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1

Beta Lactams

Penicillins
Cephalosporins
Carbapenems
Monobactams
Beta-Lactamase Inhibitors

2

Penicillins (drugs)

Penicillin G (IV)
Penicillin V (PO)

3

Penicillin Coverage

Streptococcus
Syphilis

4

Aminopenicillins (drugs)

Amoxicillin
Ampicillin

5

Penicillin Pharm

Protein bound
low BV (poor diffusion) low CSF, brain, prostate, eye, etc. concentration
Little hepatic metabolism
Eliminated renally

6

Amoxicillin Spectrum

Strep, no staph, Enterococcus faecalis, no MRSA, no G-, Haemophilius influenzae (G-)

7

Ampicillin Spectrum

Strep, no staph, Enterococcus faecalis, Listeria, no G-, Haemophilius influenzae (G-)

8

Anti-staphylococcal Penicillins (drugs)

Methicillin
Nafcillin
Oxacillin
Dicloxacillin

9

Anti-staph penicillin coverage

Staph, strep, no Enterococcus, No MRSA, little G-

10

Extended Spectrum penicillins

Piperacillin
Ticarcillin

11

Extended Spectrum penicillin coverage

Streph, minimal staph, Enterococcus faecalis, No MRSA, G- coverage**, Pseudomonas, some anaerobes

12

Beta-lactamase inhibitors (drugs)

Amoxicillin/Clavulanate
Ampicillin/Sulbactam
Pipercillin/Tazobactam
Ticarcillin/Clavulanate

13

Amoxicillin/Clavulanate

Staph, strep, E. facealis, G-! Neisseria, E coli, Proteus, Morexella, Hemophilus influenzae, Klebsiella, and anaerobes

14

Amoxicillin/Clavulanate

Staph, strep, E. facealis, G-! Neisseria, E coli, Proteus, Morexella, Hemophilus influenzae, Klebsiella, and anaerobes

15

Ampicillin/Sulbactam

Similar to amoxicillin/clavulanate + acinetobacter

16

Piperacillin/Tazobactam

Beta-lactamase inhibitor
Staph. strep, E faecalis, no MRSA, broad G-***, pseudomonas, anaerobes

17

Ticarcillin/clavulanate

Same as pipercillin/tazobactam

18

Penicillin Tox

Mainly tolerable
*Allergies - anaphylaxis, urticaria, fever, swelling, hemolytic anemia, vasculitis
Penicillin: Seizures*
Nafcillin: Myelosuppression
Oxacillin: Hepatitis
*Large PO doses = GI tox

19

Beta-lactam Resistance Mech.

Altered PBPs, reduced permeability, Beta-lactamases

20

Type 1 Beta Lactamase

Cephalosporinase
Hydrolyzes: beta-lactamase inhibitor/beta-lactam combo drugs, penicillins, 1/2/3 gen cephalosporins, monobactams
Treatments: Imipenem, fluoroquinolones, and cefepime

21

Type II Beta Lactamase

Extended Spectrum Beta-lactamases
Hydrolyzes: cephalosporins (except cefoxitin, cefmetazole, and cefotetan), Aztreonam, Extended spectrum penicillins!, combo penicillins kind of work
Treatment: Carbapenems, Non-beta lactams, Cephamycins

22

Type III Beta Lactamases

Metallo-beta-lactamases
Hydrolyzes: Carbapenems!!, older penicillins, cefotaxime, ceftriaxone
Treatment: Piperacillin, ceftazidime, some combo penicillins

23

1st Gen cephalosporins

Cefazolin
cephalexin
Cefadroxil

24

1st Gen cephalo Spectrum

NO ENTERO, staph, strep, NO MRSA, G-: proteus, e coli, klebsiella

25

1st Gen cephalo Spectrum

NO ENTERO, staph, strep, NO MRSA, G-: proteus, e coli, klebsiella

26

2nd Gen Cephalosporins

Cefuroxime
Cefaclor
Cefprozil
Cefoxitin
Cefotetan
Cefmetazole
Cefimandole

27

2nd gen Cephalo spectrum

staph, strep, no entero, less G+ that 1st gen, no MRSA, G-: HENPEK

28

3rd gen Cephalosporins

Ceftriaxone
Ceftazidime*
Cefoperazone*
Cefixime
Cefdinir
Cefpodoxime
Ceftibuten
* Pseudomonas

29

3rd gen cephalos spectrum

Steph, strep, no entero, less than 1st or 2nd gen (G+), G-: HENPEK + Serratia, Citrobacter, Acinetobacter, Morganella, Providencia

30

4th generation Cephalosporin

Cefepime (broadest spectrum cephalo)

31

Cefepime

4th gen cephalo
Staph, Strep, no Entero, G-: broad G-, +pseudomonas

32

5th generation Cephalosporin

Ceftaroline

33

Ceftaroline

Staph, MRSA**, Strep, Entero (minimal)

34

Cephalosporin Tox

Mostly tolerated
Most common = allergy: anaphylaxis, urticaria, fever, swelling, etc.
Hemolytic anema, interstitial nephritis, vasculitis
Long term = myelosupression, large PO = GI tox
Cefotetan, Cefmetazole, and Cefimandole = antabuse reaction, platelet dysfunction (bleeding)

35

Carbapenem Pharm

All eliminated in the urine (Imipenem: brush border dihydropeptidase to inactive metabolite)
Some liver metabolism (meropenem and Doripenem)
Good CSF penetration with meropenem
Otherwise similar to penicillins

36

Carbapenems (drugs)

Imipenem/Cilastatin*
Meropenem*+
Doripenem*+
Ertapenem - no pseudomonas or entero
*Pseudomonas
+minimal E. Faecalis

37

Carbapenem spectrum

Staph, Strep, no MRSA, no E faecium, no VRE
G- = broad spectrum, + pseudomonas, anaerobes

38

Carbapenem Tox

mostly tolerable
Seizures (neurotox)
most common = allergy (anaphylaxis, urticaria, fever, swelling)

39

Aztreonam

Monobactam
metabolism via liver, and renal exclusion. CSF penetration.
No IgE mediated cross-reactivity with beta-lactams except Ceftazidime.

40

Aztreonam spectrum

Similar to aminoglycosides
No G+
Broad G- coverage, pseudomonas

41

Aztreonam Tox

No penicillin allergy reaction
Well tolerated
Hepatoxicity
Allergy non-related to penicillin allergy

42

Glycopeptides

Vancomycin
Teicoplanin

43

Vancomycin/Telavancin MOA

MOA: inhibits transglycosylases preventing peptidoglycan cross linking, disrupts cell membrane resulting in loss of membrane potential
Pharm: No PO, IV only. Poor penetration CSF, brain, eye, prostate, lung, etc. Almost 100% renal eliminated

44

Glycopeptide Spectrum

G+: Staph, MRSA! Strep, Entero, no VRE, Clostridium difficile
NO G-

45

Glycopeptide Spectrum

G+: Staph, MRSA! Strep, Entero, no VRE, Clostridium difficile
NO G-

46

Lipoglycopeptides

Telavancin
Dalbavancin

47

Glycopeptide Resistance

Alteration in peptidoglycan target

48

Glycopeptide TOX

Tissue irritation, infusion related rxn Collitis, Rare: nephrotoxicity, ototoxicity

49

Polymyxins (drugs)

Polymyxin B
Polymyxin E
Colistimethate (prodrug)

50

Polymyxins MOA

Cationic detergent disrupts PM

51

Polymyxins Pharm

No PO, Renally eliminated

52

Polymyxins Spectrum

Broad G-, no Proteus (slimey membrane)

53

Polymyxins Resistance

Cell wall alterations (Thickening), PM alterations (slimey), Cell envelope protection by PM.

54

Polymyxins TOX

Nephrotoxicity, Neurotoxicity

55

Cyclic lipopeptides

Daptomycin

56

Daptomycin

Cyclic lipopeptides
MOA: Ca dependent insertion into PM = K+ efflux resulting in loss of membrane potential.
Pharm: no PO, renal elimination

57

Daptomycin Spectrum

G+: MSSA, MRSA, Staph, Strep, Entero, VRE!!!
NO G-

58

Daptomycin resistance

Alteration to reduce binding to PM

59

Daptomycin TOX

Muscle tox - rare Rabhdomyolysis (monitor CDK)

60

Aminoglycosides MOA

Binds 30S ribosomal subunit and prevents binding of 50S, inhibiting initiation of coding or miscoding effecting translocation.

61

Aminoglycoside pharm

Hexose ring, streptidine - streptomycin
more active in alkaline environments
Post-antibiotic effect! (bacteriocidal even under MIC)
O2 dependent
No PO, hydrophilic, poor penetration: CSF, brain, eye, prostate, lung, etc.
Eliminated via urine

62

Aminoglycoside Agents

Streptomycin
Gentamicin
Tobramycin
Netilmicin
Amikacin
Spectinomycin

63

Aminoglycoside Spectrum

G+ = minimal staph, synergy with beta-lactams and vanco against strep, staph, and entero, synergy against listeria (thick CW no PM penetration to get to ribosome)
G-: broad coverage, pseudomonas
Atypical: Nocardia, tuberculosis, Neisseria

64

Aminoglycoside Resistance

Modifying enzyme inactivation, reduced permeability, altered ribosome to prevent binding
1,2,3 acetyltransferase
4 phosphotransferase
5 adenylyltransferase
*Amikacin is resistant to modification at 2, 3, 4, 5 (only susceptible at 1 and enzyme that modifies is less common)

65

Aminoglycoside TOX

Hypersensitivity (rare) - except topical neomycin
Nephrotoxicity
Ototoxicity - auditory and vestibular (balance loss)
At high dose: neuromuscular blockade

66

Tetracycline MOA

Binds to 30S ribosomal subunit with inhibits protein synthesis (similar to aminoglycosides)

67

Tetracycline pharm

well absorbed PO, short half-life, PM permeable, penetrate most tissues well

68

Tetracycline drugs

Tetracycline
Doxycycline
Minocycline
Demeclocycline

69

Tetracycline Spectrum

Strep, Staph, NO entero, Listeria, Neisseria, Moraxella, Hemophilus, Atypical: Legionella, mycoplasma, chlamydia, Rickettsia

70

Tigecycline

Glycylcycline
G+: Strep, Staph, Entero, VRE, Listeria
G-: broad coverage, except the 3 P's: Pseudomonas, Proteus, Providencia
Atypicals: Legionella, Mycoplasma, chlamydia, Rickettsia

71

Tetracycline Resistance

Altered permeability, Altered ribosomal binding, Enzymatic inactivation of tetracycline

72

Tetracycline TOX

rare hypersensitivity, GI tox, tetra teeth, bone deformities (kids), hepatoxicity, nephrotoxicity, photosensitivity, vestibular tox (NR), tissue injury (IV infusion)

73

Chloramphenicol

MOA: Different! Reversibly binds the 50S subunit of the 70S ribosome inhibiting protein synthesis
Pharm: absorbed PO, high levels orally lipophilic does not solublize well. Metabolized by liver, no renal. Penetrates CSF well

74

Chloramphenicol Spectrum

Broad G+, poor staph coverage, broad G- poor pseudomonas coverage, anaerobes, atypicals: rickettsia

75

Chloramphenicol Resistance

Alterations in PM permeability, Enzymatic inactivation of drug - chloramphenicol acetyltranferase

76

Chloramphenicol Tox

A LOT
GI, Hematologic**, myelosuppression, aplastic anemia (irreversible and idosyncratic)
Gray syndrome (neonates can not glucuronidate drug)
Optic neuritis: visual issues both reversible and irreversible.

77

Macrolides

MOA: lipophilic = good penetration but no IV formula
binds the 23S ribosomal subunit on 50S ribosome inhibiting protein synthesis
Pharm: water insoluble, Erythromicin is acid labile (unstable in stomach acid). Crosses BBB

78

Macrolides drugs

Erythromycin
Azithromycin
Clarithromycin
Dirithromycin

79

Macrolide spectrum

G+: strep, staph, no VRE, Listeria, some MRSA
G-: Morexella, Hemophilus
Atypical: mycoplasma, legionella, chlamydia, rickettsia, syphilis
Strep/staph: Clarithro>erythro>azithro

80

Macrolide Resistance

Alteration of the ribosome (methylation of RNA target)
Efflux pumps
Enzymatic inactivation of drug

81

Macrolide Tox

Hypersensitivity - uncommon
GI**
Hepatotoxicity = ^^ liver metabolites

82

Ketolides

Semi-synthetic 14-member macrolides
Increased stability to acid
Similar spectrum to macrolides
Similar macrolide tox - higher hepatotoxicity

83

Lincosamides

Clindamycin
MOA: bind the 50S subunit of the 70S ribosome inhibits protein synthesis

84

Clindamycin Pharm

Well absorbed PO, poor CSF/brain penetration, metabolized by the liver* (= hepatotox)

85

Clindamycin spectrum

G+: Strep, staph, no entero
Anaerobes

86

Clindamycin Resistance

Enzymatic inactivation of the drug
Alteration of the ribosome (mutation of receptor site or methylation of the ribosome to prevent drug binding)

87

Clindamycin Tox

Hypersensitivity (not adverse)
GI
Hepatotoxicity
myelosuppression (chronic use) neutropenia

88

Oxazolidinones

Linezolid

89

Linezolid

Oxazolidinone
MOA: inhibits protein synthesis by binding 23S subunit
Pharm: well absorbed PO, hepatic metabolism, almost 100% BA

90

Linezolid spectrum

MSSA, MRSA, coagulase (-) staph, strep, entero, VRE
NO G-

91

Linezolid Resistance

Mutation in 23S binding site

92

Linezolid Tox

myelosuppression (reversible), optic neuritis, peripheral neuropathy (Irreversible), lactic acidosis (mitochondrial tox)

93

Protein synthesis inhibitors

Aminoglycosides: Streptomycin, Gentamicin, Tobramycin, Netilmicin, Neomycin, Amikacin, Spectinomycin
Tetracyclines: Tetracycline, Doxycycline, Minocycline, Demeclocycline
Glycylcyclines: Tigecycline
Chloramphenicol
Macrolides: Erythromycin, Azithromycin, Clarithromycin, Dirithromycin
Ketolides
Lincosamides: Clindamycin
Oxazolidinones: Linezolid

94

30S binding - protein synth inhibitors

Aminoglycosides
Tetracyclines

95

50S binding - protein synth inhibitors

Chloramphenicol
Lincosamides

96

23S binding - protein synth inhibitors

Macrolides
ketolides
Oxazolidinones

97

23S binding - protein synth inhibitors

Macrolides
ketolides
Oxazolidinones

98

Sulfonamides

MOA: inhibit the conversion of PABA to dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase
Pharm: Well absorbed orally, highly lipophilic. Penetrates tissues well including brain and CSF
Acetylated and glucuronidated in the liver (increased water solubility) then excreted in urine

99

Sulfonamides drugs

Sulfacytine
Sulfisoxazole
Sulfamethizole
Sulfadiazine*
Sulfamethoxazole* (SMX)
Sulfapyridine
Sulfadoxine

100

Pyrimidines (Sulfonamides)

Trimethoprim

101

Trimethoprim (TMP)

Inhibits conversion from dihydrofolic acid to trihydrofolic acid via enzyme dihydrofolate reductase
Synergistic effect with sulfonamides -- they inhibit PABA conversion via different MOA

102

Sulfonamide Resistance

Altered enzymes
Overproduction of PABA (overcome inhibition)
Alteration in permeability

103

Sulfonamide TOX

Hypersensitivity (2nd most common)
Photosensitivity, Nephrotox: allergic nephritis, Precipitation in urine (hematuria, crystalluria, renal damage), anemia (hemolytic, aplastic), Kernicterus, GI, Hepatotox

104

TMP/SMX spectrum

G+: minimal strep, staph, some MRSA, Listeria, no Entero
G-: Nieserria, morexella, hemophilus, E coli, Klebsiella, Stenotrophomonas maltophilia, Yersinia, F tularensis, Brucella
Atypical: PCP, Nocardia
*Niche or uncommon pathogens

105

Trimethoprim resistance

Alterations in permeability, overproduction of dihydrofolate reductase, alterations in dihydrofolate reductase

106

TMP/SMX tox

Same as sulfonamide tox except more anemia, including megaloblastic

107

Fluoroquinolones

MOA: effects topoisomerase I and II, inhibit nicking and closing activity
Pharm: absorbed PO, absorption decreased when given with cations (Ca, Mg, Fe, Cu, etc)
penetrates well

108

Fluoroquinolones

MOA: effects topoisomerase I and II, inhibit nicking and closing activity
Pharm: absorbed PO, absorption decreased when given with cations (Ca, Mg, Fe, Cu, etc)
penetrates well

109

Fluoroquinolones (drugs)

Ciprofloxacin
Gatifloxacin
Gemifloxacin
Levofloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Lomefloxacin

110

Fluoroquinolones spectrum

G+: staph, strep, no entero (except Cipro)
G-: good coverage, +pseudomonas
Anaerobic in Gati and Moxi only
Atypical: mycoplasma, legionella, chlamydia, mycobacterium

111

Fluoroquinolone Resistance

Altered DNA gyrase target
Efflux pump or reduced PM permeability

112

Fluoroquinolone Tox

Hypersensitivity, GI, CNS tox (more in elderly), hepatox (uncommon), alterations in glucose (Gatifloxacin), QTc prolongation, tendon rupture (athletes), arthropathy

113

Sulfonamides drugs

Sulfacytine
Sulfisoxazole
Sulfamethizole
Sulfadiazine*
Sulfamethoxazole* (SMX)
Sulfapyridine
Sulfadoxine

114

Fluoroquinolones (drugs)

Ciprofloxacin
Gatifloxacin
Gemifloxacin
Levofloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Lomefloxacin

115

Nucleic Acid Inhibitors

Sulfonamides: Sulfacytine, Sulfisoxazole, Sulfamethizole, Sulfadiazine*, Sulfamethoxazole* (SMX), Sulfapyridine, Sulfadoxine
Trimethoprim
Fluoroquinolones: Ciprofloxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Lomefloxacin

116

Anti-Fungals

Polyenes: Amphotericin B, Nystatin (not systemic)
Flucytosine
Azoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole
Echinocandins: Capsofungin, Micafungin, Anidulafungin
Griseofulvin
Terbinafine
Tolnaftate
Saturated Solution of Potassium Iodide (SSKI)

117

Polyenes MOA

Bind ergosterol in fungal PM. A potassium channel is formed causing an efflux of K and loss of PM potential
Ergosterol is inhibited (PM instability)

118

Polyenes Pharm

Not absorbed well PO, and insoluble in water. Must be complexed in colloidal suspension with bile acid salt to make water soluble for IV use.
Hepatic and renal elimination
Penetrates tissues well, concentrates in liver, spleen and kidney
Long 1/2 life, once/day dose (can accumulate in bone)

119

Amphotericin B agents/spectrum

Liposomal and lipid complex Amph. B have decreases nephrotoxicity and side effects.
Spec: Candida (minus lusitaniae), Aspergillus, Histoplasma, Blastomyces, Coccidioides, Zygomycetes

120

Lipid Amphotericin B

Lower toxicity, but less evidence
*Used in patient that won't tolerate regular Amph-B, or those at high risk for adverse events (renal compromised patients!!)

121

Amph-B resistance

Impaired Ergosterol binding:
decreasing ergosterol in PM or altered ergosterol target

122

Amph-B tox

**Nephrotoxicity! (long term use)-- electrolyte wasting (K and Mg need to supplement) and bicarbonate wasting
Need to monitor renal fxn and electrolytes
Renal vasospasm: ischemia, decrease GFR and increased creatinine (duration and dose dependent, reversible)
Infusion reactions
Anemia

123

Nystatin

Polyene
Very high nephrotoxicity, only use PO and topical, not systemic

124

Flucytosine MOA

MOA: converted to 5-FU, and then FdUMP and FUTP which inhibit DNA and RNA synthesis respectively

125

Flucytosine Pharm

absorbed PO, renal elimination, penetrate tissue well CSF/brain

126

Flucytosine Spectrum

Cryptococcus neoformans
Candida (not often used)

127

Flucytosine Resistance

Can develop quickly-- often used with other anti-fungal drugs
Altered metabolism of flucytosine (must become triphosphorylated)

128

Azoles MOA

imidazoles have only 2 N groups, triazoles have 3 N groups
Imidazoles are less fungal selective and cause more tox
Triazoles are more selective with less tox
Azole work by inhibiting lanosterol 14-a-demethylase = decreases ergosterol synthesis
Decreased ergosterol = unstable PM
*decreases efficacy of Amph-B

129

Azole Pharm

Triazoles have greater affinity for fungal cells than mammalian cells = less tox
Drug intxns! - induction or inhibition of drug metabolism thru CYP450 enzymes

130

Azole drugs

Fluconazole
Itraconazole
Voriconazole
Posaconazole

131

Azole drugs

Fluconazole
Itraconazole
Voriconazole
Posaconazole

132

Fluconazole

Azole anti-fungal
IV and PO
Hepatic metabolism, renal elimination (only 10% is metabolites, 90% unchanged drug in kidney BAD, requires adjustment in renally compromised patients)
Penetrate CSF/tissues
USE: Dermatophytes, cryptococosis, candidiasis, coccidiodes
Tox: GI, hepatotox, alopecia*

133

Itraconazole

Azole anti-fungal
IV and PO *decreased oral absorption with increased stomach pH - don't use PPI's or antacids before use
metabolized in liver
good tissue/CSF penetration
USE: dermophytes, onychomycosis, blastomycosis, histoplasmosis
Tox: GI, Hepatotox, mineral corticoid excess*, negative inotropy* (low EF and heart fxn, can increase BP with fluids)

134

Voriconazole

Azole anti-fungal
IV and PO
Long 1/2 life
Metabolized hepatically
penetrate tissue/CSF well
USE: aspergillus, candidiasis, blastomycosis, histoplasmosis
TOX: GI, hepatotox, visual changes* (rule of 30s), photosensitivity*

135

Posaconazole

azole anti-fungal
PO only
liver metabolized
penetrates well
USE: "BAD molds": aspergillus, candidiasis, blastomycosis, histoplasmosis, zygomycectes
TOX: no significant, GI, and hepatotox

136

Posaconazole

azole anti-fungal
PO only
liver metabolized
penetrates well
USE: "BAD molds": aspergillus, candidiasis, blastomycosis, histoplasmosis, zygomycectes
TOX: no significant, GI, and hepatotox

137

Azole resistance

Increased efflux of azole
Over expression of lanosterol 14-a-demethylase (overcomes inhibition of ergosterol synthesis)
point mutation leading to decreases affinity of azoles for lanosterol

138

Echinocandin MOA

inhibit beta-glucan synthase preventing synthesis of beta-glucan resulting in weak cell wall and structural instability

139

Echinocandin pharm

Not absorbed orally, IV only (large cyclic peptides)
metabolized in situ
Hepatic metabolism (capsofungin and Micafungin)

140

Echinocandin Spectrum

Candidas and Aspergillus ONLY
minus C. parapsilosis due to high MIC required

141

Echinocandin Resistance

Mutation at Beta-(1,3)-glucan preventing synth inhibition
Up-regulation of chitin synthesis, makes up for beta-glucan loss.

142

Echinocandin Tox

Histamine release during infusion
hypersensitivity
hypokalemia
hepatotoxicity (increase ALT/AST with cyclosporines)

143

Echinocandin drugs

Capsofungin
Micafungin
Anidulafungin

144

Griseofulvin

anti-fungal
MOA: inhibits fungal mitosis by binding microtubules disrupting mitotic spindle
binds keratin precursor cells, preventing new nails from infection
Tox: GI, (not as used due to replacement therapy)

145

Terbinafine

Anti-fungal
MOA: Allylamine inhibits ergosterol synthesis (enzyme squalene epoxidase)
Topical and oral only
Use: skin/nail infections, athletes foot/ skin-skin infections
Tox: hepatitis, and hepatotoxicity

146

Tolnaftate

Anti-fungal
MOA: thiocarbamate, topical
USE: limited spectrum, Tinea infections
-don't need to know much

147

Saturated Solution of Potassium Iodide (SSKI)

Anti-fungal
Oral solution
TOX: nausea, bitter emesis, hypersalivation
USE: former treatment of Sporotrichosis (now itraconazole)

148

Anti-Herpes agents

Acyclovir
Valacyclovir
Famciclovir
Penciclovir
Docosanol
Trifluridine

149

Anti-herpes agents MOA

*Must be triphosporylated to work (to look like NTPs)
Acyclovir and Penciclovir require all 3 phosphorylations, first by virus-specific enzymes, thymidine kinase, (point of resistance) and the 2nd and 3rd phosphorylation are by mammalian enzymes
Trifluridine, cidofovir, and foscarnet already have 1st phosphate, so they can bypass the viral kinase step directly phophorylated by mammalian kinases.
After activation, drug is either directly bound to DNA polymerase to prevent replication or incorporated into DNA resulting in early termination.

150

Acyclovir

Anti-herpes
Acyclic guanosine derivative
HSV-1 HSV-2 and VZV
MOA: requires 3 phosphorylations, prevents or terminates DNA synthesis
IV and PO
Renal elimination, minimal hepatic
Penetrates most tissues

151

Acyclovir Resistance

Alteration of thymidine kinase
Alteration in DNA polymerase

152

Acyclovir TOX

GI
nephrotox - must be renally adjusted
Neurotox - tremors, delirium, seizures, AMS

153

Famciclovir

Anti-herpes
Prodrug of penciclovir
Hepatically metabolized
HSV-1 HSV-2 and VZV
MOA: requires 3 phosphorylation to inhibit DNA synthesis

154

Famciclovir Resistance

Alteration in thymidine Kinase

155

Famciclovir TOX

GI, less nephro- and neurotox
concentration dependent

156

Valacyclovir

Anti-herpes
Prodrug of acyclovir - hydrolyzed to acyclovir in liver/intestine
improved PO absorbance
Same resistance/tox as acyclovir

157

Penciclovir

Anti-herpes agent
Active metabolite of famciclovir
Topical only
treatment of oral herpes

158

Docosanol

Anti-herpes agent
USE: HSV-1 and HSV-2
MOA: inhibits fusion of PM and viral envelope
Topical
Tox: minimal

159

Trifluridine

Fluorinated pyrimidine nucleoside
Use: HSV-1, HSV-2, CMV
MOA: phosphorylated intracellularly by host enzymes, then competes with thymidine triphosphate for incorporation by viral DNA polymerase

160

Cytomegalovirus agents

Ganciclovir
Valganciclovir
Foscarnet
Cidofovir

161

Cytomegalovirus agents MOA

Same as anti-herpes agents
Ganciclovir needs all 3 phosphorylations, relies on protein kinase phosphotransferase (UL97).
Cidofovir and Foscarnet come with 1 phosphate group, do not rely on thimidine kinase and are directly phosphorylated by host enzymes

162

Ganciclovir

CMV agent
acyclic guanosine derivative
Use: CMV, HSV1, HSV2 and VZV
MOA: requires 3 phosphorylations to be active and inhibit DNA synthesis (protein kinase UL97)
IV and PO, poor oral absorption
Renally eliminated
Penetrates most tissues

163

Ganciclovir Resistance

Alterations in protein kinase (UL97)
Alteration in DNA polymerase (UL54)

164

Ganciclovir TOX

GI
myelosuppression - leukopenia
hepatotoxicity
Teratogenic**
Neurotox - (more without renal adjustment)

165

Valganciclovir

CMV agent
Ganciclovir plus valine group (improved BA)
acyclic guanosine derivative
USE: CMV, HSV1, HSV2, VZV
100x more active against CMV than acyclovir
MOA: Requires 3 phosphorylation steps to be active
1st phosphate group added by protein kinase phosphotransferase UL97
Only PO renally eliminated
Penetrates most tissue - no CNS

166

Valganciclovir Resistance

Alteration of UL97
Alteration in DNA polymerase (UL54)

167

Valganciclovir TOX

GI
Myelosuppression
hepatotox
teratogenic
neurotox
Same as ganciclocvir

168

Foscarnet

CMV agent
MOA: does not require viral enzyme for 1st phosphorylation, inhibits DNA polymerase, RNA polymerase, HIV reverse transcriptase
Use: HSV1, HSV2, VZV, CMV, EBV, HIV-1
IV only
penetrate +CNS
Renal elimination

169

Foscarnet Resistance

Point mutation in DNA polymerase and HIV reverse transcriptase

170

Foscarnet Tox

Nephrotox - serum creatinine and must monitor electrolytes
Electrolyte disturbances
GI
Hepatotox
CNS
Infusion arrhythmias, numbness, tingling

171

Cidofovir

CMV agent
HIGHLY NEPHROTOXIC
acyclic cytosine analog
MOA: does not require first phosphorylation, independent of protein kinase. Inhibits DNA polymerase, or incorporated into DNA.
Use: CMV, HSV1, HSV2, VZV, EBV, polyomavirus
Poor CNS penetration
Renally eliminated

172

Cidofovir Resistance

Point mutation in DNA polymerase (no UL97)
*Cidofovir resistance isolates are usually also resistant to ganciclovir, but susceptible to foscarnet
Cidofovir resistance predicts foscarnet resistance but not the other way around!

173

Cidofovir Tox

Nephrotox!!
Ocular tox
neutropenia
Mutagenic, gonadotoxic, and embryotoxic (infertility)

174

NRTI drugs

HIV agents
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine

175

NNRTI drugs

HIV agents
Nevirapine
Delavirdine
Efavirenz
Etravirine
Rilpivirine

176

NRTIs

Looks like nucleoside/nucleotides
Need to be triphosphorylated to be active
Same as guanaline analogs
= early termination or direct inhibition of enzymes

177

NRTIs

Looks like nucleoside/nucleotides
Need to be triphosphorylated to be active
Same as guanaline analogs
= early termination or direct inhibition of enzymes
MOA: competitive inhibition of HIV-1 reverse transcriptase, incorporation into growing viral DNA chain = termination
Hepatic and renal elimination

178

NRTIs TOX

Mitochondrial tox (inhibits mitochondrial DNA polymerase gamma), lactic acidosis, hepatotoxicity

179

NNRTIs

Bind directly to HIV-1 reverse transcriptase, DO NOT require phosphorylation
Hepatically metabolized

180

NNRTI tox

GI, skin rash
Liver enzyme induced drug interactions! CYP450

181

Protease Inhibitors

Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir/ritonavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir

182

Protease Inhibitor MOA

Prevents post-translational cleavage of the Gag-Pol polyprotein = prevents processing of viral proteins into functional conformations, or results in production of immature/non-infectious particles
Do not require intracellular activation
Hepatic metabolism

183

Protease Inhibitor Tox

Redistribution of body fat - peripheral and facial fat wasting, central obesity, buffalo hump, breast enlargement
Hyperlipidemia
Hyperglycemia, diabetes
Osteoporosis
Live enzyme drug interactions, CYP450

184

Entry inhibitors

HIV agent
CCR5 Antagonist: Maraviroc
Fusion inhibitor: Enfuvirtide

185

Maraviroc MOA

Binds CCR5 entry of CCR5 tropic HIV
Co-receptors are necessary for the entrance of HIV into CD4 cells: CCR5 CXCR4
HIV has 2 receptors, one of each, or both or one or the other
**Only active against CCR5 + CCR5 HIV
Hepatically metabolized
Not 1st line, only for resistance HIV with CCR5/CCR5 receptors

186

Maraviroc Resistance

Mutation in CCR5 receptor
Presence of non-CCR5 tropic HIV

187

Maraviroc TOX

Cough
Respiratory problems
Muscle/joint pain
Diarrhea
Sleep disturbances**
Hepatotox

188

Enfuvirtide

MOA: inhibits HIV entry into cell by binding gp41
metabolized via proteolytic hydrolysis
Resistance: mutations in gp41 codon, no cross-resistance
TOX: injection site reactions, hypersensitivity

189

Intergrase Inhibitor

Raltegravir
Dolutegravir
Elvitegravir

190

Intergrase Inhibitors

HIV agents
Pyrimidinone analog
MOA: binds intergrase which inhibits strand transfer thus interfering with integration of reverse transcribed viral DNA into the chromosome of the host cell
Drug is glucuronidated, liver metabolism but not CYP450.
Glucuronidated = increased water solubility.

191

Intergrase Inhibitors

HIV agents
Pyrimidinone analog
MOA: binds intergrase which inhibits strand transfer thus interfering with integration of reverse transcribed viral DNA into the chromosome of the host cell
Drug is glucuronidated, liver metabolism but not CYP450.
Glucuronidated = increased water solubility.

192

Intergrase Inhibitors Resistance

Mutations in intergrase

193

Intergrase Inhibitors Resistance

Mutations in intergrase

194

1st line Anti-mycobacterials

Isoniazid
Rifampin
Ethambutol
Pyrazinamide
Streptomycin

195

2nd line Anti-mycobacterials

Amikacin
Aminosalicylic Acid
Capreomycin
Ciprofloxacin
Clofazamine
Cycloserine
Ethionamide
Levofloxacin
Rifabutin
Rifapentine

196

Isoniazid

Anti-mycobacterial
Prodrug
MOA: most active against M tuberculosis. Inhibits the synthesis of mycolic acid
Bactericidal
Hepatically metabolized

197

Isoniazid Resistance

Point mutations in katG (low level - effective at higher doses)
Large mutation or deletion in katG (high level - no efficacy)
Mutations in inhA (low level resistance)

198

Isoniazid Toxicity

Hepatotox** significant drug interactions, minor increases in liver enzymes, hepatitis/liver failure
Neurotox - peripheral neuropathy due to clearance of pyridoxine (usually supplemented)
Hypersensitivity rxn

199

Isoniazid OD

Large doses = metabolic acidosis, hyperglycemia, Seizures**, coma**

200

Rifampin

Anti-mycobacterial
MOA: binds to beta subunit of bacterial DNA dependent RNA polymerase and inhibits RNA synthesis
Bactericidal
Penetrates tissues
Hepatically metabolized

201

Rifampin Resistance

Mutations in rpoB - gene for beta subunit of RNA polymerase.

202

Rifampin TOX

Hepatotox - hepatitis, drug interactions*, failure (fatal)
Nephrotox - nephritis, acute tubular necrosis (rare)
Hypersensitivity
Orange body fluid discoloration
Flu-like symptoms - more common with high dose/intermittent therapy

203

Ethambutol

Anti-mycobacterial
MOA: inhibits arabinosyl transferase enzyme involved in arabinogalactan biosynthesis within cell wall, = instability
*bacteriostatic
Hepatically metabolized

204

Ethambutol Resistance

The embCAB operon codes for synthesis of arabinogalactan and lipoarabinogalactan (overcomes inhibition of enzymes)
Mutations in emb = loss of ethambutol activity

205

Ethambutol TOX

Optic Neuritis (larger doses)
Hypersensitivity rxn

206

Pyrazinamide

Anti-microbacterial
MOA: synthetic analog of nicotinamide. prodrug- must be converted to pyrazanoic acid to be active. MOA unknown
Bactericidal
Hepatically metabolized

207

Pyrazinamide Resistance

Mutations in pncA (codes for pyrazinamidase) = decreased activation of pyrazinamide into pyrazanoic acid = decreased concentration)

208

Pyrazinamide TOX

Hepatotox
N/V
Polyarthalgias* (joint pain)
Nephrotoxicity
Hypersensitivity
Urate retention (exacerbates gout)
Photosensitivity