Intro to Antibiotics Flashcards
1
Q
How do glycopeptdes and lipoglycopeptides differ mechnistically from the beta lactams?
A
- Beta lactams bind to an inhibit transpeptidase
- Glycopeptides and lipoglycopeptides bind the cell wall precursors and prevent cell wall cross-linking and extension
2
Q
Which antibiotic relies on the renal dipeptidase inhibitor, celastatin?
A
Imipenem
3
Q
What differentiates second generation cephalosporins from cephamycins?
A
- The bacterial spectrum
- Cephamycins are active against B. fragils and some Serratia spp.
- Second generation cephalosporins (cefaclor, cefprozil, and cefuroxime) are NOT
4
Q
What is the general spectrum of coverage for the monobactam, aztreonam?
A
Gram-negative, aerobes
5
Q
What is the difference in MOA between oxazolidinones and streptogramins?
A
- Oxazolidinones bind to the P site on the ribosome and prevent initiation of protein synthesis
- Streptogramins have a two-headed mechanism as they are given clinically in a combine ratio (30% quinupristin and 70% dalfopistin)
- Quinupristin inhibits polypeptide elongation and induces early termination of protein synthesis
- Dalfopistin impedes the polypeptide chain formation and induces conformational change in the 50S ribosomal subunit that enhances quinupristin binding!
6
Q
Why are the macrolides grouped w/ the ketolides?
What distinguishes a macrolide from a ketolide?
A
- Grouped together because of similar MOA, chemical structure, and adverse effects
- Their bacterial coverage differs, Ketolides can be active in macrolide resistant strains
7
Q
What is the MOA for Penicillins?
What must bacterial cells be doing in order for Penicillin to be effective?
A
- Interfering w/ the transpeptidase (peniciilin-binding protein) rxn, which inhibits peptidoglycan cell wall crosslinking and leads to a lack of cell wall rigidity
- Only kill bacterial cells when they are actively growing!
8
Q
What are the 4 bacterial mechanisms for resistance to Penicillins?
A
1) Beta lactamases
2) Alteration of porin channels (porins are the gateway for penicillins to access the cell wall in a gram-negative bacteria)
3) Altering molecular structure of PBP/transpeptidase (point mutation in binding pocket)
4) Upregulation of efflux pumps (actively transports penicillin out of cell)
9
Q
Penicillin G has its greatest bacterial coverage against?
A
- Gram-positive cocci (**S. pneumoniae, S. pyogenes, and Viridans group Streptococci)
- Certain Gram-negative cocci
- non-β-lactamase-producing anaerobes (C. perfringens)
10
Q
Aminopenicillins were created for improvement of?
Their expanded coverage is attributed to?
A
- Gram negative coverage
- Increased binding affinity to transpeptidase/PBP and increased penetration through the outer membrane of gram negative bacteria
11
Q
Aminopenicillins cover gram positives and what major gram negatives?
A
- E. coli
- The enterics (Proteus, Salmonella, Shigella etc..)
12
Q
Combination with what improves the effectivness of Aminopenicillins?
A
Beta-lactamase inhibitors
13
Q
What are the 4 drugs that fall in the class known as Penicillinase resistant penicillins?
A
1) Methicillin
2) Nafcillin
3) Oxacillin
4) Dicloxacillin
14
Q
What is the one key difference in bacterial mechanisms of resistance to penicillinase resistant penicillins?
Specifically this class of drugs is resistant to the penicillinase produced by?
Can resistant phenotypes still arise?
A
- They are less susceptible to penicillinase (beta lactamase) when compared to other penicillins
- Specifically they are resistant to the penicillinase produced by staphylococcal specices (S. aureus and S. epidermidis)
- -* Resistant phenotypes can still arise as seen in development of MRSA and methicillin resistant S. epidermidis (MRSE)
15
Q
What is considered the primary antibiotic for staphylococcal infections once methicillin resistance has been ruled out?
A
Penicillinase resistant penicillins
16
Q
Ticarcillin, carbenicillin, piperacillin, and mezlocillin belong to what antibiotic drug class?
A
Anti-pseudomonal penicillins
17
Q
Which antipseudomonal penicillin is the only one in the drug class still used clinically in the US?
A
Piperacillin
18
Q
Which antibiotic has the broadest spectrum out of all other penicillins?
A
Piperacillin
19
Q
What was the main aim in the creation of the antipseudomal penicillins, why?
A
- To make a penicillin that would cover P. aeruginosa, due to it being resistant to many differnt antibiotics
- Another goal, was to expand penicillin gram negative coverage
20
Q
What is the MOA of action for Cephalosporins; work best when?
How are they different from penicillins in regards to resistance and coverage?
A
- Almost identical MOA as penicillins; work best in rapidly proliferating bacteria
- Although, they can be degraded by beta-lactamases, they are more stable to many beta-lactamases that would degrade penicillins
- Tend to have broader spectrum of activity versus penicillins
21
Q
What are the 4 bacterial mechanisms of resistance to Cephalosporins?
A
1) Beta-lactamases
2) Altering porin channels (preventing cephalosporin from entering the gram negative cell to inhibit cell wall synthesis)
3) Altering cephalosporin binding to transpeptidase due to point mutations in the cephalosporing binding pocket
3) Increased efflux of cephalosporin out of the cell
*Same mechanism used against penicillin!
22
Q
What is the general rule for cephalosporin coverage by the first, second, and third generation classes?
A
- First generations have better gram positive coverage (i.e., S. aureus)
- Second generations fall in the middle and provide ok coverage for both gram positive and gram negative
- Third generations have better gram negative coverage (i.e., E. coli)
23
Q
What is the most common side effect to Cephalosporin?
A
- Just like penicillin, hypersensitivity to the beta lactam ring
- Most common manifesting as a maculopapular rash developing several days after therapy
*A hypersensitivity reaction to cephalosporin would likely have cross reactivity to penicillin, due to the structural similarities. Important to note so that you can avoid these drugs if allergy of either is known.
24
Q
Cefazolin and cephalexin belong to what antibiotic class?
A
First generation cephalosporins
25
First generation cephalosporins are known for their acitivity against which bacteria?
What are the exceptions?
- Gram positive cocci such as ***S. aureus***
- Most gram-positive cocci are susceptible
- Main exceptions include **MRSA, enterococci**, and **S. epidermidis**
26
Cefuroxime, cefaclor, and cefprozil belong to what antibiotic class?
Second-generation cephalosporines
27
Cefotetan and cefoxitin belong to what antibiotic class?
Second generation cephalosporins known as **cephamycins**
28
Second generation cephalosporins should not be used to treat which bacteria due to the increased propensity to select for resistant mutants that posses constitutive expression of beta lactamases.
*Enterobacter spp*
29
Which adverse effects may be produced by the cephamycin (second generation cephalosporin), Cefotetan?
- **Hypoprothrombinemia** and **bleeding** due to the methylthiotetrazole ring on its structure
- Also, due to this ring, cefotetan can elicit a **disulfiram-like reaction**, therefore **alcohol must be avoided**
30
Cefotaxime, cefixime, cefdinir, ceftibuten, ceftazidime, ceftriaxone, cefpodoxime proxetil, and cefditorem pivoxil are antibiotics in what class?
Third generation cephalosporins
31
What is the only third generation cephalosporine that is active against *P. aeruginosa?*
Ceftazidime
32
What are 2 of the important side effects produced by an antiobiotics in the third generation cephalosporin class?
Which antibiotic specifically?
- **Ceftriaxone** may displace bilirubin due to its **high binding affinity** for serum albumin ---\> **jaundice in neonates**
- Also has a **high affinity** for **calcium**, and may also lead to **biliary pseudolithiasis (i.e., gallstones)**
33
Cefepime belongs to what class of antibiotics?
Fourth generation cephalosporin
34
Although, fourth generation cephalosporins (cefepime) are bacterially resisted like the other cephalosporins these drugs are resistant to certain beta lactamases, what are they?
Allows it to exhibit activity against which bacteria?
- **AmpC beta lactamases**
- Activity in ***Enterobacter spp. and Pseudomonas spp.***
35
The fourth generation cephalosporins provide what type of bacterial coverage?
Expanded **gram-negative** coverage: ***P. aeruginosa, Entrobacter spp. (EXCELLENT coverage)**,* and most gram positives
36
Ceftraroline fasamil and ceftolozane are part of what antibiotic class?
Fifth generation cephalosporines
37
The fifth generation cephalosporine, ceftazidime is normally found co-formulated with?
Beta-lactamase inhibitor tazobactam
38
Fifth generation cephalosporins really shine when it comes to tough bugs like?
- Ceftaroline is active against **MRSA** and **penicillin-resistant *S. pneumoniae***
- Ceftolozane against ***Pseudomonas spp.*** and is co-formulated w/ beta-lactamase inhibitor tazobactam to provide increased activity against **enterobacteriaceae (GRAM NEGATIVES)**
39
Imipenem, meropenem, doripenem, and ertapenem are part of what antibiotic class?
Carbapenems
40
What is the clinical relevancy of imipenem?
- First drug of the Carbapenem class and tends to have **more adverse effects**
- Requires **combination** w/ a **renal dipeptidase inhibitor**, celastatin, in order to maintain clinically relevant concentrations in the body
41
Carbapenems tend to be relatively resistant to what?
Other than the mechanisms bacteria use to resist penicillin and cephalosporins, what is another way they may have reistance to these drugs?
- Relatively resistant to degradation by beta lactamases
- Batceria can upregulate enzymes to degrade carbapenems, called carbapenemases, which degrade the drugs structure
42
Carbapenems as a class are good agents for targeting?
Gram-negative bacteria
43
Aztreoname belongs to what antibiotic class?
What is unique about this class?
What MOA does this class have?
- Monobactams
- Have a **monolytic beta lactam ring**
- Cell wall inhibitor, like penicillins and cephalosporins
44
Vancomycin is part of what class of antibiotics?
Telavancin, dalbavancin, and oritavancin are part of what class?
- Glycopeptides
- Lipoglycopeptides
45
Monobactums cover which bacteria class?
A major use of this class of antibiotics is what?
- Gram negative and aerobes
- **Major use** = tx of gram-negative infections in pts that cannot tolerate other beta lactam drugs due to an allergy
46
What is the MOA for glycopeptides vs. lipoglycopeptides antibiotics?
**- Glycopeptides** are cell wall synthesis inhibitors and bind to the D-alanyl-D-alanine terminus of cell wall precursor units w/ high affinity. Leading to **inhibition of transglycosylase**
**- Lipoglycopeptides** improve on this process by **dimerizing** and embedding their lipid structures into the bacteral cell membrane. Allows for improved binding to the D-alanyl-D-alanine terminus and **increased potency**
47
Oritavancin and telavancin (lipoglycopeptides) have a more rapid cidal effect how?
Directly disrupt the bacterial membrane
48
What bacterial method of resistance exists for the glycopeptides antibiotics?
Changes to the glycopeptide binding site, which is located on a **transposon**, and allows site to change from D-alanyl-D-alanine --\> D-lactate or D-serine
49
Glycopeptide and lipoglycopeptides have affects on what bacterial class?
Gram-positive bacteria
50
How must glycopeptides and lipoglycopeptides be administered, why?
- Are poorly absorbed after oral administration, will just sit in the gut
- Must be given by IV
51
Clavulanic acid, sulbactam, and tazobactam are part of what antibiotic class?
Beta lactamase inhibitors
52
Which antibiotic is always co-formulated with the beta lactamase inhibitor tazobactam and why?
**Piperacillin** to give it the best possible **gram-negative coverage**
53
Linezolid and tedizolid are part of what class of antibiotics?
Oxazolidinones (protein synthesis inhibitors)
54
What is the MOA of Oxazolidinones?
Bactericidal or bacterostatic?
- Protein synthesis inhibitor --\> bind to the **P site** on the **50S ribosomal subunit**. Preventing formation of the (fMet) tRNA complex.
- Primarily bacteriostatic, however are bactericidal against **streptococci**
55
What are the bacterial mechanisms of resistance to Oxazolidinones?
- Point mutations on the **23S rRNA** (binding site) on the 50S ribosomal subunit
- Methyltransferase that can modify th ribosome and alter binding
56
Oxazolidinones are active against majority of what type of bacteria?
Gram-positive
57
What are the 3 different categories of adverse effects caused by oxazolidinones?
1) **Myelosuppression**, and most commonly thrombocytopenia (mainly linezolid)
2) **Mitochondrial toxicity**: lactic acidosis, optic neuritis, and perirpheral neuropathy (mainly \>6 wks use of linezolid)
3) **Drug-drug interactions**: weak inhibitor of MAO --\> avoid andrenergic or serotonergic agents (SSRIs) can cause serotonin syndrome (linezolid)
58
Erythromycin, clarithromycin, azithromycin, and fidaxomicin are part of what class of antibiotics?
Telithromycin?
- Macrolides
- Telithromycin = Ketolide
59
What is the MOA for macrolides and ketolides?
Bacteriostatic or bactericidal?
- Protein synthesis inhibitors --\> bind **reversibly** to the **50S ribosomal subunit** and prevents translocation of the tRNA from the A-site to P-site
- Can also elicit a **confomational change** in the bacterial ribosome which can result in **indirect** inhibition of **transpeptidation**
- Can **inhibit** the formation of the **50S ribosomal subunit**
- Are **bacteriostatic**, but bactericidal at high enough concentrations
60
What are the 4 mechanism of bacterial resistance to macrolides and ketolides?
1) Active drug **efflux**
2) Production of **methylase** which shields th ribosome
3) **Degradation** of the drug itself
4) **Mutations** in the 50S subunit can occur
61
Which antibiotic used to tx C. difficile colitis?
Fidaxomicin (macrolide)
62
Macrolides and ketolides are active against what main bacteria?
Streptococci, pneumococci, staphylococci
63
Quinupristin and dalfopristin are part of what antibiotic class?
How are they available clinically?
- Streptogramins
- Dalfopristin = Streptogramin A
- Quinupristin = Streptogramin B
- Only available in a **combined ratio of 30% q and 70% d**
64
What is the MOA for streptogramins; how do they work in synergy?
- Quinupristin **inhibits polypeptide elongation** and induces early termination of protein synthesis
- Dalfopristin binds 50S ribsosomal subunit, at a site nearby the quinupristin site, inducing conformational change and enhancing the binding of quinupristin + impedes polypeptide chain formation
65
What are the 3 bacterial mechanism of resistance to Streptogramins?
1) Enzymatic inactivation of dalfopristin
2) Altering quinupristin binding site
3) Both drugs can be subjected to active drug efflux
66
Streptogramins are active against what class of bacteria?
- Gram-positives
- Important to note this combo is **inactive** against gram-negatives
67
Tigecycline belongs to what class of antibiotics?
Glycylcyclines
68
What is the MOA for tetracyclines and glycylcylines?
Bactericidal or bacteriostatic?
- Bind the **30S ribosomal subunit** and **prevent aminoacyl tRNA** from entering the **acceptor (A) site**; inhibits protein synthesis by indirectly blocking polypeptide elongation
- Bacteriostatic
69
What are the 3 mechanisms of bacterial resistance to tetracyclines and glycylcyclines?
1) Reduced intracellular concentration of the drug due to reduced influx or increased efflux (glycylcylines can resist the efflux sometimes)
2) Upregulation of protein that dislodges the drugs from their target
3) Can be enzymatically inactivated
70
What types of bacteria do tetracyclines and glycylcyclines provide coverage for?
- Tetracyclines: broad-spectrum, but more active against **gram +** and **anaerobes**
- Glycylcyclines: same as tetra w/ added activity against some bacteria that have resistance to tetracyclines
71
Streptomycin, gentamycin, tobramycin, amikacin, neomycin, paromomycin, kanamycin, and netilmicin are part of what class of antibiotics?
Aminoglycosides
72
What is the MOA for aminoglycosides? (hint: there are 3 of them)
- Bind to the 30S ribosomal subunit and act as **irreversible** inhibitors of protein synthesis by:
1) Inhibiting initiation by fixing the 50S and 30S subunits to the AUG start codon on the mRNA
2) Inhibit continuation of translation by inhibiting formation of 70S complex
3) Introduce errors into protein synthesis (i.e., incorrect AAs)
73
Aminoglycosides are bacteriostatic or bactericidal?
BACTERICIDAL!
74
Transport of aminoglycosides into bacteria is enhanced by?
Cell wall active antibiotics such as: **penicillin** and **vancomycin**
75
What are the 3 distinct mechanisms in which bacteria can be resistant to aminoglycosides?
1) Enzymatic inactivation (**most common**) - modify structure thru phosphorylation, acetylation, or adenylation
2) Mutation or deletion of porins inhibiting entry into gram-negatives
3) Mutations of the 30S ribosomal subunit
76
The spectrum of aminoglycosides mainly consists of antibacterial activity against?
**Aerobic gram-negative bacteria** (i.e., Enterobacter, E. coli, Klebsiella, Pseudomonas, Serratia spp.)
77
Antibiotics ending in the suffix "-oxacin" belong to what group?
Fluoroquinones
78
What proteins do fluoroquinolones inhibit (MOA)?
**Topoisomerase II (DNA gyrase)** and **topoisomerase IV**
## Footnote
**\*DNA/RNA synthesis inhibitors!**
79
What is the primary MOA of fluoroquinolones antibacterial action in gram-positive bacteria?
Gram negative?
- Inhibition of **DNA gyrase** is primary method for **gram-negative**
- Inhibition of **topoisomerase IV** is primary method for **gram-positive**
80
What mechanisms of bacterial resistance exist for fluoroquinolones?
- Mutations to the quinolone binding region on either DNA gyrase or topoisomerase IV
- Active drug **efflux**
- Least common = upregulation of proteins that protect and shield both DNA gyrase and topoisomerase IV
81
Why are sulfonamides and benzylpyrimidine synergistic?
- **Inhibit subsequent steps** in the **tetrahydrofolate biosynthetic pathway**
**- Trimethoprim** is potent and selective competitive inhibitor of bacterial **dihydrofloate reductase**
- **Sulfamthoxazole** is structural analog of **PABA** and acts as a competitive non-functional **mimic** of PABA to inhibit **dihydropteroate synthase**
82
What class of antibiotics does sulfamethoxazole belong to?
Trimethoprim?
- Sulfonamides
- Benzylpyrimidines
83
What are mechanisms of bacterial resistance to sulfonamides and benzylpyrimidines?
- Changes to the bacterial tetrahydrofolate biosynthetic pathway
- Sulfamethoxazole resistance can develop due to bacterial **overproduction** of PABA (outcompetes the drug) or reduced binding to dihydropteroate synthase or decreased entry into the cell
- Trimethoprim resistance due to reduced bacterial permeability or upregulation of dihydrofolate reductase or mutations in dihydrofolate which reduce binding
84
TMP/SMX is used to treat what bacterial infections?
Many kinds, but notabl is **MRSA** and ***P.jiroveci* pneumonia**
85
What are the MOA for polymyxins?
- Are strongly attracted to the phospholipid bilayer that makes up outer membrane of **gram-negative** bacteria and act as **cationic detergents**, disrupting the membrane
- Bind to and **inactivate endotoxin**, preventing its release into circulation, preventing fever, diarrhea, and potential endotoxic shock (i.e, **septic shock**)
- Are **bactericidal**
86
Polymyxins are used for antibiotic coverage of which bacteria?
Why only one type?
- Gram-negative ONLY, primarily aerobes
- Gram positives **do not** posses an outer membrane
