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Microbiology lecture > Antibiotics I > Flashcards

Antibiotics I Flashcards

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1
Q

antimicrobial agents

A

are natural products, synthetic products, and semi-synthetic products
-these are agents that inhibit the growth of bacteria and are referred to as bacteriostatic
-cidal and static can differ depending on dose and organisms

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2
Q

Antibiotics

A

-are natural products synthesized by microorganisms

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3
Q

bactericidal

A

-antimicrobial agents that kill bacteria

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4
Q

spectrum

A

the range of organisms that a particular drug is active against

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5
Q

Characteristics of a successful antimicrobial agent

A

-Drugs have a narrow spectrum and target a specific pathogen to avoid collateral damage
-the drug has broad spectrum activity that targets several different potential pathogens (collateral damage will occur)
-the drug must be able to penetrate into the site of the infection at sufficient concentration for a sufficient period of time
-the drug must be safe and well tolerated with limited or no side effects
-the drug must be affordable
-oral vs. parenteral formulations

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6
Q

The golden age of antibiotic discovery

A

1930s- sulfonamides
1940s- penicillin, aminoglycosides, beta-lactams
1950s- chloramphenicol. tetracyclines, macrolides, glycopeptides
1960s- streptogramins, quinolones, lincosamides
1970s- trimethoprim, newer beta-lactam agents
2000s- cyclic lipopeptides, oxazolidinones
chloramphenicol has dangerous side effects not used in the US

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7
Q

What antimicrobial target protein synthesis?

A

-aminoglycosides
-chloramphenicol
-glycylcyclines
-macrolides
-oxazolidinones
-streptogramins
-tetracyclines

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8
Q

What antimicrobial target metabolic pathways?

A

-sulfonamides
-trimethoprim

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9
Q

What antimicrobial target cell membrane?

A

-lipopeptides
-polymyxin
-daptomycin

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10
Q

What antimicrobial targets the cell wall?

A

-beta-lactams
-cephalosporins
-glycopeptides
-glycolipopetides

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11
Q

What antimicrobial targets DNA and RNA synthesis?

A

-fluoroquinolones
-nitrofurantoin
-rifampin

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12
Q

Beta-lactam antimicrobial agents

A

-beta-lactam agents contain a four-member, nitrogen-containing ring at the core
-these antimicrobial agents kill bacteria by inhibiting PBPs (transpeptidase) that catalyze the final step in the cell wall biosynthesis, the cross-linking of the peptidoglycan

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13
Q

Beta-lactam class: Pencillins

A

1st generation
- penicillin
-ampicillin
-piperacillin
-mezlocillin

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14
Q

Beta-Lactam class: Cephalosporins

A

3rd generations
-cefazolin
-cefuroxime
-cefotetan
-cefotaxime
-ceftriaxone
-ceftazidime
-cefepime

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15
Q

Beta-lactam class: monobactams

A

3rd generations
-aztreonam

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16
Q

Beta-lactam class: Carbapenems

A

3rd generation
-imipenem
-meropenem
-doripenem

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17
Q

Structure-activity relationship in beta-lactam antimicrobial agents

A

-the core chemical structure of all penicillins consists of a beta lactim ring, a thiazolidine ring, and a side chain (6-aminopenicillanic acid)
-the antibiotic activity of penicillins lies within the ring
-the core chemical structure of cephalosporins is a beta-lactam ring fused to a dihydrothiazine ring
-changes in R1 and R2 vary by individual cephalosporin

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18
Q

What happens when the R1 group is changed

A

-affect the spectrum of activity

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19
Q

What happens when the R2 group is changed?

A

-affects pharmacology

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20
Q

Spectrum of activity for penicillin

A

-many gram positives, some gram negatives, many anaerobes
-can be used to treat streptococcal pharyngitis, syphilis, actinomyces

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21
Q

Penicillin (natural)

A

-first isolated by Alexander Flemming in 1982
-produced from penicillium molds
-estimated to save 12-15 % of Allied lives in WWII
-benzylpenicillin (Pen G) and Phenoxymethyl penicillin (Pen V)
** Pen V has greater oral availability

22
Q

What diseases can penicillin treat?

A

-can be used to treat streptococcal pharyngitis, syphilis, actinomyces

23
Q

Penicillinase stable penicillins

A

-they are resistant to natural penicillins and were discovered immediately upon widespread intro in the 1940s
-approx. 90% of staphylococci produce beta-lactamase rendering natural penicillins ineffective
-used to treat MSSA (methicillin-susceptible staphylococci)

24
Q

What are some anti-staphylococcal penicillins?

A

-oxacillin, nafcillin, dicloxacillin, methicillin

25
Q

What are anti-staphylococcal penicillins?

A

have a bulky hydrophobic side chain to protect the beta-lactam ring

26
Q

Aminopenicillins

A

-developed to expand the spectrum into gram negatives
-ampicillin (1962) and amoxicillin (1972)
-amoxicillin is preferred for oral formulations
-susceptible to beta-lactamases
-can be combined with a BL inhibitor (amox-clavulanate or amp-sulbactam)
-useful for group B streptococci, Otitis media ( S pnemo, H. influenzae), some UTIs

27
Q

Ureidopenicillins

A

ex: piperacillin
-A wide spectrum of activity, including many gram-positive and negative bacteria. Including pseudomonas and anaerobes
-combined with tazobactam (piperacillin-Tazobactam Zosyn)

28
Q

Cephalosporins

A

-derived from cephalosporium acremonium (acremonium chrysogenum)
-discovered in 1954 by Giuseppe Brotzu in sewage outflow which has broad-spectrum antimicrobial properties
-purified culture extracts yielded cephalosporin C, which was the basis of future development
-The core structure is a beta-lactam ring fused to a dihydrothiazine ring. The R1 and R2 groups vary
-cephalothin was the first pharmaceutical form introduced in 1964

29
Q

Generations of cephalosporins

A

-cephalosporins are grouped by generations which refer to their spectrum of activity

30
Q

1st generation of cephalosporins

A

Activity: primarily gram positives (staph and strep)
ex: cephalothin, cefazolin, cefadroxil

31
Q

2nd generation of cephalosporins

A

Activity: some gram-negative (H. influenzae, M.catarrhalis, and Neisseria), primarily gram-positive.
ex: cefuroxime, cephamycins (cefotetan, cefoxitin)
** Cephamycins are less effective for staph but more effective for Enterobacteriaceae and very effective for anaerobes such as B.fragilis

32
Q

3rd generation of cephalosporins

A

activity: much more effective against gram negatives (including pseudomonas)
ex: ceftazidime, ceftriaxone

33
Q

4th generation of cephalosporins

A

activity: widest spectrum of all generations (including pseudomonas)
ex: cefepime

34
Q

5th generation of cephalosporins

A

activity: MRSA-active cephalosporins
ex: ceftaroline

35
Q

Carbapenems

A

-were first isolated from the soil bacterium streptomyces cattleya in 1976 (Thienamycin)
-contain a “C” at position 1 and a double bond at 2-3 in the lactam-linked ring
-broad range (G+, G-, anaerobes)
-resistant to most beta-lactamases
-often considered drugs of last resort for serious G- infections though resistance to them is spreading rapidly
-IV only, distributed widely throughout the body
-Imipenem is degraded by DHP-1 in the renal tubules, so must be co-administered with cilastatin

36
Q

monobactams

A

-consist of a monocyclic beta-lactam core structure
-originally isolated from choromobacterium violaceum
-high affinity for PBP3 of G-s
-Aztreonam is the only FDA-cleared monobactam
-highly effective G-infections, no activity against G+ or anaerobes
-IV formulation only (no oral)
-distributed widely throughout the body

37
Q

General mechanisms of antimicrobial resistance

A

-enzymatic degradation or modification of the antimicrobial agent
-decreased uptake or accumulation of the antimicrobial agent
-altered target of the antimicrobial agent
-any combo of the above
** Resistance can be intrinsic or acquired

38
Q

Emergence of resistance

A
  1. Emergence of new genes (methicillin-resistant staphylococci, vancomycin-resistant enterococci)
  2. spread of old genes to new hosts (ex: penicillin-resistant Neisseria gonorrhoeae)
  3. Mutations of old genes resulting in more potent resistance (ex: beta-lactamase-mediated resistance to advanced cephalosporins in Escherichia coli and Klebsiella spp.)
  4. Emergence of intrinsically resistant opportunistic bacteria (stenotrophomonas)
39
Q

What does lateral (horizontal) gene transfer allow in bacteria?

A

-for a tremendous amount of information to flow from one organism to another

40
Q

Resistance to beta-lactam antibiotics

A

-this emerged almost simultaneously with the introduction of the drugs themselves

41
Q

Major mechanisms of B-lactam resistance?

A
  1. Decreased entry: porin mutation
  2. Degrade antibiotic: B-lactamases
  3. Remove antibiotic: efflux pumps
  4. Altered target: PBP mutation
42
Q

Altered PBP (Penicillin Binding protein) mediated resistance to beta-lactams

A

-predominantly in gram-positive
different mechanism:
*overproduction (rare)
*mutation (to low-affinity protein that isn’t bound by a drug) ex: AmpR in E.faecium
*uptake of foreign PBPs (PBP2a MecA) in MRSA
-transferred by SCC (staphylococcal chromosomal cassette)
*Hybrid PBPs in S pneumoniae

43
Q

Beta-lactamase mediated resistance to Beta lactams

A

-predominantly in gram negatives and some gram-positive
-staphylococcal beta-lactamase is responsible for early resistance against penicillin, driving the development of anti-staphylococcal penicillins (Nafcillin, etc.)
-beta-lactamase production is most characterized in gram-negative organisms
-organized by sequence (ambler) or substrate (Bush-Jacoby)

44
Q

What are the several agents formulated with beta-lactamase inhibitors?

A

-amoxicillin-clavulanic acid (Augmentin)
-Ampicillin-Sulbactam (Unasyn)
-Piperacillin-Tazobactam (zosyn)
-Ceftazidime-Avibactam (Avycaz)
-Meropenem-Vaborbactam (Vabomere)

45
Q

Beta-Lactamase Inhibitors

A

-they structurally resemble beta-lactams, though they do not have an anti-bacterial activity they inhibit Class A beta-lactamases, and allow their partner beta-lactam to work
- five are in use: clavulanic acid, sulbactam, tazobactam, avibactam, vaborbactam
-avibactam can also inhibit Class C beta-lactamases and is also more effective against KPC beta-lactamases than the others

46
Q

Common combinations of beta-lactamase inhibitors

A
  1. Amoxicillin-clavulanate
  2. Ampicillin-sulbactam
  3. Pipercillin-tazobactam
  4. Ticarcillin-clavulante
    5.Ceftazidime- avibactam
  5. Meropenem-vaborbactam
47
Q

Glycopeptide and Glycolipopeptides

A

-bind to the end of the peptidoglycan, interfering with transpeptidation
-inhibit cell wall synthesis and growth of gram-positive bacteria
-are large and cannot effectively penetrate gram-negative cell walls
-ex of glycopeptides: vancomycin and teicoplanin
- ex of glycolipopeptides: oritavancin and telavancin (also depolarizes membranes)

48
Q

Vancomycin resistance to Enterococci

A
  • 9 different “Van” variations, all of which change the terminal D-ala – D-ala to either D-lac or D-ser
    -The most common is vanA, a 9-gene operon spread on a transposon (Tn1546) almost exclusively in E.Faecium. Not well understood why it isn’t found in E. faecalis. Confers resistance to vancomycin and teicoplanin
    -VanC is intrinsic to E.gallinarum and E.casseliflavus and confers lower-level resistance to vancomycin, VanR
    -the resistance is mediated by VanA to produce an altered ligase enzyme with altered substrate specificity allowing for amino acids other than alanine to be added to the terminal peptide
49
Q

Vancomycin resistance to S.aureus

A

-much feared and closely monitored
-currently <20 reported cases in the US, all due to VanA acquisition
-VISA (intermediate resistance) appears to be a non-specific resistance linked to a thickened cell wall phenotype

50
Q

How does vancomycin work?

A

-the usual peptidoglycan terminus in the bacterial cell wall is d-ala-d-ala. Vancomycin can bind to the terminal d-ala-d-ala and prevent cross-linking of peptidoglycan sheets resulting in cell death
-terminal peptides composed of d-ala-d-X where X is not alanine do not bind to vancomycin
-vancomycin resistance is caused by an altered peptidoglycan terminus (ex: d-ala-d-lac instead of ala) resulting in reduced vancomycin binding and failure to prevent cell wall synthesis

51
Q

Lipopeptides (Daptomycin)

A

-are membrane-disrupting agents
-have a hydrophobic tail that can be inserted into the membrane of gram-positive organisms, causing permeabilization and death (bactericidal)
-resistance is rare and most often occurs with prolonged therapy
-not well described, appears to involve multiple changes to the cell wall/ membrane, including a nonspecific thickening as seen in VISA strains

52
Q

Polymxin (colistin)

A

-membrane disrupting agent
-cationic polypeptides that bind to LPS and disrupt the inner and outer membranes of gram-negative organisms
-isolated from Bacillus polymyxa in 1949
-colistin was used in the 1950s then abandoned due to nephrotoxicity until the 2010s due to increasing resistance to other antibiotics (drug of last resort)
-poorly distributed to cerebrospinal fluid, biliary tract, pleural fluid and joint fluid
-poor activity against many species of Gram-negative bacilli (proteus, Serratia, Providencia) as well as most gram-negative cocci, G+S, and anaerobes
-recently described plasmid-borne resistance (Mrc-1) in E.coli, this gene produces an enzyme which alters lipids in the cell membrane of GNB (<10 cases so car)

Microbiology lecture (5 decks)

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