Antimicrobials Flashcards
1
Q
Sulfonamides: Examples
A
Sulfadiazine
Sulfamethoxazole (SMX)
Sulfisoxazole
2
Q
Target: DNA topoisomerases
A
Fluoroquinolones
3
Q
Fluoroquinolones: Examples
A
Ciprofloxacin
Levofloxacin
4
Q
Target: Damages DNA
A
Metronidazole
5
Q
Target: mRNA synthesis (RNA polymerase)
A
Rifampin
6
Q
Target: Protein Synthesis (50S subunit)
A
Chloramphenicol
Clindamycin
Linezolid
Macrolides
Stretogramins
7
Q
Macrolides: Examples
A
Azithromycin
Clarithromycin
Erythromycin
8
Q
Streptogramins: Examples
A
Dalfopristin
Quinupristin
9
Q
Target: Protein synthesis (30S subunit)
A
Aminoglycosides
Tetracyclines
10
Q
Aminoglycosides: Examples
A
Amikacin
Gentamicin
Neomycin
Streptomycin
Tobramycin
‘“Mean” (aminoglycosides) GNATS caNNOT kill anaerobes.’
11
Q
Tetracyclines: Examples
A
Doxycycline
Minocycline
Tetracycline
12
Q
Target: Peptidoglycan cross-linking (cell wall synthesis)
A
Penicillinase-sensitive penicillins
Penicillinase-resistant penicillins
Antipseudomonals
Cephalosporins
Carbepenems
Monobactams
13
Q
Penicillinase-sensitive penicillins: Examples
A
Amoxicillin
Ampicillin
Penicillin G, V
14
Q
Penicillinase-resistant penicillins: Examples
A
Dicloxacillin
Nafcillin
Oxacillin
15
Q
Antipseudomonals: Examples
A
Piperacillin
Ticarcillin
16
Q
1st generation cephalosporins: Examples
A
Cefazolin
Cephalexin
17
Q
2nd generation Cephalosporin: Examples
A
Cefoxitin
Cefaclor
Cefuroxime
18
Q
3rd generation cephalosporin: Examples
A
Ceftriaxone
Cefotaxime
Ceftazidime
19
Q
4th generation Cephalosporin: Examples
A
Cefepime
20
Q
5th generation cephalosporin: Example
A
Ceftaroline
21
Q
Carbapenems: Examples
A
Doripenem
Ertapenem
Imipenem
Meropenem
22
Q
Monobactams: Examples
A
Aztreonam
23
Q
Penicillin G, V: routes of administration
A
Penicillin G (IV and IM)
Penicillin V (oral)
24
Q
Penicillin G, V: Mechanism
A
Bind penicillin-binding proteins (transpeptidases).
Block transpeptidase cross-linking of peptidoglycan in cell wall.
Activate autolytic enzymes.
25
Penicillin G, V: Clinical Use
Mostly used for **gram-positive organisms** (*S. pneumoniae, S. pyogenes, Actinomyces*).
Also used for **gram-negative cocci** (mainly *N. meningitis*) and spirochetes (namely *T. pallidum*).
Bactericidal
Penicillinase sensitive.
26
Penicillin G, V: Toxicity
Hypersensitivity reactions
Hemolytic anemia
27
Penicillin G, V: Resistance
Penicillinase in bacteria (a type of beta-lactamase) cleaves beta-lactam ring.
28
Amoxicillin, ampicillin: Mechanism
Same as penicillin.
Wider spectrum; penicillinase sensitive.
Also combine with clavulonic acid to protect against destruction by beta-lactamase.
29
Amoxicillin, ampicillin: Clinical use
Extended spectrum penicillin: *H. influenzae*, *H. pylori*, *E. coli*, *Listeria monocytogenes*, *Proteus mirabilis*, *Salmonella*, *Shigella*, *enterococci*
Ampicillin/amoxicillin HHELPSS kill enterococci.
30
Amoxicillin, ampicillin: Toxicity
Hypersensitivity reactions;
Rash
Pseudomembranous colitis
31
Amoxicillin, ampicillin: Mechanism of resistance
Penicillinase in bacteria (a type of beta-lactamase) cleaves beta-lactam ring.
32
Penicillinase-resistance penicillins: Mechanism
Same as penicillin
Narrow spectrum;
penicillinase resistant because bulky R group blocks access of beta-lactamase to beta-lactam ring.
33
Penicillinase-resistant penicillins: Clinical Use
*Staph aureus* (except MRSA; resistant because of altered penicillin-binding protein target site).
"Use naf (nafcillin) for staph"
34
Penicillinase-resistant penicillins: Toxicity
Hypersensitivity reactions
Intersitital nephritis
35
Antipseudomonals: Mechanism
Same as penicillin.
Extended spectrum.
36
Antipseudomonals: Clinical use
*Pseudomonas spp*. and gram-negative rods;
susceptible to penicillinase;
use with beta-lactam inhibitors.
37
Antipseudomonals: toxicity
Hypersensitivity reactions
38
Beta lactamase inhibitors: Examples
Clavulonic Acid,
Sulbactam,
Tazobactam.
(CAST).
Often added to penicillin antibiotics to protect the antibiotic from destruction by beta-lactamase.
39
Cephalosporins (I-V): Mechanism
Beta-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases.
Bactericidal
Organisms typically not covered by cephalosporins are LAME: Lysteria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci.
Exception: ceftaroline covers MRSA
40
1st generation Cephalosporins: Clinical Use
Gram-positive cocci
* Proteus mirabilis*
* E. coli*
* Klebsiella pneumoniae* (PEcK)
Cefazolin used prior to surgery to prevent *S. aureus* wound infections.
41
2nd generation cephalosporins: Clinical Use
Gram positive cocci
* Haemophilus influenzae*
* Enterobacter aerogenes*
* Neisseria spp.*
* Proteus mirabilis*
* E. coli*
* Klebsiella pneumoniae*
* Serratia marcescens*
HEN PEcKS
42
3rd generation Cephalosporins: Clinical use
Serious gram-negative infections resistant to other beta-lactams
**Ceftriaxone**: meningitis, gonorrhea, disseminated Lyme disease
**Ceftazidime**: Pseudomonas
43
4th generation Cephalosporins: Clinical use
Gram negative organisms,
with increased activity against Pseudomonas and gram-positive organisms.
44
5th generation Cephalosporin: Clinical use
Broad gram-positive and gram-negative organism coverage, including MRSA;
does not cover Pseudomonas
45
Cephalosporins (generations I-V): toxicity
Hypersensitivity reactions
Autoimmune hemolytic anemia
Disulfiram-like reaction
Vitamin K deficiency
Exhibit cross-reactivity with penicillins
Increase nephrotoxicity of aminoglycosides
46
Cephalosporins (generations I-V): Mechanism of Resistance
Structure change in penicillin-binding proteins (transpeptidases)
47
Carbapenems: Mechanism
Imipenem is a **broad-spectrum**, **beta-lactamase-resistant carbapenem**. Always administered with cilastatin (inhibitor of renal dehydropeptidase I) to decrease inactivation of drug in renal tubules. With imipenem, "the kill is lastin' with cilastatin."
Ertapenem has limited Pseudomonas coverage
48
Carbapenems: Clinical use
Gram-positive cocci, gram negative rods, and anaerobes.
Wide spectrum, but significant side effects limit use to life-threatening infections or after other drugs have failed.
Meropenem has a decreased risk of seizures and is stable to dehydropeptidase I.
49
Carbepenems: Toxicity
GI distress
Skin rash
CNS toxicity (seizures) at high plasma levels
50
Monobactams (Aztreonam): Mechanism
Less susceptible to beta-lactamases.
Prevents peptidoglycan cross-linking by binding to penicillin-binding protein
Synergistic with aminoglycosides.
No cross-allergenicity with penicillins.
51
Monobactams (Aztreonam): Clinical Use
Gram-negative rods only -- no activity against gram-positives or anaerobes.
For penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides.
52
Monobactams (Aztreonam): Toxicity
Usually nontoxic;
occasional GI upset
53
Vancomycin: Mechanism
Inhibits cell wall peptidoglycan formation by binding D-ala D-ala portion of cell wall precursors.
Bactericidal.
Not susceptible to beta-lactamases.
54
Vancomycin: Clinical Use
Gram-positive bugs only -- serious, multidrug-resistant organisms, including MRSA, *S. epidermidis*, sensitive *Enteroccocus* species, and *Clostridium difficile* (oral dose for pseudomembranous colitis).
55
Vancomycin: Toxicity
Well tolerated in general -- but NOT trouble free.
Nephrotoxicity,
Ototoxicity,
Thrombophlebitis,
diffuse flushing -- red man syndrome (can largely prevent by pretreatment with antihistamines and slow infusion rate).
56
Vancomycin: Mechanism of resistance
Occurs in bacteria via amino acid modification of D-ala D-ala to D-ala D-lac.
"Pay back 2 D-Dalas (dollars) for vandalizing (vancomycin)."
57
Protein synthesis inhibitors: 30S inhibitors
A = Aminoglycosides (bactericidal)
T = Tetracylcines (bacteriostatic)
"Buy AT 30, CCEL (sell) at 50."
58
Protein synthesis inhibitors: 50S inhibitors
C = Chloramphenicol, Clindamycin (bacteriostatic)
E = Erythromycin (macrolides) (bacteriostatic)
L = Linezolid (variable)
"Buy AT 30, CCEL (sell) at 50."
59
Aminoglycosides: Mechanism
Bactericidal;
irreversible inhibition of initiation complex through binding of the 30S subunit.
Can cause misreading of mRNA.
Also block translocation.
Require O2 for uptake;
therefore ineffective against anaerobes.
"Mean" (aminoglycosides) GNATS caNNOT kill anaerobes.
60
Aminoglycosides: Clinical use
Severe gram-negative rod infections.
Synergistic with beta-lactam antibiotics.
Neomycin for bowel surgery.
61
Aminoglycosides: Toxicity
Nephrotoxicity,
Neuromuscular blockade,
Ototoxicity (especially when used with loop diuretics).
Teratogen
'"Mean" (aminoglycoside) GNATS caNNOT kill anaerobes.'
62
Aminoglycosides: Mechanisms of Resistance
**Bacterial transferase enyzmes** inactivate the drug by **acetylation**, **phosphorylation**, or **adenylation**.
63
Tetracyclines: Mechanism
Bacteriostatic;
Bind to 30S and prevent attachment of aminoacyl-tRNA
Limited CNS penetration.
**Doxycycline is fecally eliminated and can be used in patients with renal failure**.
Do not take tetracyclines with milk (Ca2+), antacids (Ca2+ or Mg2+), or iron-containing preparations because divalent cations inhibit drugs' absorption in the gut.
64
Tetracyclines: Clinical Use
*Borrelia burgdorferi*, *M. pneumoniae*.
Drugs' ability to accumulate intracellularly makes them very effective against *Rickettsia* and *Chlamydia*. Also used to treat acne.
65
Tetracyclines: Toxicity
GI distress
Discoloration of teeth and inhibition of bond growth in children
Photosensitivity
Contraindicated in pregnancy
66
Tetracyclines: Mechanism of Resistance
Decreased uptake or increased efflux out of bacterial cells by plasmid-encoded transport pumps.
67
Folic acid synthesis (DNA methylation)
Sulfonamides
Trimethoprim
68
Chloramphenicol: Mechanism
Blocks peptidyltransferase at 50S ribosomal subunit.
Bacteriostatic
69
Chloramphenicol: Clinical use
Meningitis: H*aemophilis influenza, Neisseria meningitis, Streptococcus pneumoniae*)
Rocky Mountain spotted fever (*Rickettsia rickettsii*)
Limited use owing to toxicities but often still used in developing countries because of low cost
70
Chloramphenicol: Toxicity
Anemia (dose dependent),
aplastic anemia (dose independent),
gray baby syndrome (in premature infants becaue they lack liver UDP-glucuronyl transferase)
71
Chloramphenicol: Mechanism of resistance
Plasmid-encoded **acetyltransferase** inactivates the drug
72
Clindamycin: Mechanism
Blocks peptide transfer (translocation) at 50S ribosomal subunit.
Bacteriostatic
73
Clindamycin: Clinical Use
Anaerobic infects (e.g., *Bacteroids spp*., *Clostridium perfringens*) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection.
Treats anaerobic infections **above** the diaphragm vs. metronidazole (anaerobic infections **below** diaphragm)
74
Clindamycin: Toxicity
Pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea
75
Linezolid (Oxazolidinones): Mechanism
Inhibit protein synthesis by binding to 50S subunit and preventing formation of the initiation complex.
76
Linezolid (Oxazolidinone): Clinical Use
Gram-positive species including MRSA and VRE
77
Linezolid: Toxicity
Bone marrow suppression (especially thrombocytopenia),
peripheral neuropathy,
**serotonin syndrome**
78
Linezolid: Mechanism of Resistance:
Point mutation of ribosomal RNA
79
Macrolides: Mechanism
Inhibit protein synthesis by blocking translocation ("macro**slides**"); bind to the **23S rTNA** of the **50S** ribosomal subunit.
Bacteriostatic
80
Macrolides: Clinical Use
Atypical pneumonias (*Mycoplasma, Chlamydia, Legionella*),
STIs (*Chlamydia*),
gram-positive cocci (streptococcal infections in patients allergic to penicillin), and
*B. pertussis*
81
Macrolides: Toxicity
MACRO:
Gastrointestinal **M**otility issues,
**A**rrhythmia caused by prlonged QT interval, acute **C**holestatic hepatitis, **R**ash, e**O**sinophilia.
Increases serum concentration of theophylines, oral anticoagulants.
**Clarithromycin** and **erythromycin** inhibit **cytochrome P-450**
82
Macrolides: Mechanism of Resistance
Methylation of 23S rRNA-binding site prevents binding of drug
83
Trimethoprim: Mechanism
Inhibits bacterial dihydrofolate reductase
Bacteriostatic
84
Trimethoprim: Clinical Use
Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMP-SMX]), causing sequential block of folate synthesis.
Combination used for UTIs, *Shigella*, *Salmonella*, *Pneumocystis jirovecii* pneumonia treatment and prophylaxis, toxoplasmosis prophylaxis.
85
Trimethoprim: Toxicity
Megaloblastic anemia, leukopenia, granulocytopenia.
(May elleviate with supplemental folinic acid).
**TMP** **T**reats **M**arrow **P**oorly
86
Sulfonamides: Mechanism
Inhibit folate synthesis. Para-aminobenzoic acid (PABA) antimetabolites inhibit dihydropteroate synthase. Bacteriostatic (bactericidal when combined with trimethoprim).
(Dapsone, used to treat lepromatous leprosy, is a closely related drug that also inhibits folate synthesis).
87
Sulfonamides: Clinical Use
Gram-positives, gram-negatives, *Nocardia*, *Chlamydia*.
Triple sulfas or SMX for simple UTI.
88
Sulfonamides: Toxicity
Hypersensitivity reactions,
hemolysis if G6PD deficient,
nephrotoxicity (tubulointerstital nephritis),
photosensitivity,
kernicterus in infants,
displace other drugs from albumin (e.g., warfarin).
89
Sulfonamides: Mechanism of Resistance
Altered enzyme (bacterial dihydropteroate synthase),
decreased uptake, or
increased PABA synthesis.
90
Fluoroquinolones: Mechanism
Inhibit prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV.
Bactericidal
Must not be taken with antacids
91
Fluoroquinolones: Clinical Use
Gram-negative rods of urinary and GI tracts (including *Pseudomonas*), *Neisseria*, some gram-positive organisms.
92
Fluoroquinolones: Toxicity
GI upset, superinfections, skin rashes, headache, dizziness.
Less commonly, can cause leg cramps and myalgias.
Contraindicated in pregnant women, nursing mothers, and children \<18 years old due to possile damage to cartilage. Some may prolong QT interval. May cause tendonitis or tendon rupture in people \>60 years old and in patients taking prednisone.
Fluoroquino**lones** hurt attachments to your **bones**.
93
Fluoroquinolones: Mechanism of Resistance
Chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps.
94
Daptomycin: Mechanism
Lipopetide that disrupts cell membrane of gram-positive coci.
95
Daptomycin: Clinical use
S. aureus skin infections (especially MRSA), bacteremia, endocarditis, VRE
Not used for pneumonia (avidly binds to and is inactivated by surfactant).
96
Daptomycin toxicity
Myopathy, rhabdomyolysis
97
Metronidazole: Mechanism
Forms toxic free radical metabolites in the bacterial cell that damage DNA.
Bactericidal
Antiprotozoal
98
Metronidazole: Clinical Use
Treats ***G**iardia*, ***E**ntamoeba*, ***T**richomonas*, ***G**ardnerella vaginialis*, **A**naerobes (*Bacteroides*, *C. difficile*).
Use with a proton pump inhibit and clarithromycin for "triple therapy" against *H. **P**ylori*.
**GET** **GAP** on the **Metro** with **metro**nidazole! Treats anaerobic infection **below** the diaphragm vs. clindamycin (anaerobic infections **above** diaphragm).
99
Metronidazole Toxicity
Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alchohol; headache, metallic taste
100
Treatment and prophylaxis for
## Footnote
*Mycobacterium tuberculosis*
**Prophylaxis**: Isoniazid
**Treatment**: **R**ifampin, **I**soniazid, **P**yrazinamide, **E**thambutol (**RIPE** for treatment)
101
Treatment and prophylaxis for
## Footnote
*Mycobacterium avium - intracellulare*
**Prophylaxis**: Azithromycin, rifabutin
**Treatment**: *M. avium-intracellulare* is more drug resistant than M*. tuberculosis*. Azithromycin or clarithromycin + ethambutol. Can add rifabutin or ciprofloxacin.
102
Treatment and prophylaxis for
## Footnote
*Mycobacterium leprae*
Prophylaxis: N/A
Treatment: Long-term treatment with dapsone and rifampin for tuberculoid form. Add clofazimine for lepromatous form.
103
Rifamycins: Examples
Rifampin
Rifabutin
104
Rifamycin: mechanism
Inhibits DNA-dependent RNA polymerase
**Rifampin's 4 R's:**
**R**NA polymerase inhibitor
**R**amps up microsomal cytochrome P-450
**R**ed/orange body fluids
**R**apid resistance if used alone
**R**if**amp**in **ramp**s up cytochrome P-450, **but** rifa**but**in does not.
105
Rifamycins clinical use
| (Rifampin, rifabutin)
Mycobacterium tuberculosis; delay resistance to dapsone when used for leprosy.
Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with *Haemophilus influenzae* type B.
106
Rifamycins: Toxicity
| (Rifampin, rifabutin)
Minor hepatotoxicity and drug interactions (increase cytochrome P-450); orange body fluids.
Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation.
107
Rifamycins: Mechanism of resistance
| (Rifampin, rifabutin)
Mutations reduce drug binding to RNA polymerase. Monotherapy rapidly leads to resistance.
108
Isoniazid: Mechanism
Decrease synthesis of mycolic acids
Bacterial catalase-peroxidase (encoded by KatG) needed to convert INH to active metabolite.
109
Isoniazid: Clinical Use
*Mycobacterium tuberculosis*
The only agent used as solo prophylaxis against TB.
Different INH half-lives in fast versus slow acetylators.
110
Isoniazid: Toxicity
Neurotoxicity, hepatotoxicity.
Pyridoxine (vitamine B6) can prevent neurotoxicity
**INH** **I**njures **N**eurons and **H**epatocytes
111
Isoniazid: Mechanism of Resistance
Mutations leading to underexpression of KatG (bacterial catalase-peroxidase needed to convert INH to active metabolite).
112
Pyrazinamide: Mechanism
Mechanism Uncertain
Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid.
113
Pyrazinamide: Clinical Use
*Mycobacterium tuberculosis*
114
Pyrazinamide: Toxicity
Hyperuricemia
Hepatotoxicity
115
Ethambutol: Mechanism
Decrease carbohydrate polymerization of mycobacterium cell wall by blcoking arabinosyltransferase
116
Ethambutol: Clinical Use
*Mycobacterium tuberculosis*
117
Ethambutol: Toxicity
Optic neuropathy (red-green color blindness). Pronounce "eyethambutol")
118
Antimicrobial prophylaxis:
High risk for endocarditis and undergoing surgical or dental procedures
Amoxicillin
119
Antimicrobial prophylaxis:
Exposure to gonorrhea
Ceftriaxone
120
Antimicrobial prophylaxis:
History of recurrent UTIs
TMP-SMX
121
Antimicrobial prophylaxis: Exposure to meningococcal infection
Ceftriaxone, ciprofloxacin, or rifampin
122
Antimicrobial prophylaxis:
Pregnant woman carrying group B strep
Penicillin G
123
Antimicrobial prophylaxis:
Prevention of gonococcal conjunctivitis in newborn
Erythromycin ointment
124
Antimicrobial prophylaxis:
Prevention of postsurgical infection due to *S. aureus*
Cefazolin
125
Antimicrobial prophylaxis:
Prophylaxis of strep pharyngitis in child with prior rheumatic fever
Banzathine penicillin G or oral penicillin G
126
Antimicrobial prophylaxis:
Exposure to syphilis
Benzathine penicillin G
127
Prophylaxis in HIV patients:
CD4 \< 200 cells/mm3
Prophylaxis: TMP-SMX
Infection: *Pneumocystis* pneumonia
128
Prophylaxis in HIV patients:
CD4 \< 100 cells/mm3
Prophylaxis: TMP-SMX
Infection: *Pneumocystis* pneumonia and toxoplasmosis
129
Prophylaxis in HIV patients:
CD4 \< 50 cells/mm3
Prophylaxis: Azithromycin or clarithromycin
Infection: *Mycobacterium avium* complex
130
Treatment of MRSA
Vancomycin
Daptomycin
Linezolid
Tigecycline
Ceftaroline
131
Treatment of VRE
Linezolid and streptogramins (quinupristin, dalfopristin)
132
Treatment for multidrug-resistant *Pseudomonas aeruginosa*
Polymixins B and E (colistin)
133
Treatment for multidrug-resistant *Acinetobacter baumannii*
Polymixins B and E (colistin)
134
Amphotericin B: Mechanism
Binds ergasterol (unique to fungi); forms membrane pores that allow leakage of electrolytes
Ampho**ter**icin "**tear**s" holes in the fungal membrane by forming pores.
135
Amphotericin B: Clinical Use
Serious, systemic mycoses
*Cryptococcus* (amphotericin B with/without flucytosine for cryptococcal meningitis), *Blastomyces*, *Coccidioides*, *Histoplasma*, *Candida*, *Mucor*.
Intrathecally for fungal meningitis.
Supplement K+ and Mg2+ becaues of altered renal tubule permeability.
136
Amphotericin B: Toxicity
Fever/chills ("shake and bake"), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis ("**amphoterri**ble").
Hydration decreases nephrotoxicity.
Liposomal amphotericin decreases toxicity.
137
Nystatin: Mechanism
Same as amphotericin B. **Topical use only** as too toxic for systemic use.
Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes.
138
Nystatin: Clinical Use
"Swish and swallow" for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis.
139
Flucytosine: Mechanism
Anti-fungal
Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase
140
Flucytosin: Clinical Use
Systemic funal infections (especially meningitis caused by *Cryptococcus*) in combination with amphotericin B.
141
Flucytosine: Toxicity
Bone marrow suppression
142
Azoles: Examples
(Anti-fungals)
Clotrimazole
Fluconazole
Itraconazole
Ketoconazole
Miconazole
Voriconazole
143
Azoles: Mechanism
Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol.
144
Azoles: Clinical Use
Local and less serious systemic mycoses. **Fluconazole** for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infection sof all types.
**Itraconazole** for *Blastomyces*, *Coccidioides*, *Histoplasma*.
**Clotrimazole** and **miconazole** for topical fungal infections.
145
Azoles: Toxicity
Testosterone synthesis inhibition (gynecomastia, especially with **ketoconazole**),
liver dysfunction (inhibits cytochrome P-450)
146
Terbinafine: Mechanism
Inhibits the fungal enzyme **squalene epoxidase**
147
Terbinafine: Mechanism
Dermatophytoses (especially onchymomycosis--fungal infection of the finger or toe nails).
148
Terbinafine: Toxicity
GI upset, headaches, hepatotoxicity, taste disturbance
149
Echinocandins: Examples
Anidulafungin
Caspofungin
Micafungin
150
Echinocandins: Mechanism
Inhibit cell wall synthesis by inhibiting synthesis of **beta-glucan**
151
Echinocandins: Clinical Use
Invasive aspergillosis, *Candida*
152
Echinocandins: Toxicity
GI upset,
flushing (by histamine release)
153
Griseofulvin: Mechanism
Anti-fungal
Interferes with microtubule function; disrupts mitosis
Deposits in keratin-containing tissues (e.g., nails)
154
Griseofulvin: Clinical Use
Anti-fungal
Oral treatment of superficial infections;
Inhibits growth of dermatophytes (tinea, ringworm)
155
Griseofulvin: Toxicity
Teratogenic
Carcinogenic
Confusion
Headaches
Increased cytochrome P-450 and warfarin metabolism
156
Treatment for **toxoplasmosis**
Pyrimethamine
157
Treatment for ***Typanosoma brucei***
Suramin and melarsoprol
158
Treatment for ***Trypanosoma cruzi***
Nifurtimox
159
Treatment for **leishmaniasis**
Sodium stibogluconate
160
Anti-mite/louse therapy
Used to treat scabies (*Sarcoptes scabei*) and lice (*Pediculus* and *Pthirus*)
Permethrin (blocks Na+ channels -\> neurotoxicity)
Malathion (acetylcholinesterase inhibitor)
Lindane (blacks GABA channels -\> neurotoxicity)
161
Chloroquine: Mechanism
Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia.
162
Chloroquine: Clincal Use
Treatment of plasmodial species other than *P. falciparum* (frequency of resistance in *P. falciparum* is too high). Resistance due to membrane pump that decreases inctracellular concentration of drug. Treat *P. falciparum* with **artemether/lumefantrine** or **atovaquane/proguanil**. For life-threatening malaria, use **quinidine** in U.S. (quinine elsewhere) or **artesunate**.
163
Chloroquine: Toxicity
Retinopathy;
Pruritis (especially in dark-skinned individuals)
164
Anti-helminthic therapy
Mebendazole
pyrantel pamoate
ivermectin
diethylcarbamazine
praziquantal
165
Inhibitors of Influenza **neuraminidase**
1. Examples
2. Mechanism
3. Clinical use
**Examples**: **Oseltamivir**, **Zanamivir**
**Mechanism**: Inhibit influenza neuraminidase, **decreasing release of progeny virus**
**Clinical Use:** Treatment and prevention of both influenza A and B
166
Guanasine analogs: Examples
Acyclovir
Famiciclovir
Valacyclovir
167
Acyclovir, famiciclovir, valacyclovir: Mechanism
Guanosine analogs
Monophosphorylated by **HSV/VZV thymidine kinase** and not phosphorylated in uninfected cells -\> few adverse effects.
Triphosphate formed by cellular enzymes.
Preferentially inhibit viral DNA polymerase by chain termination.
168
Acyclovir, famiciclovir, valacyclovir: Clincial Use
HSV and VSZV.
Weak activity against EBV.
No activity against CMV. Used for HSV-induced mucocutaneous and genital lesions as well as for encephalitis.
Prophylaxis in immunocompromised patients. No effect on latent forms of HSV and VZV.
Valacyclovir, a prodrug of acyclovir, has better oral bioavailability.
169
Acyclovir, famiciclovir, valacyclovir: Toxicity
Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated
170
Acyclovir, famiciclovir, valacyclovir: Mechanism of resistance
Mutated viral thymidine kinase
171
Ganciclovir: Mechanism
5'-monophosphate formed by a CMV viral kinase.
Guanosine analog.
Triphosphate formed by cellular kinases.
Preferentially inhibits viral polymerase by chain termination.
172
Gancyclovir: Clinical Use
CMV, especially in immunocompromised patients.
Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability.
173
Ganciclovir: Toxicity
Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir.
174
Ganciclovir: Mechanism of resistance
Mutated viral kinase
175
Foscarnet: Mechanism
Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Dose not require activation by viral kinase.
**Fos**carnet = pyro**fos**phate analog
176
Foscarnet: Clinical use
CMV retinities is immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV.
177
Foscarnet: Toxicity
Nephrotoxicity, electrolyte abnormalites (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to **seizures**.
Foscarnet is a **pyrophosphate analog** and can **chelate calcium**. Foscarnet-induced renal wasting of magnesium may lead to hypomagnesemia and a reduction in the release of parathyroid hormone, which contributes to the hypocalcemic state. Both hypocalcemia and hypomagnesemia can promote **seizures**.
178
Foscarnet: Mechanism of resistance
Mutated DNA polymerase
179
Cidofovir: Mechanism
Preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase.
180
Cidofovir: Clinical Use
CMV retinitis in immunocompromised patients; acyclovir-resistant HSV. **Long half-life**.
181
Cidofovir: Toxicity
Nephrotoxicity (coadminister with probenecid and IV saline to decrease toxicity)
182
HAART therapy
3 drugs to prevent resistance
2 Nucleoside Reverse Transcriptase inhibitors
AND
Non-nucleoside reverse transcriptase inhibitor
or
Protease inhibitor
or
Integrase Inhibitor
183
Protease inhibitors: Examples
All end in -navir
"**Navir** (never) **tease** a **protease**"
Ataza**navir**
Daru**navir**
Fosampre**navir**
Indi**navir**
Lopi**navir**
Rito**navir**
Saqui**navir**
184
Protease inhibitors: Mechanism
Assemply of virions depends on HIV-1 protease (*pol* gene), which cleaves the polypeptide products of HIV mRNA into their functional parts. Thus, protease inhibitors prevent maturation of new viruses.
Ritonavir can "boost" other drug concentrations by inhibiting cytocrhome P-450.
All protease inhibitors end in -*navir*.
185
Protease inhibitors: Toxicity
Hyperglycemia, GI intolerance (nausea, diarrhea), lipodystrophy
Nephropathy, hematuria (indinavir)
Rifampin (a potent CYP/UGT inducer) contraindicated with protease inhibitors because it can decrease protease inhibitor concentration.
186
Nucloside/Nucleotide Reverse Transcriptase Inhibitors: Examples
Abacavir (ABC)
Didanosine (ddl)
Emtricitabine (FTC)
Lamuvidine (3TC)
Stavudine (d4T)
Tenofovir (TDF)
Zidovudine (ZDV, formerly AZT)
187
NRTIs: Mechanism
Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3' OH group). **Tenofovir** is a nucleo**T**ide; the others are nuceosides and need to be phosphorylated to be active.
ZDV is used for general prophylaxis and during pregnancy to reduce risk of fetal transmission.
Ha**ve you dined** (**vudine**) with my **nuclear** (**nucleo**sides) family?
188
NRTIs: Toxicity
Bone marrow supprssion (can be reversed with granulocyte colony-stimulating factor [G-CSF] and erythropoietin), peripheral neuropathy, lactic acidosis (nucleosides), anemia (ZDV), pancreatitis (didanosine)
189
NNRTIs: Examples
Delavirdine
Efavirenz
Nevirapine
190
NRTIs: Mechanism
Bind to reverse transcriptase at site different from NRTIs. Do not require phosphorylation to be active or compete with nucleotides.
191
NNRTIs: Toxicity
Rash and hepatotoxicity are common to all NNRTIs. Vivid dreams and CNS symptoms are common with **efavirenz**. **Delavirdine** and **efavirenz** are contraindicated in pregnancy.
192
Ingegrase Inhibitors: Example(s)
Raltegravir
193
Integrase inhibitor: Mechanism
Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase.
194
Integrase inhibitor: Toxicity
Increases creatinine kinase
195
Fusion inhibitors: Examples
Enfuvirtide
Maraviroc
196
Enfuvirtide: Mechanism
Fusion inhibitor
Binds gp41, inhibiting viral entry
197
Enfuvirtide: Toxicity
Skin reaction at injection sites
198
Maraviroc: Mechanism
Fusion inhibitor
Binds CCR-5 on surface of T cells/monocytes, inhibiting interaction with gp120
199
Interferons: Mechanism
Glycoproteins normally synthesized by virus-infected cells, exhibiting a wide range of antiviral and antitumoral properties
200
Interferon alpha: Clinical Use
Chronic heptatis B and C
Kaposi sarcoma
Hairy cell leukemia
Condyloma acuminatum
Renal cell carcinoma
Malignant melanoma
201
Interferon Beta: Clinical Use
Multiple sclerosis
202
Interferon gamma: Clinical Use
Chronic granulomatus disease
203
Ribavarin: Mechanism
Hepatitis C therapy
Inhibits synthesis of guanine nucleotides by competitively inhibiting **inosine monophosphate dehydrogenase**
204
Ribavarin: Clinical Use and toxicity
Chronic HCV, also used in RSV (palivizumab preferred in children)
Toxicity: hemolytic anemia; severe teratogen
205
Simeprevir: Mechanism
Hepatitis C Therapy
HCV protease inhibitor; prevents viral replication
206
Simeprevir: Clinical Use and Toxicity
**Clinical Use**: Chronic HCV in combination with ribavirin and peginterferon alfa.
Do not use as monotherapy
**Toxicity**: Photosensitivty reactions, rash
207
Sofosbuvir: Mechanism
Hepatitis C therapy
Inhibits HCV RNA-dependent RNA polymerase acting as a chain terminator
208
Sofosbuvir: Clinical Use and Toxicity
Clinical Use: Chronic HCV in combination with ribavirin, =/- pegineterferon alfa.
DO not use as monotherapy.
Toxicity: fatigue, headache, nausea
209
Disinfection: definition
Reduction of pathogenic organisms to safe levels
210
Sterilization: definition
Inactivation of self-propogating biological entities
211
Autoclave
Pressurized steam at \>120 degrees C.
May be sporicidal
212
Alcohols
Denature proteins and disrupt cell membranes.
Not sporicidal.
213
Chlorhexidine
Denatures proteins and disrupts cell membranes.
Not sporicidal.
214
Hydrogen peroxide
Free radical oxidation
Sporicidal
215
Iodine and iodophors
Halogenation of DNA, RNA, and proteins
May be sporicidal
216
Antibiotics to avoid in pregnancy
**S**ulfonamides: Kernicterus
**A**minoglycosides: Ototoxicity
**F**luoroquinolones: Cartilage damage
**C**larithromycin: Embryotoxic
**T**etracyclines: Discolored teeth, inhibition of bone growth
**R**ibavarin (antiviral): Teratogenic
**G**riseofulvin (antifungal): Teratogenic
**C**hloramphenicol: Gray baby syndrome
**SAF**e **C**hildren **T**ake **R**eally **G**ood **C**are
