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Block 2 - Bugs and Drugs > Antibacterials > Flashcards

Antibacterials Flashcards

0
Q

Sulfonamides - mechanism of resistance

A

Clinical isolates have higher concentrations of pABA

Altered DAS that doesn’t bind sulfonamides as well

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1
Q

Sulfonamides - mechanism of action

A

Bacteriostatic only
Resistance is common
Analogs of pABA = comp. inhibitors of dihydropteroic acid synthase (humans don’t have) - bacteria cannot synthesize folate for NT synthesis
Bacterial DHFR inhibited by trimethoprim

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2
Q

Sulfonamides - pharmacokinetics

A

Well absorbed orally
Distribution everywhere including CNS
Antagonized by tissue breakdown products
Sig. Amount acetylated and inactivated in liver
Glomerular filtration elimination

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3
Q

Sulfonamide - adverse effects

A

Allergies
GI nausea and stomach distress
Hemolytic anemia - don’t give to patients with G6PD deficiency - cant neutralize ROS generated by sulfa drugs
Crystalluria - drink water!

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4
Q

Sulfonamides - therapeutic uses

A

Alone - nocardia (often with trimethoprim), minor UTIs (also)
Sulfonamide plus DHFR inhibitor - synergistic, co-trimoxazole active against many gram- and gram+, some fungi, some MRSA, inactive against anaerobes

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5
Q

Sulfisoxazole

A

Most popular for single drug therapy
Free and acetylated forms soluble
Few adverse reactions
Good CSF concentration

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6
Q

Sulfamethoxazole

A

Pharmacokinetics matched to trimethoprim

Longer half life than sulfisoxazole

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7
Q

Co-trimoxazole

A 
Combo can be bacteriocidal 
Both absorbed into CSF 
Active against gram+ and gram- 
Major use is UTIs 
Broad spectrum used in variety of infections
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8
Q

Fluoroquinolones - mechanism of action

A

Synthetic drugs
Bacteriostatic or bacteriocidal depending on dose
Binds to topoisomerase-DNA complex inhibiting replication and transcription
Main target in gram+ = topoisomerase IV
main target in gram- = gyrase

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9
Q

Fluoroquinolones - pharmacokinetics

A

Orally or IV - well absorbed from GI
Absorption inhibited in presence of cations (no milk, antacids)
Good penetration except not into CSF
Most eliminated by kidney, some by liver

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10
Q

Fluoroquinolones - adverse effects

A

Severe side effects rare
GI disturbances
CNS effects - dizziness, headaches, insomnia
Cartilage weakening in children - don’t give pregnant women either
Inhibit theophylline metabolism - can cause seizures
Phototoxicity from uv or sun

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11
Q

Fluoroquinolones - resistance

A

Altered topoisomerase target
New mechanisms emerging
Recommend use only for life threatening infections or failure of first agents

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12
Q

Fluroquinolones - therapeutic uses

A

Used in many infections
Only aerobes affected
Can sometimes replace amino glycosides for serious gram-

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13
Q

Ciprofloxacin

A

Fluoroquinolone
Not for resp - poor activity against strep
Gram- and some gram+

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14
Q

Levofloxacin

A

Fluoroquinolone
Active against strep –> resp inf
Also against staph, and many gram+ and gram-

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15
Q

Nitrofurantoin

A

Used for chronic suppression of bacterial UTIs
Bacteriostatic and bacteriocidal
Reduced, then oxidized - generates toxic intermediates that damage DNA and macromolecules
Best at pH 5.5
Can cause hemolytic anemia in newborns - don’t give to pregnant women near term

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16
Q

Rifamycins - mechanism of action

A

Bind to DNA directed RNA polymerase and allosterically inhibit it - transcription blocked
Bacteriocidal
Selectivity for prokaryotic polymerase
Resistance often develops - rarely used alone

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17
Q

Rifampin

A 
Major use against Tb
Prophylaxis of close contact to meningococcal meningitis 
Activity against legionella 
Synergistically with other drugs
Concentrates in saliva
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18
Q

Rifabutin

A

Useful for both Tb and mycobacterium avium (but not mainline)

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19
Q

Beta lactams - mechanism of action

A

Bacteriocidal
Mainly penicillin and cephalosporin
Interfere with cell wall production remodeling
Activate autolysins - cause cell to lyse after beta lactam acts
Final step in cell wall assembly is catalyzed by transpeptidase (aka penicillin binding proteins = PBPs) - binds to d-ala-d-ala
Beta lactams resemble d-ala-d-ala and irreversibly bind to enzyme

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20
Q

Beta lactams - resistance

A

Outer membrane of gram- restrict access to periplasm which is site of action
Acquired beta lactamase activity - hydrolyze amine linkage
Alteration of PBPs
Alteration of porins in outer membrane of gram-

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21
Q

Beta lactams - pharmacokinetics

A

Most acid labile - not administered orally
IV injection preferred for life threatening infection
Short half lives
Distribution good except limited in CSF and eye
Renal elimination - glomerular filtration and secretion pump (blocked by probenecid)

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22
Q

Beta lactams - adverse reactions

A

Allergy - major frequency determinants are penicillin molecules linked to lysine residues of serum proteins, minor frequency determinants are penicillin itself and breakdown products - can be life threatening
If MUST use - desensitization but its dangerous
Large amounts of sodium can cause problems
Pen can accumulate in brain due to probenecid - seizures
Cephalosporin may cause super infections

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23
Q

Beta lactams - therapeutic uses

A

Most sensitive are gram+ and spirochetes
Broader spectrums have some use against gram- but less against gram+
*mainline bacteriocidal drugs for gram+ infections

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24
Q

Penicillin g

A

Narrow spectrum penicillin
Half life 30-60 min
Acid labile –> I.m. Injection
Pen g benzathine - half life 1-2 weeks
Effective for gram+ cocci (except entero) and bacilli if not resistant, neisseria, spirochetes
Staph a. And most neisseria gonorrhea now resistant

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25
Q

Nafcillin

A

Anti staph penicillin

Acid labile –> given IV

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26
Q

Oxacillin

A

Anti staph penicillin

Acid stable –> oral for less severe infections, also IV

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27
Q

Ampicillin and amoxicillin

A

Broad spectrum penicillins
Acid stable –> oral
F higher for amoxicillin, admin less often
Useful against some gram- bacilli
Activity against gram+ adequate but not as good as pen g

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28
Q

Ticarcillin

A

Anti pseudomonal penicillin
Parenteral admin
Less active against gram+ than pen g
More potent than original

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29
Q

Piperacillin

A 
Broadest spectrum penicillin
Most active drug in this class 
Useful for wide variety of serious gram- inf
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30
Q

Cephalosporins - general attributes

A

Good subs for pen in allergics
Less sensitive to beta lactamases than pen (but still to staph a.)
Penetration into CSF
Prophylaxis during surgery

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31
Q

First generation cephalosporins

A

Good gram+ coverage
Useful but limited gram- coverage
Good for penicillinase producing staph strains

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32
Q

Cefazolin

A

Parenteral first generation cephalosporin

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33
Q

Cephalexin

A

Oral first generation cephalosporin

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34
Q

Second generation cephalosporins

A

Increased coverage of gram- bacilli

Some have good activity against anaerobes

35
Q

Cefuroxime and cefoxitin

A

Parenteral second generation cephalosporins

Cefoxitin - good anaerobic agent but resistance in b. fragilis

36
Q

Third generation cephalosporins

A

Useful for gram-
Good CSF penetration
Super infections are a problem

37
Q

Cefotaxime

A

Third generation cephalosporins
Resistant to beta lactamases
Good against gram+ and gram-
Great for meningitis

38
Q

Ceftriaxone

A

Third generation cephalosporins
Longest half life of class
Drug of first choice for gonorrhea

39
Q

Ceftazidime

A

Third generation cephalosporins

Antipseudomonal

40
Q

Cefepime

A

Fourth and fifth generation cephalosporins
Stronger activity against staph
More resistant to beta lactamases

41
Q

Imipenem

A

Part of carbopenem class of beta lactams
Broad spectrum - active against gram+, gram-, aerobes, anaerobes
Resistant to beta lactamases
Inactivated in renal tubules by dihydropeptidases - give with cilastatin which inhibits this
Given in combo with amino glycosides for serious gram- inf

42
Q

Beta lactamase inhibitors

A

Clavulanic acid

Used in combo with other beta lactams

43
Q

Vancomycin - mechanism of action

A

Inhibit cell wall synthesis
Bacteriocidal
Limited for gram+ - cant penetrate outer membrane
Binds to d-ala-d-ala shielding from transpeptidase
Drug of last resort for MRSA, drug resistant eneterococci, others
Resistance - bacteria sub d-ala-d-lactate

44
Q

Vancomycin - pharmacokinetics

A

Poorly absorbed from GI
Parenteral admin
Good penetration but not across BBB unless meninges inflamed
Glomerular filtration

45
Q

Vancomycin - adverse effects

A

Rapid admin can cause histamine release –> flushing, rashes, hypotension
Can be ototoxic
Possible nephrotoxicity
Do NOT combine with aminoglycosides

46
Q

Vancomycin - therapeutic indications

A

Useful for serious gram+
First choice for MRSA
Useful against enterococcus, endocarditis from strep viridans, and c. Dificile

47
Q

Aminoglycosides - mechanism of action

A

Often given in combo with pen or cephalosporin esp for entero. Endocarditis
Bacteriocidal - mostly against gram-
Diffuse through porins but must be pumped across plasma membrane - dependent on neutral or high external ph, oxy, normal osmolarity - not effective in anaerobic environment
Low concentrations cause mRNA misreading by binding to 30s on ribosome - altered proteins get into membrane and destabilize it leading to influx and lysis

48
Q

Aminoglycosides - mechanism of resistance

A

Transferase enzyme add moieties to carb groups and render drug unable to bind ribosomes

49
Q

Aminoglycosides - pharmacokinetics

A

Polar and charged - poor absorption from GI tract
Given IV or I.M or s.q
Distribution limited to extra cellular fluids
Elim by glomerular filtration

50
Q

Aminoglycosides - adverse effects

A

Therapeutic index is low
Potential for ototoxic and nephrotoxicity
Bacteria have post antibiotic effect
Neuromuscular blockade in susceptible patients (myasthenia)
Damage to optic nerve

51
Q

Streptomycin

A

Now resistance

Useful combo with beta lactam for endocarditis from entero, viridans, drug resistant tb, tularemia, and plague

52
Q

Gentamicin and tobramycin

A

Mainline aminoglycosides
Imp for gram- inf
Admin intrathecally or intraventricularly for CNS inf

53
Q

Amikacin

A

Aminglycoside
More potent against gram-
More resistant to transferase enzymes

54
Q

Neomycin

A

Aminoglycosides
Treatment or prophylaxis of topical inf
Too toxic for parenteral use
Frequently to prepare bowel for surgery

55
Q

Tetracyclines - mechanism of action

A

Bacteriostatic

Target is 30s ribosomal subunit - inhibits tRNA binding

56
Q

Tetracycline - resistance

A

Enter cell through transporter

Some cannot accumulate drug in cytoplasm - acquire gene to pump it right back out

57
Q

Tetracyclines - pharmacokinetics
Also doxycycline
And minocyclin

A

Oral admin
T - incomplete oral aborption, short half life, glom filtration
D and m - almost completely absorbed, longer acting, more
lipophilic, hepatic elim (But mino also a little by kidney)
Absorption limited in presence of cations
Lipophilic accumulates in fat, all stored in bone (Vd > body water)
Penetration into all tissue good including fetus

58
Q

Tetracyclines - adverse effects

A

Broad spectrum - superinfections
Discolor teeth in children - don’t give during pregnancy either
Inhibit bone growth and cause stunting in children
Hepetatoxicity - esp during pregnancy
Photooxidize from uv
Acute GI distress

59
Q

Tetracyclines - therapeutic uses

A

Broad spectrum - lots of resistance but still niche uses
First choice for rickettsia
Can be used for MRSA
Freq use for mycoplasma pneumonia and chlamydia
Gonorrhea and syphilis in pen allergic patients

60
Q

Macrolides - mechanism of action and resistance

A

Bind to 50s ribosomal subunit - inhibit peptidyl transferase
Bacteriostatic for the most part
For gram+
Subs for beta lactams in allergic patients
Resistance by either decrease in influx, elaboration of inactivating enzymes, change in ribosomal subunit

61
Q

Macrolides - pharmacokinetics

A

Usually oral admin
Erythromycin - acid labile but has preparation that protects it
Clarithromycin and azithromycin more acid stable
Wide distribution but not to CSF
Elim in bile

62
Q

Macrolides - adverse effects

A

Serious are rare
Epigastric distress
Many drug drug interactions

63
Q

Macrolides - therapeutic uses

A

Gram+ inf esp strep and listeria
Chlamydia after tetracyclines
First choice for legionella
Gonorrhea and syphillis in pen allergic pregnant women

64
Q

Erythromycin

A

Macrolide
Can concentrate several fold in bacterial cells
Stronger against gram+

65
Q

Clarithromycin

A

Macrolide
Better f than erythro
Activity against mycobacterium avium

66
Q

Azithromycin

A

Macrolide
Can concentrate in many tissues as well as macrophages and is released over several days
5 day treatment usually sufficient

67
Q

Clindamycin

A

Major use against anaerobes or prophylaxis of endocarditis
50s ribosomal binder - antagonized by macrolides
Oral or IV - doesn’t cross BBB
Superinfections and skin rashes common

68
Q

Quinupristin-dalfopristin

A

D binds first and stimulates binding of the other - synergy
Binds 50s ribosome subunit
Bacteriocidal
Bacteria have post antibiotic effect
IV admin
Metabolized in liver and excreted in bile
Inhibits p450 - watch for drug interactions
Reserved for treatment of multidrug resistant infections

69
Q

Linezolid

A

Good for resistant gram+ inf
Bind to unique site of 50s ribosome subunit
Bacteriostatic except cidal for strep
Oral or IV - good f
Tongue discoloration, superficial fungus inf, headache, bone marrow suppression if more than 14 days

70
Q

Daptomycin

A

Good for resistance gram+ inf
Preferentially binds to phosphatidyl glycerol in bacterial membranes (absent in mammals) and causes depolarization
No interactions
Binds to surfactant - don’t use for pulmonary inf
Many serious side effects - reserved for life threatening inf

71
Q

Metronidazole

A

Kills anaerobic bacteria and Protozoa
Reduced drug generate intermediates toxic to macromolecules
Patients should not drink alcohol

72
Q

Bacitracin

A

Topical use for gram+ and gram- inf

Orally for c. Dificile in GI tract

73
Q

What are the drugs for leprosy?

A

Dapsone - sulfonamide like action

Usually in combo with rifampin

74
Q

What are the two techniques of susceptibility testing?

A

Broth dilution - inoculate tube of broth with particular bacterium and test effects of different antimicrobials - mean inhibitory concentration is one that inhibits growth of bacteria
Disk diffusion - place anti microbial impregnated disk on top of agar plate inoculated with lawn of bacterium

75
Q

What is the mean bactericidal concentration?

A

One required to kill 99.9% of bacteria in solution over 24 hr period
Must plate on agar to measure

76
Q

What is an e test?

A

Variant of disk diffusion test
Strip with gradient of increasing concentrations of anti microbial placed onto lawn of bacteria
MIC is where zone of inhibition starts

77
Q

What is the technical difference between bacteriocidal and Bacteriostatic drugs?

A

Bacteriocidal kills more than 99.9% in 24 hrs = 3 log kill

Bacteriostatic only kills 99% = 2 logs

78
Q

What is the 90-60 rule?

A

Infections due to susceptible isolates will respond only 90% of time to therapy
Infections due to resistant isolates or wrong anti microbial will respond 60% of the time
Host factors more important in determining outcome than simply knowing MIC

79
Q

How do abscesses interact with antibiotics?

A

Low ph inside cavities inactivate many antibiotics, especially aminoglycosides

80
Q

What are three special situations difficult to treat?

A

Endocarditis
Febrile neutropenia
Prosthetic devices

81
Q

What is the difference between time dependent and concentration dependent killing?

A

Time dependent - longer above MIC is more effective

Concentration - higher concentration above MIC more and more effective (Cmax/MIC), show post antibiotic effect

82
Q

Which antibiotics show time dependent killing?

A 
Penicillins and cephalosporins
Max killing occurs when drug concentration/MIC is 2-4
Tetracyclines
Azole antifungals
Linezolid and ketolides
Streptogramins
83
Q

Which antibiotics show concentration dependent killing?

A 
Aminoglycosides 
Peak level 10 fold greater than MIC desired
Fluoroquinolones
Amphotericin b
Echinocandins
Flucytosine
Nystatin
Daptomycin
84
Q

Which drugs have both types of killing?

A

Macrolides
Primary parameter is AUC/MIC
active intracellularly and extracellularly

85
Q

Which antibiotics cannot penetrate into cells?

A

Beta lactams
Aminoglycosides
Vancomycin
Daptomycin

Block 2 - Bugs and Drugs (9 decks)

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