Antimicrobial Drugs Flashcards Preview

USMLE Step 1 > Antimicrobial Drugs > Flashcards

Flashcards in Antimicrobial Drugs Deck (170):
1

Block cell wall synthesis by inhibition of peptidoglycan cross-linking

Penicillin, Methicillin, Ampicillin, Piperacillin, Cephalosporins, Aztreonam, Imipenem

2

Block peptidoglycan synthesis

Bacitracin, Vancomycin

3

Block nucleotide synthesis by inhibiting folic acid synthesis (involved in methylation)

Sulfonamides, trimethopram

4

Block DNA topoisomerases

Fluoroquinolones

5

Block mRNA synthesis

Rifampin

6

Damage DNA

Metronidazole

7

Block protein synthesis at *50S* ribosomal subunit

Chloramphenicol, Macrolides, Clindamycin, Streptogramins (Quinupristin, Dalfopristin, Linsezolid)

8

Block protein synthesis at *30S* ribosomal subunit

Aminoglycosides, Tetracyclines

9

Penicillin

Penicillin G (IV and IM form), penicillin V (oral), Prototype B-lactam antibiotics

10

Penicillin Mechanism

Bind penicillin-binding proteins (transpeptidases)
Block transpeptidase cross-linking in peptidoglycan
Activate autolytic enzymes

11

Penicillin Clinical Use

*Mostly used for gram-positive organisms* (S. pneumoniae, S. pyogenes, Actinomyces)
Bacterocidal for gram-positive rods, gram-negative cocci, and spirochetes

12

Penicillin: Penicillinase resistant?

No. Duh!

13

Penicillin Toxicity

Hypersensitivity reactions, Hemolytic anemia

14

How does penicillin resistance occur?

B-lactamases cleave B-lactam ring

15

Penicillinase resistant penicillins

Oxacillin, Nafcillin, Dicloxacillin

16

Penicillinase resistant penicillins Mechanism

*Narrow spectrum* Bind penicillin-binding proteins (transpeptidases)

17

How are the "-cillins" penicillinase resistant?

Bulky R group blocks access of B-lactamase to B-lactam ring

18

Penicillinase resistant penicillins Clinical Use

S. aureus (except MRSA; resistant because of altered penicillin-binding protein target site)

19

Penicillinase resistant penicillins Toxicity

Hypersensitivity reactions, interstitial nephritis

20

Aminopenicillins

Ampicillin, Amoxicillin

21

Aminopenicillins: Mechanism

*Same as penicillin but wider spectrum*

22

Aminopenicillins: Penicillinase resistant or penicillinase sensitive

*Penicillinase sensitive* Also combine with clavulanic acid to protect against B-lactamase

23

Which has greater oral bioavailability? Amoxicillin or Ampicillin

Amoxicillin

24

Aminopenicillins (Ampicillin, Amoxicillin) : Clinical Use

Extended spectrum penicillin - (HELPSS) *H*aemophilus influenzae, *E.*coli, *L*isteria monocytogenes, *P*roteus mirabilis, *S*almonella, *S*higella, enterococci

25

Aminopenicillin (Ampicillin, Amoxicillin) Toxicity

Hypersensitivity reactions; ampicillin rash; pseudomembranous colitis

26

Aminopenicillin (Ampicillin, Amoxicillin) Resistance

B-lactamases cleave B-lactam ring

27

Antipseudomonals

Ticarcillin, Piperacillin

28

Antipseudomonals (Ticarcillin, Piperacillin) Mechanism

*Same as penicillin* Extended spectrum

29

Ticarcillin, Piperacillin Clinical Use

Pseudomonas spp. and gram-negative rods

30

Ticarcillin, Piperacillin: Penicillinase resistant or Penicillinase sensitive?

*Penicillinase sensitive* Use with clavulanic acid to protect against B-lactamase

31

B-lactamase inhibitors

*CAST* - *C*lavulanic *A*cid *S*ulbactam, *T*azobactum

32

Cephalosporins: Mechanism

B-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal

33

Which organisms are not covered by cephalosporins?

Organisms typically not covered by cephalosporins are *LAME*:
Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci

34

Which cephalosporin is the exception to the *LAME* organism rule?

Ceftaroline covers MRSA

35

1st generation cephalosporins

Cefazolin, Cephalexin

36

1st generation cephalosporins coverage

1st generation - *PEcK*
Proteus
E.Coil
Klebsiella

37

2nd generation cephalosporins

Cefoxitin, Cefaclor, Cefuroxime

38

2nd generation cephalosporin coverage

2nd generation cephalosporins - *HEN PEckS*
H.influenza
Enterobacter
Neisseria
Proteus
E.Coli
Klebsiella

39

3rd generation cephalosporins

Ceftriaxone, Cefotaxime, Ceftazidime

40

3rd generation cephalosporins coverage

Serious gram-negative infections resistant to other B-lactams

41

4th generation cephalosporins

Cefepime

42

4th generation cephalosporin coverage

Cefepime - increased activity against Pseudomonas and gram-positive organisms

43

Cephalosporin Toxicity

Hypersensitiity reactions, vitamin K deficiency.

44

Aztreonam: Mechanism

A monobactam resistant to B-lactamases. Prevents peptidoglycan cross-linking by binding to PBP3

Synergistic with aminoglycosides. No cross-allergy with penicillins

45

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*

46

Imipenem/Cilastatin, Meropenem: Mechanism

Imipenem is a broad-spectrum, B-lactamase-resistant carbapenem. Always administered with *cilastatin* (inhibitor of renal dehydropeptidase I) to decreased inactivation of drug in renal tubules.

47

Imipenem/Cilastatin, Meropenem: Clinical Use

Gram-positive cocci, gram-negative rods, and anaerobes.

48

Discuss Meropenem and seizure risk

Unlike imipenem/cilastatin, meropenem has reduced risk of seizures, and is stable to dehydropeptidase I

49

Imipenem/Cilastatin, Meropenem: Toxicity

GI distress, skin rash, and CNS toxicity (seizures at high plasma levels)

50

Vancomycin: Mechanism

Inhibits cell wall peptidoglycan formation by binding *D-ala D-ala* portion of cell wall precursors. Bactericidal

51

Vancomycin: Clinical Use

Gram-positive only - serious, amultidrug-resistant organisms, including MRSA, enterococci, and Clostridium difficile (oral dose for pseudomembranous colitis)

52

Vancomycin: Toxicity

Well tolerated in general - does *NOT* have many problems
N-ephrotoxicity
O-totoxicity
Tthrombophlebitis
Diffuse flushing

53

How can one prevent *red man syndrome*?

Red man syndrome - associated w/ vancomycin toxicity.
- mediated by histamine

54

Vancomycin Resistance

Occurs with amino acid change of *D-ala D-ala* to D-ala D-lac.

55

Protein synthesis inhibitors target which bacterial ribosome?

70S (made up of 50S and 30S subunits), which leave 80S ribosome (human ribosome) unaffected

56

Aminoglycosides

*G*entamicin, *Neomycin*, *Amikacin, *T*obramycin, *S*treptomycin

57

Macrolide: Clinical Use

Atypical pneumonias (Mycoplasma, Chlamydia, Legionella)
STDs (for Chlamydia)
Gram-positive cocci (Streptococcal infections in patients allergic to penicillin

58

Macrolides: Toxicity

*MACRO*: *M*otility issues, *A*rrhythmia caused by prolonged QT, acute *C*holestatic hepatitis, *R*ash, e*O*sinophilia. Increases serum concentration of theophyllines, oral anticoagulants

59

Macrolide Resistance

Methylation of 23S rRNA binding site

84

30 S inhibitors

"AT" 30
Aminoglycosides
Tetracyclines

85

50S inhibitors

CCEL at 50
Chloramphenicol, Clindamycin
Erythromycin (macrolides)
Linezolid

86

Aminoglycoside: Mechanism

Bacteriocidal
- bind to 30S ribosomal subunit unit to inhibit formation of initiation complex and cause misreading of mRNA
- blocks translocation
- Requires oxygen for uptake thus inaffective against anaerobes

87

Aminoglycoside: Clinical USe

Severe gram-negative rod infections
Syngergistic with B-lactam antibiotics
Neomycin for bowel surgery

88

Amingoglycoside Toxiciity

Nephrotoxicity (esp. when used with cephalosporins)
Neuromusclar blockade
Ototoxicity (esp. when used with loop diuretics - furosemide)
Teratogen

89

Aminoglycoside resistance

Transferase enzymes that inactivate trug by acetylation, phosphorylation or adenylation

90

Tetracycline

Tetracycline, Doxycycline, Demeclocycline

91

Demeclocycline

- ADH antagonist
- acts as diuretic in SIADH. Rarely used as an antiobiotic

92

Tetracycline mechanism

Bacterostatic:
bind to 30S and prevent attachment of aminoacyl-tRNA
limited CNS prenetration

93

Contraindications for tetracyclines

Don't use with milk, antacids, or Fe-containing substances because divalent cations inhibit absorption in gut

94

Doxycycline special considerations

fecally eliminated
can be used in patients with renal failure

95

Tetracyclines: Clinical Use

Borellia borgdoferi
M. pneuominae
- ability to accumulate intracellularly makes it effective against Ricksettia and Chlamydia

96

Tetracycline: Toxicity

GI distress
Discoloration of teeth and inhibition of bone growth in children
Photosensitivity
Contraindicated in pregnancy

97

Tetracycline: Resistance

Decreased uptake into cells
Increased efflux out of cell by plasmid-encoded transport pumps

98

Macrolides

azithromycin, clarithromycin, erythromycin

99

Macrolide: Mechanism

Inhibit protein synthesis by blocking translocation;
bind to 23S rRNA of 50 S ribosomal subunit

100

Chloramphenicol

- blocks peptidyltransferase at 50S ribosomal subunit
- used for Meninigitis (H. influenzae, N. meningitis, S. pneumoniae)
- not used widely because of toxicity

101

Chloramphenicol: Toxicity

anemia (dose dependent)
aplastic (dose INDEPENDENT)
Gray baby syndrome - in premature babies because they lack liver UDP-gluconyl transferase

102

Chloramphenicol: Resistance

Plasma-encoded acetyltransferase that inactivates drug

103

Clindamycin

- blocks peptide transfer (transpeptidation) at 50S ribosomal subunit. Bacteriostatic
- used to treat ANAEROBIC infections in aspiration pneumonia or lung abscesses
- also treats oral infections with mouth anaerobes

104

Metronidazole vs. Clindamycin

Clindamycin - treats anaerobes ABOVE diaphragm

Metronidazole - treats anaerobes BELOW diaphragn

105

Clindamycin: Toxicity

Pseudomonas colitis ( C. difficile overgrowth), fever, diarrhea

106

Sulfonadmides:

SMX, Sulfisoxiazole, Sulfadiazine

107

Sulfonamide

PABA antimetabolit inhibit dihydropteroate synthase. Bacteriostatic

- treats gram-positive, gram-negative, Nocardia, Chlamydia,
- Triple sulfas or SMX for simple UTI

108

Sulfonamide: Toxicity

Hypersensitivity reactions
Hemolysis if G6PD deficiency
Nephrotoxicity (tubulointerstitial nephritis)
Photosensitivity
Kernicterus in infants
Displace other drugs from albumin

109

Trimethoprim

- inhibits bacterial dihydrofolate reductase. Bacteriostatic
- used in combination with sulfonamides (TMP-SMX), causing sequential block of folate synthesis
- used for UTIs, Shigella, Salmonella, PCP (treatment & prophylaxis)

110

Trimethoprim: Toxicity

Megaloblastic anemia, Leukopenia, Granulocytopenia
** Treat Marrow Poorly
-May be alleviated with folinic acid (leuvovorin rescue)

111

Fluoroquinolones

"-floxacin" , "enoxacin", nalidixic acid
Ciprofloxain, Norflozacin

112

Fluoroquinolones

Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV)
- Don't take with antacids
- use to treat gram-negative rods of urinary and GI tracts (e.g Psuedomonas, Neisseria, gram-positive organisms)

113

Floroquinolones: Toxicity

GI upset
Superinfections
Skin rashes
Dizziness
- Can cause tendon rupture (esp. in Achilles tendon) in patients > 60
- Contraindicated in pregnant women and children because may damage cartilate

114

Floroquinolone: Resistance

Chromosome-encoded mutation in DNA gyrase
Plasma mediated resistance
Efflux pumps

115

Metronidazole

- forms free radical toxic metabolites in bacterial cell that damages DNA. Bactericdial, Antiprotozoal
- treats "GET GAP" - Giardia, Entoameoba, Trichomonas Gardnerella vaginalis, Anaerobes
- Used with proton pump inhibitor and clarithromycin for "triple therapy" for H. pylori

116

Metronidazole: Toxicity

Disulfram-like reactiin with alcohol
Headache
Metallic Taste

117

Treatment from M. tuberculosis

Prophylaxis: Isoniazid

Treatment: RIPE (Rifampin, Isoniazid, Pyrazinamide, Ethamutol)

118

Treatment for M. avium-intracellulaire

Prophylaxis: Azithromycin

Treatment: Azithromycin, Rifampin, Ethambutol, Streptomycin

119

Treatment for M. leprae

NO PROPHYLAXIS

Tuberculoid: Dapsone and Rifampin for 6 months
Lepromatous: Dapsone, Rifampin, Clofazimine for 2-5 years

120

Isoniazid:

- inhibits mycolic acid synthesis. Bacterial catalase-peroxidase (KatG) needed to convert INH to active form
- used for M. tuberculoisis. Only solo prophylaxis for TB

121

Isoniazid Metabolism

- Different INH half lives in fast vs. slow acetylators

- seen in bi-modal plasma concentration graphs

122

Isoniazid: Toxicity

Neurotoxicity
Hepatotoxicity
Pyroxidine (VB6) can prevent neurotoxicity, lupus
B6 needed to make NTs (e.g. GABA)

123

Rifampin

- inhibits DNA dependent RNA polymerase
- treats M. tuberculosis
- delays resistance to dapsone when leprosy
- Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with H. influenzae type b

124

Rifampin: Toxicity

minor hepatotoxicity and drug interactions (increase in P-450)
Orange body fluids

125

Pyrazinamide

- uncertain mechanism but may acidify intracellular enviroment by converting to pyrazinoic acid
- effective in acidic pH of phagolysosomes where TB is engulfed by macrophages are found
- used to treat TB

126

Pyraniamide: Toxicity

Hyperuricemia, Hepatotoxicity

127

Ethambutol

- decreased carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase
- treats TB

128

Ethambutol: Toxicity

optic neuritis
- central scotomas
- decreased visual acuity
- red-green color blindness

129

Prophylaxis for meningococcal infection

Ciprofloxacin (1st line)
Rifampin for children

130

Prophylaxis for Gonorrhea

Ceftriazone

131

Syphilis prophylaxis

Penicillin G

132

Hx of recurrent UTIs

Penicillins

133

Encocarditis with surgical or dental procedures - Prophylaxis

Penicillins

134

Pregnant women carrying Group B Strep prophylaxis

Intrapartum ampicillin

135

Prophylaxis of strep pharyngitis in child with prior rheumatic fever

Oral penicillin

136

Prevention of post surgical infection due to S. aureus

Cefazolin

137

Prevention of gonoccocal or chlamydial conjunctivitis in newborn

Erythomycin ointment

138

HIV prophylaxis : CD4 < 200 cells/mm3

TMP-SMX to prevent PCP pneumonia

139

HIV prophylaxis: CD4 < 100 cells/mm3

TMP-SMX to prevent PCP pneumonia and Toxoplasmosis

140

HIV prophylaxis: CD4 < 50 cells/mm3

Azithromycin to prevent M. avium complex

141

Treatment of Vancomycin Resistance Enterococci

Linezolid
Streptogramins (Quinupristin/Dalfopristin)

142

Amphotericib B

- binds to ergosterols in fungi - forms membrane pores that allow leakage of electrolytes
- treats systemic mycoses (Cryptococcus, Blastomyces, Coccidioides, Histoplasma, Candida, Mucor
- Intrathecally for fungal meningitis
- Supplement K and Mg for altered renal tubule permeability

143

Amphotericin B: Toxicity

Fever/chills ("shake and bake")
Hypotension
Nephrotoxicity
IV phlebitis
Hydration reduces nephrotoxicity
Liposomal amphotericin reduces toxicity

144

Nystatin

- bind to ergosterols
- can only be used topically
- used to treat oral candiadis (thrush)
- topic for diaper rash or vaginal candiadiasis

145

Azoles

- inhibit fungal sterol (ergosterol) synthesis by inhibiting P-450 enzyme that converts lanosterol to ergosterol
- treats local and less serious mycoses

146

Fluconazole

used for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infections of all types

147

Itraconazole

treats Blastomycoses, Coccidoides, Histoplasma

148

Clotrimazole and Miconazole

treats topical fungal infections

149

Azoles: Toxicity

testerone synthesis inhibition - leads to gynecomastia esp. with ketoconazole
- Liver dysfunction (inhibits P-450)

150

Flucytosine:

- inhibits DNA and RNA biosynthesis by conversion to 5-FU by cytoseine deaminase
- used in systemic fungal infections (esp. in meningitis caused by Cryptococcus) in combination with amphotericin B

TOXICITY:: causes bone marrow suppression

151

Caspofungin, Micafungin

inhibits cell wall synthesis by inhibiting synthesis of B-glucan
- treats invasive aspergillosis, Candida

** associated with GI upset, flushing (histamine release)

152

Terbinafine

- inhibits fungal enzyme 2,3 squalene epoxide (thus inhibiting sterol synthesis)
- used to treat dermatophytes (esp. fungal infections of skin and nails)


** associated with abnormal LFTs, visual disturbances

153

Griseofulvin

- interferes with microtubule function; disrupts mitosis.
- deposits in keratin containing tissues (e.g. nails)
- used for oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm)

154

Griseofulvin: Toxicity

teratogenic
carcinogenic
confusion
headaches
-increase P450 and warfarin metabolism

155

Antiprotozan therapy

Pyrimethamine (toxoplasmosis)
Suramin and Melarsoprol (T. cruzei)
Nifuritmox (T. cruzei)
Sodium Stibogluconate (Leischmaniasis)

156

Chloroquine

- blocks detoxification of heme into hemoizin. Heme accumulates and is toxic to plasmodia
- treats plasmodial species EXCEPT P. falciprum (resistance too high)

** resistance due to membrane pump that decreases intracellular concentration of drug
*** associated with retinopathy

157

Treatment of P. falciprum

- treatment with artemether/lumifantrine
- atovaquone/proguanil

158

Antihelminthic therapy

Metrobendole
Pyrantel pamoate
Ivermectin
Diethycarbamazine

159

Zanamivir

inhibit influenza neuraminase, decreasing release of progeny virus
- treats and prevents both influenza A and B

160

Ribavirin

inhibits synthesis of guanine nucleotide by competively inhibiting IMP dehydrogenase
- used to treat RSV, chronic Hep C


*** associated with hemolytic anemia
** Severe teratogen

161

Acyclovir

- monophosphoryalated by HSV/VZV thymidine kinase
- Guanosine analog
- Triphosphate formed by cellular enzymes. Preferentially inhibits viral DNA polymerase by chain termination

162

Acyclovir: Use

- treats HSV and VZV
- Weak against EBV
- NO ACTIVITY against CMV
- Used for mucotaneous and genital lesions and for encephalitis
- Prophylaxis in immunocompromised patients
- Valacyclovir, a prodrug has better oral bioavailability
** Few serous side effects

163

Acyclovir Resistance

Mutated viral thymidine kinase

164

Ganciclovir

5'-monophophate formed by a CMV viral kinase
Guanosine analong
Triphosphate formed by cellular kinases
Preferentially inhibits viral DNA polymerase
- treats CMV esp in immunocompromised patients
- Valganiclovir - has better oral bioavailability

165

Ganciclovir: Toxicity

mutated CMV DNA polymease or lack of viral kinase

166

Foscarnet

- viral DNA polymerase inhibitor that binds to pyrophosphate binding site of enzyme
- does not require activation by viral enzyme
- treats CMV retinits in immunocompromised patients when ganciclovir fails
- treats acyclovir resistant HSV

** associated with nephrotoxicity

167

Forscarnet Resistance

mutated DNA polymerase

168

Cidofovir

preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase
- CMV retinintis in immunocompromised patients
- acyclovir resistant HSV
- Long half-ide

*** associated with nephrotoxicity (coadminister with probenecid and IV saline to reduce toxicity

169

HIV therapy

HAART - highly active antiretroviral therapy
- initiated when patients present with AIDS defining illness
- low CD4 cell counts (< 500 cells/mm3) OR high viral load
- Regimen consists of 3 drugs to prevent resistance

170

HIV therapy HAART cocktail

TWO NRTIs (nucleoside reverse transcriptase) +
1 non-nucleoside reverse transcriptase inhibitor OR 1 protease inhibitor OR integrase inhibitor

171

Protease inhibitors ("-inavirs")

Assembly of virions depends on HIV-1 protease which cleaves polypeptide products of HIV mRNA into their functional parts
- Protease inhibitors prevent maturation of new viruses

172

Ritonavir and drug concentrations

Ritonavir can book other drug concentrations by inhibiting cytochrome P-450

173

Protease inhibitor (-inavir) Toxicity

Hyperglycemia
GI intolerance (nausea, diarrhea)
Lipodystrophy
Nephropathy
Heamturia (assciated with indinavir)

174

NRTIs ("-vudine"), Emtrictabine, Abacavir, Didanosine

- competitively inhibit nucleotide binding to reverse transcriptase and terminate DNA chain (lack a 3' OH group)

175

Special note about NRTI activation

Tenofovir is a nucleoTide analog and doesn't have to be activated

Other NRTIs are nucleoSide analog and have to be phosphorylated to bec active

176

Drug used for HIV prophylaxis and during pregnancy to reduce risk of fetal transmission

Zidovudine
- formerly known as AZT

177

NRTI Toxicity

Bone marrow suppression
- can be reversed with G-CSF and erythropoietin
Peripheral neuropathy
Lactic acidosis (nucleosides)
Anemia (ZDV/ AZT)

178

Non- Nucleoside Reverse Transcriptase INhibitors

Nevirapine, Efavirenz, Delavirdine

179

NNRTIs

bind to reverse transcriptase at site different from NRTIs
- do not require phosphorylation to be active or compete with nucleotides

180

NNRTI Toxicity

Bone marrow suppression (can be reversed with G-CSF and erythropoietin)
Peripheral neuropathy
Rash

181

Raltegravir

inhibits HIV genome integration into host cell chromosome by reversible inhibiting HIV integrase

** associated with hypercholestermias as toxicity

182

Interferons

- glycoproteins synthesized by virus-infected cells; block replication of both RNA and DNA viruses

183

IFN-alpha as treatment

- treats chronic hepatitis B and C, Kaposi's sarcoma

184

IFN-alpha

treats Multiple sclerosis

185

IFN-gamma

treats NADPH oxidase deficiency

186

IFN- Toxicity

Neutropenia, Myopathy

187

Sulfonamide effect on pregnacy

Kernicterus (accumulation of bile in the brain - associated with sever jaundice in newborns)

188

Aminoglycosides' effect on pregnacy

Ototoxicity

189

Floroquinolones' effect on fetus

Cartilage damage

190

Clarithromycin's effect on fetus

Embryotoxic

191

Tetracyclines' effect on fetus

Discolored teeth
Inhibition of bone growth

192

Ribavirin (antiviral) effect on fetus

Teratogenic

193

Griseofulvin (anti-fungal) effect on fetus

Teratogenic

194

Chloramphenicol effect on fetus

"Gray baby"