins and allylamines—depending on infection site and severity

Answer 18

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

Answer 19

Echinocandins

Answer 20

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

Answer 21

* 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

Answer 22

* 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

Answer 23

• Infrequent, but is from decreased ergosterol content of the fungal membrane

Answer 24

• 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

Answer 25

* 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

Answer 26

• 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

Answer 27

• 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

Answer 28

• Adding heparin to the infusion prevents this ADE

Answer 29

• 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

Answer 30

* 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]

Answer 31

• 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

Answer 32

* 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

Answer 33

* 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

Answer 34

``` Fluconazole [Diflucan]—prototype drug Itraconazole [Sporanox] Posaconazole [Noxafil] Voriconazole [Vfend] Isavuconazole [Cresemba] ```

Answer 35

🟣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

Answer 36

• Fungistatic • Inhibit 14-a demethylase and block demethylation of lanosterol to ergosterol • Inhibiting ergosterol biosynthesis disrupts fungal membrane structure and function

Answer 37

• 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

Answer 38

• 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

Answer 39

* All oral azoles are teratogenic | * Avoid in pregnancy unless the potential benefit outweighs the risk

Answer 40

🟣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

Answer 41

🟣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

Answer 42

🟣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

Answer 43

• 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

Answer 44

🟣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

Answer 45

* 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

Answer 46

``` 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 ```

Answer 47

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)

Answer 48

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)

Answer 49

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)

Answer 50

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)

Answer 51

* 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

Answer 52

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

Answer 53

* 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

Answer 54

``` 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 ```

Answer 55

``` •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 ```

Answer 56

``` Squalene Epoxidase Inhibitors Griseofulvin Nystatin Imidazoles Tolnaftate ```

Answer 57

``` • Act by inhibiting squalene epoxidase; blocking the biosynthesis of ergosterol, essential part of the fungus cell wall • Terbinafine [Lamisil] ```

Answer 58

• Disrupts mitotic spindle and inhibits fungal mitosiS

Answer 59

• Polyene antifungal and its MOA is similar to | Amphotericin B

Answer 60

* Butoconazole [Gynazole] * Clotrimazole [Desenex; Lotrim AF] * Econazole [Spectazole] * Ketoconazole [Nizoral] * Miconazole [Zeasorb] * Oxiconazole [Oxistat] * Sertaconazole [Ertaczo] * Sulconazole [Exelderm] * Terconazole [Terazol] * Tioconazole [Monistat]

Answer 61

* Topical thiocarbamate that distorts hyphae and stunts mycelial growth in susceptible fungi * Tinactin

Answer 62

Efinaconazole Ciclopirox Tavaborole

Answer 63

• 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

Answer 64

* 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

Answer 65

• 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

Answer 66

Amphotericin B

Answer 67

Aspergillosis