Antibiotics Flashcards
1
Q
What is ‘selective toxicity’?
A
An ideal antimicrobial agent exhibits selective toxicity, which means that the drug is harmful to a pathogen without being harmful to the host.
2
Q
List four mechanisms of action under which antimicrobial drugs can be discuseed.
A
(1) Inhibition of cell wall synthesis
(2) Inhibition of cell membrane function (e.g., cell wall integrity)
(3) Inhibition of protein synthesis
(4) Inhibition of nucleic acid synthesis
3
Q
What are the four main categories of Beta lactam antibiotics? And what is their mechanism of action?
A
Penicillins
Cephalosporins
Monobactams
Carbapenems
All Beta -lactam drugs are selective inhibitors of bacterial cell wall synthesis –targeting peptidoglycan (Peptidoglycan (unique to bacteria) consists of polysaccharides and a highly cross-linked polypeptides. This cross-linkage is an important drug target.)
4
Q
What is penicillin’s mechanism of action?
A
Penicillins binds to bacterial PBPs (Penicillin Binding Proteins)–some of which are enzymes involved in transpeptidation of the peptidoglycan component of the bacterial cell wall. Penicillins’ binding to PBP blocks final transpeptidation and thus peptidoglycan synthesis is inhibited. It interferes with the releasing of the D-Alanine and thus the cell wall cannot grow poperly.
5
Q
As you get more advanced in the penicillin family, what are you getting more coverage of?
A
You get more gram negative coverage with the more recently developed, higher class, antibiotics.
6
Q
What are the four subcategories of penicillins?
A
Natural penicillins
Anti-staphylococcal penicillins
Aminopenicillins (Ampicillin, Amoxicillin)
Anti-pseudomonal penicillins (Piperacillin)
7
Q
How good is penicillin’s coverage of Streptococcus pyogenes (Group A)?
A
EXCELLENT! Drug of choice!!!
8
Q
Describe natural penicillins spectrum of activity
A
(1) Streptococcus examples
- Group A (excellent)
- Pneumococcus (major resistance problems - up to 40% are non-susceptible to penicillin.)
- Viridans (coverage okay—however, resistance occasionally)
(2) Enterococcus (some)
(3) Few Gram negative cocci: Neisseria meningitides okay; but now too much resistance among Neisseria gonorrhoeae
(4) Gram-positive anaerobes (some mouth flora - often used for dental abscess)
(5) Spirochetes (e.g., syphilis)
9
Q
What are aminopenicillins? List two examples.
A
Amionpenicllins are Beta Lactams. They were discussed after natural penicillins in class. Cover even more than penicillins. Ampicillin (IV) and Amoxicillin (PO) are examples of aminopenicillins.
10
Q
What is the spectrum of activity for aminopenicilins?
A
Similar to penicillin plus (better gram negative coverage, but still simple coverage) -
- More enterococcus are susceptible
- Some “simple” community-acquired Gram-negatives (e.g., E. coli, Proteus, Haemophilus influenzae), although resistance is rising
- Important/unique use: Listeria (Gram-positive rod causing meningitis in neonates and immunocompromised pts)
11
Q
Give an example of an Anti-pseudomonal ureidopenicillins.
A
Piperacillin (IV)
12
Q
What, because of developed resistance can natural penicillins no longer be used to treat?
A
Neisseria gonorrhoeae
13
Q
What is the benefit to piperacillin?
A
Similar to ampicillin plus greatly improved Gram-negative coverage including for hospital-acquired organisms (e.g., Pseudomonas, Enterobacter, Acinetobacter)
Much more gram negative coverage!!
14
Q
What are penicillin and ampicillin, piperacillin all still susceptible to?
A
Penicillin and ampicillin, and piperacillin are susceptible to Beta-lactamases and thus have poor staphylococcal activity and poor Gram negative anaerobic coverage
15
Q
What is beta-lactamase?
A
Beta-lactamases can cleave the beta-lactam ring of penicillin, ampicillin, piperacillin. This was brought up in relation to staphylococci, which are able to produce this enzyme, and thus this is an example of a bacteria evolving to evade antibiotics, beta lactam antibiotics.
16
Q
What did pharm do in response to the discovery of beta-lactamase?
A
Started adding beta-lactamase inhibitors, clavulanate (to amoxicillin PO), sulbbactam (to ampicillin IV), tazobactam (to piperacillin IV). This change expands the coverage to include methicillin-sensitive Staphylococci and more anaerobic coverage, including gram negative anaerobes. (Now have really great anaerobic coverage.)
Nafcillin (IV) and Dicloxacillin (po) also work against bacteria with beta-lacatamase, becuase they are not affected by these enzymes
17
Q
What is special about Nafcillin (IV) and
Dicloxacillin (po)?
A
They are part of the penicillin family. They are penicillinase-resistant penicillins. The bacteria evolved beta lactamase, and these handle this because they are not affected by these enzymes.
18
Q
What is methicillin and when is it used?
A
Methicillin was the first penicillinase-resistant penicillin developed, but it is no longer used secondary to high incidence of intestinal nephritis (kidney toxicity)
19
Q
Discuss Nafcilin (IV) and Dicloxacillin (po) coverage.
A
These penicillinase-resistant (anti-staph) penicillins only cover methicillin-sensitive staphylococci and some streptococci (particularly beta-hemolytic—like Group A)
- No coverage against methicillin-resistant Staphylococcus aureus (MRSA). Most coagulase-negative staphylococci are also methicillin-resistant.
- No coverage against enterococci
20
Q
How do cephalosporins act?
A
They too contain a Beta lactam ring and target cell wall synthesis
21
Q
As you increase in class of the cephalosporins, what coverage do you get more of?
A
More gram negative coverage!
22
Q
What is the spectrum of activity for 1st generation cephalosporins (Cefazolin (IV), cephalexin (po)) ?
A
Gram-positives: methicillin-sensitive Staphylococcus aureus (MSSA), Beta-hemolyitic Streptococci, penicillin-sensitive Strep pneumoniae
Some “simple” community-acquired aerobic Gram negative rods
NOT MRSA (none of the commonly used cephalosporins have activity against MRSA) NOT enterococcus (no cephalosporin has activity against enterococcus)
23
Q
What is the benefit of 2nd generation cephalosporin (Cefuroxime (IV/po), cefoxitin (IV)) coverage and when is it used?
A
2nd generation coverage, Cefuroxime (IV/po), cefoxitin (IV), has More Gram-negative coverage. Cefuroxime particularly for better respiratory coverage (e.g., outpatient pneumonia)—Haemophilus influenzae, Streptococcus pneumoniae, some enteric Gram negatives. Cefoxitin unique feature—decent anaerobic coverage too. However, these 2nd generation drugs are being phased out.
24
Q
What is the added benefit of 3rd generation (Ceftriaxone (IV), cefotaxime (IV)) cephalosporin?
A
- greater activity against gram-negative bacteria
- maintains gram-positive coverage
- Ceftriaxone has activity against Borrelia burgdorferi (Lyme disease).
- **Ceftriaxone, cefotaxime cross blood-brain barrier—effective for treatment of central nervous system infections (e.g., meningitis)
25
What is going on with 4th generation (Cefepime (IV)) cephalosporins?
Most advanced, greater and greater gram negative coverage – very broad coverage – can now cover the resistant gram negatives found in hospitals.
Like the third generation can cross the blood brain barrier and can treat meningitis – used in healthcare setting
26
What is ceftraroline?
*New drug: ceftaroline is only cephalosporin
| with activity against MRSA
27
With cephalosporins what allergy are you worried about?
Cross-allergenicity between the penicillins and cephalosporins is uncertain but is probably around 5–10%
28
As a physician should you use narrow or broad spectrum antibiotics first?
Use most narrow-spectrum antimicrobial whenever possible. Save broadest-spectrum antimicrobials for the patients who most need them the most. With liberal use of antibiotics, including our current “broad-spectrum” antibiotics, drug resistance can be expected to further increase.
29
Does penicillin have good activity against Group A streptococci?
Yes
30
Does penicillin have good activity against Staphylococci?
No
31
Does ampicillin have good activity against enterococcus?
Yes
32
Does ampicillin have good activity against Staphylococci?
No
33
What agent can be added to ampicillin to deal with beta-lactamases commonly produced by Staphylococci?
Sulbactam
34
Does ampicillin-sulbactam have good activity against methicillin-sensitive Staphylococci?
Yes
35
Which has activity against Pseudomonas and overall a wider Gram negative spectrum, ampicillin or piperacillin?
Piperacillin
36
Does piperacillin have good activity against Staphylococci?
No
37
Does piperacillin-tazobactam have good activity against methicillin-sensitive Staphylococci?
Yes
38
Do Amoxicillin-clavulanate and Piperacillin-tazobactam have good activity against GI anaerobes?
YES!
39
Does dicloxacillin have good activity against Group A streptococci and methicillin-sensitive Staphylococci?
Yes
40
As a general rule, 3rd and “4th” generation cephalosporins have more or less coverage against Gram-negative bacteria than the 1st gen?
More
41
Does cefazolin have good activity against methicillin-sensitive Staphylococcus aureus (MSSA)?
Yes
42
. Can cefazolin be used to treat MSSA meningitis?
No, cefazolin does not cross blood-brain barrier. This is a 1st generation. Only 3rd and 4th generation can cross the blood brain barrier.
43
Can ceftriaxone be used to treat Neisseria meningitides meningitis?
Yes, 3rd generation, can cross the blood brain barrier.
44
Does ceftriaxone have good activity against Pseudomonas?
NO - psudomonas coverage comes with 4th generation
45
Which cephalosporin has most activity against Pseudomonas?
Cefepime, 4th generation
46
Which cephalosporin has activity against enterococci?
NONE!
47
Which cephalosporin has activity against MRSA?
Only ceftaroline - newest cephalosporin
48
What are the 3 carbapenems and what is their route?
Impienem-cilastatin, Meropenem, and Ertapenem. All are IV
49
What organism does ertapenem fail to cover as well as its family members?
-Gram negatives, particularly PSEUDOMONAS
50
What is the spectrum of coverage for the principal carbapenems?
Imipenem, Meropenem
- Gram (+): Staphylococccus, Streptococcus, Enterococcus faecalis
- Gram (-): Very broad - broader than piperacillin or cefepime.
- Anaerobes: Good coverage
Not covered - MRSA, enterococcus faecium
51
Which single family of antibiotics has the broadest coverage? What acquired bug do they treat very well?
- Carbapenems
| - Fight hospital-acquired, resistant, Gram-negative infections
52
To what degree is there resistance against carbapenems?
Low resistance, although some Gram-negatives have begun producing carbapenemase
53
What toxicities are associated with Carbapenems? Is it safe to give to a severely penicillin-allergic patient
- GI Upset
- Hypersensitivity (rash)
- Seizures (particularly with Imipenem)
NO, has 5-10% cross-reactivity
54
What is the class, name, and route, of the only clinically used monobactam?
- Beta lactam
- Aztreonam
- IV
55
What is the coverage of aztreonam?
Only covers Gram-negatives, Pseudomonas particularly well.
56
What kinds of toxicities are associated with aztreonam? Is it okay to give to a severely penicillin-allergic patient?
- GI Upsets
| - YES, there is no cross-reactivity or hypersensitivity reactions known
57
What is the mechanism of action of Glycopeptide antibiotics? What drug(s) belong to this class?
MOA: Inhibits cell wall synthesis - binding terminal Ala-Ala prevents extension/cross-linking of cell wall.
-Vancomycin is the only relevant one.
58
What class does vancomycin belong to? What is its spectrum?
- Glycopeptide antibiotics
| - Only covers Gram positives - very broad coverage, including MRSA.
59
To what extent are organisms resistant to vancomycin?
Some resistance is present in the Enterococcus - VRE
60
What toxicities are associated with vancomycin? Describe them
1) "Red Man Syndrome" - red, pruritic rash on face, neck, upper chest. Hypotension(?)
2) Nephrotoxicity - uncommon, seen with use of other nephrotoxic drugs
3) Leukopenia
4) Ototoxicity: Very rare
61
What is the only indication for oral Vancomycin? Why is it well suited for this task?
- Treatment of Clostridium difficile colitis
| - Cannot exit the GI lumen
62
How do Folic Acid Synthesis Inhibitors kill bacteria? What drugs inhibit this pathway and how?
-Nucleic Acid Inhibitors: Bacteria synthesize folic acid de novo for use in purine synthesis
1) Sulfonamides - Compete with PABA for enzyme binding site
2) Trimethoprim/Pyrimethamine - Inhibits different synthetic enzyme
63
In what form are Folic Acid Inhibitors generally administered? What is their coverage?
- Bactrim = Sulfamethoxazole + Trimethoprim (TMP/Sx)
- Gram(+) : Staphylococci, including MRSA
- Gram(-) : Some community acquired, including varieties of E. coli
- Pneumocystis jirovecci: Fungus causing pneumocystis pneumonia (PCP)
- Toxoplasmosis
- NO anaerobe coverage
64
What toxicities are associated with Bactrim
- GI upset
- Allergic reactions (sulfa allergy) - Varies from rash to Stevens Johnson Syndrome. Allergies in 3-5% of population, higher in HIV+
- Hyperkalemia
- Kernicterus: If used during 3rd trimester.
65
What are the penicillin toxicities?
```
Generally well-tolerated
Nausea (especially with clavulanate)
Diarrhea (including Clostridium difficile colitis)
Hypersensitivity e.g., rash, fever
Other hypersensitivites: Anaphylaxis
```
*Same toxicities with cephalosporins and remember, Cross-allergenicity between the penicillins and cephalosporins is probably around 5–10%. Many individuals with a history of penicillin allergy will tolerate cephalosporins
However, patients with a history of severe hypersensitivity (e.g., anaphylaxis) to penicillins should not receive cephalosporins.
66
What are the three ways bacterial protein synthesis is inhibited by antibiotics?
Inhibitors of amino acid t-RNA synthetase
Inhibitors of peptide initiation reactions
Inhibitors of peptide bond formation and elongation reactions
67
What is the mechanism of action for rifampin?
Inhibitor of RNA polymerase
- Interacts directly with bacterial RNA polymerase - one molecule of the drug binds to one molecule of RNA polymerase, probably the β chain.
- Does not inhibit RNA polymerase in eukaryotic cells.
- Wide spectrum, but resistance develops rapidly
68
How is rifampin administered? Where does it distribute? How is it eliminated? What is its half life?
- Almost always given orally
- Wide tissue distribution
- Eliminated chiefly through bile; enterohepatic circulation
- T1/2 = 1.5 -5 hrs; by 40% in 2 wks of Rx
69
What is the difference between rifampin and rifampentine?
Rifampentine has a half life of 14-18 hours. This is a significant increase from rifampin's half life of 1.5 - 5 hours. (Some studies indicate that on months of treatment, rifampentine can be given every other day.)
70
What will rifampin do to body fluids?
Will color body fluids - urine, sweat, stools, tears orange. (You should warn your patient.)
71
What are the side effect of rifampin?
```
Side effects: <4% of patients
staining of body secretions
rash
fever
gastrointestinal upset
mild hepatotoxity
drug interaction: induces P450 enzymes- may interfere with digoxin, coumadin, oral contraceptives,methadone
```
72
What is the clinical use of rifampin?
- treatment of tuberculosis and leprosy
- prophylaxis against meningococcal and H. influenzae meningitis ~ only use as monotherapy
- adjunct therapy with other antibiotics against “tolerant” organisms
73
Which antibiotics inhibit RNA polymerase?
- rifampin
| - clofazimine
74
What is the mechanism of action for Clofazimine?
Binds to DNA of mycobacteria and inhibits RNA polymerase – other mechanisms?
--> Increases activity of phospholipase A2
75
What are the pharmacokinetics of clafazimine?
- Oral absorption 50%; slowly excreted in feces T 1/2 = 70 days on chronic Rx
- Bactericidal activity very slow - may take weeks to months. Treat 2 years to life
- Toxicity - GI upset; stains skin reddish-brown
(Made the point that half life refers only to plasma concentration. Doesn’t say anything about organ concentrations. (Important for psychotropic drugs – plasma half life may have no relation to brain half life))
76
What is clofazimine used to treat?
Leprosy
| Both antibiotics which inhibit RNA polymerase - clofazimine and rifampin - treat leprosy
77
What are the Inhibitors of DNA synthesis/replication? And what is the mechanism of action?
- Quinolones (poor tissue penetration, was only used for UTI)
- Fluoroquinolones (quinolone with a flourine atom - expanded the spectrum to both gram negative and gram positive organisms)
Inhibit DNA gyrase (topoisomerase II) and/or Topoisomerase IV. These enzymes, when they function normally, introduce negative supercoils into closed duplex DNA and facilitate unwinding which is important in initiation of DNA transcription
78
List some Fluoroquinolones and what is their pharmacology?
- Ciprofloxacin, norfloxacin, ofloxacin, levofloxacin, moxifloxacin
- Well absorbed orally; may replace i.v. use
- Half lives long enough (5 to 8 hrs) to permit once daily or twice daily dosing
- High tissue and intracellular levels
79
When are fluoroquinolones used?
Should NOT be used as first line of treatment. Fluoroquinolones are reserved for serious infections for which other antibiotics are ineffective.
Can treat a lot - urinary tract infections, chronic suppurative infections including, osteomyelitis, cystic fibrosis, mycobacterium infectionsbacterial gastroenteritis, community acquired pneumonia, and resistant gram negative infections
80
What are some precautions (side effects) with fluoroquinolones?
Side Effects: occasional gastrointestinal upset, interferes with cartilage formation (human experience less impressive especially in children), prolongation of QTc interval on ECG
- Resistance may develop rapidly with widespread use
- Use with caution in children (for a long time thought that it couldn't be used with children, but it can for a short period of time)
- increased risk of tendinitis and tendon rupture in all ages
- , may exacerbate muscle weakness in persons with myasthenia gravis (autoimmune neuromuscular disease)
81
How do the Inhibitors of RNA and DNA synthesis work?
- These drugs are analogs of bases or nucleosides
| - They are incorporated into the growing DNA and/or RNA chain and terminates chain elongation
82
What are the macrolide antibiotics? One of these has a slight structural difference that affects its spectrum of coverage - what is it?
Erythromycin
Clarithromycin
Azithromycin
Ketolides
Of the 4, Erythromycin has an unsubstituted lactone ring, which reduces its spectrum.
83
Describe the pharmacology (route, half-life, distribution, excretion) of Erythromycin
Route: PO *unstable in gastric juice
T-1/2: 1.6 hours
Distribution: Widely spread in total body water (like metronidazole), but not to the CSF - can't treat meningitis.
Excretion: Biliary tract, can undergo enterhepatic circulation.
84
What is the mechanism of action for Erythromycin and what are its clinical indications?
MOA: Inhibits translocase, preventing AA-tRNA movement from A to P site.
- Mycoplasma infections
- Impetigo from Staph or Strep
- Gram + infections in ß-lactam allergic patients
- Legionnaire's bacillus
- Pertussis, particularly good at disrupting the carrier state.
- Tetanus
- Campylobacter
85
What are the toxic side effects of Erythromycin?
- GI Upsets: stimulates gastric emptying (like motilin)
- Cholestatic Hepatitis
- Potent P450 inhibitor
* **Potentially potentiating actions of carbaamazepine, cyclosporine, digoxin, warfarin, pimozide, which can cause death.
86
What is different about the other macrolides compared to Erythromycin?
- Clarithromycin and azithromycin have substituted lactone rings, broadening their spectrum.
- Azithromycin is not broken down by stomach acid
87
Describe the pharmacology (half life, distribution, dosing time) of Azithromycin. Is there resistance?
- T 1/2: 70 hours
- Distribution: Accumulates in tissues and WBCs
- Dosing: 1-5 days
- Resistance: YES!
88
What is Telithromycin? Describe its mechanism, spectrum, dosing, and issues
Other macrolide - trade name Ketek
- Binds 2 regions of ribosome, making resistance more difficult
- Treats respiratory pathogens
- Daily dosing
- Never used anymore: Serious p450 inhibitor, and causes rare but severe hepatotoxicity.
89
What are the indications for macrolide use (non-Erythromycin)
- Community acquired pneumonia
- Otitis media/sinusitis
- Pharyngitis
- Skin and soft tissue infections
- Chlamydia
- Gonorrhea
- Mycobacterium avium in HIV patients
90
What is Synercid? What is its mechanism and spectrum? It has 2 particular clinical uses, what are they?
- Combination of Quinupristin (70%) and Dalfopristin (30%) - macrolide type drug.
- MOA: Q binds translocase, D binds 50S ribosome, enhancing Q binding.
- Spectrum: Gram + cocci, Mycoplasma, Legionella, Chlamydia
KEY USES
1) Vancomycin Resistant Enterococcus faecium
2) Staph and Strep skin infections
91
Describe the route, half life, metabolism, and potential problem with Synercid
- Route: IV
- Half life: <1 hour for both components (quinpristin and Dalfopristin)
- Metabolism: Hepatic conjugation and biliary excretion
* * Can inhibit P450 enzymes.
92
There are two main classifications for resistance in tuberculosis - define them
Multidrug (MDR): Resistant to isonazid and rifampin
| Extreme (XDR): Resistant to isonazid, rifampin, fluoroquinolines, and more.
93
What are the goals of Tuberculosis therapy?
1) Rapidly kill all M. tuberculosis
2) Prevent emergence of resistance
3) Eliminate persistent bacilli - prevent relapse
4) Minimize/eliminate disease transmission
94
Describe the mechanism of action of Isoniazid. What is its predominant indication?
MOA: Once activated, it contains radicals that inhibit formation of mycolic acid, and thus the mycobacterial cell wall. Adducts also inhibit nucleic acid synthesis.
Use: First line against tuberculosis with Rifampin.
95
Describe the route, degree of absorption, distribution, and metabolism of Isoniazid
Route: PO
Absorption: 100%
Distribution: Wide, including CSF
Metabolism: Genetically controlled acetylation, ranging from 1-4 hours depending on the person.
96
Describe the toxicity associated with isoniazid. Why is this problematic with Rifampin use?
- Metabolite (acetylisoniazid) can cause hepatitis, particularly in slow metabolizers. Rifampin induces metabolism, increasing toxicity risks.
- Peripheral neuropathy: prevented with B6
- Optic Neuritis
97
Describe Ethambutol (mechanism, use, absorption, half life)
- Use: 2nd line TB drug used with other drugs to delay resistance.
- MOA: Inhibits cell wall synthesis
- Absorption: Good
- Half life: 3-4 hours
98
In 2012, there were 2 new drugs released for treatment of TB. What are they, how do they work, and what are their benefits?
Delamanid - inhibits mycolic acid synthesis, twice effective against MDR-TB with few side effects.
Bedaquiline: Inhibits mycobacterial ATP synthase (starving bacteria for energy), producing faster sputum conversion.
99
Describe the three strata for treatment of TB. Why may the cure rate be somewhat low?
Minimal/moderate: 4-6 months of treatment
Advanced w/ extrapulmonary disease: 6-12 months
HIV co-infection: 18+ months.
-As people improve, they don't comply with treatment. Directly Observed Therapy shows greater efficacy in treatments.
100
What are the four main drugs utilized in the treatment of Leprosy?
1) Dapsone
2) Rifampin
3) Clofazimine
4) Thalidomide
101
What is the mechanism of action, uses, absorption, distribution, peak time, half life, metabolism, and side effects of Dapsone
MOA: Inhibits PABA use in folic acid synthesis (same as sulfonamides) - anti-inflammatory, anti-microbial, anti-protozoal
- Uses: (1), Leprosy, (2) malaria
- Absorption: Through GI tract - complete
- Distribution: To total body water
- Peak time: 2-8 hours
- Half life: 20-30 hours
- Metabolism: Acetylation, same enzyme as isoniazid
- Side effects: Hemolysis, methemoglobulinemia
102
What are the main mechanisms of drug resistance?
- Alter receptors (ß lactams, rifampin, quinolones)
- Alter entry/removal rates (aminoglycosides)
- Inactivate drug (ß lactams, chloramphenicol)
- Resistant metabolic pathways (trimethoprim)
- Prevent drug activation (metronidazole)
103
What are the best ways to prevent development of drug resistance?
- Wash your hands
- Prescribe appropriate antibiotcs (account for resistances and viruses)
- Limit use of broad spectrum antibiotics
- Limit prophylaxis.
104
What drug acts via a DNA breakage mechanism and please provide the proposed mechanism.
- Metronidazole
- Drug action appears to be mediated by a reduced form of the -NO2 group which forms a highly active radical that binds to DNA and perhaps other critical macromolecules
105
What are the pharmacokinetics of Metronidazole?
- Well absorbed orally; i.v. form available
- T1/2 = 8 hrs.
- Diffuses well into all tissues
- Toxicity: rare
gastrointestinal upset
seizures
peripheral neuropathy
in vitro mutagen (? clinical significance)
no alcohol use - Antibuse-like reaction
106
What is the clinical use for Metronidazole?
```
Clinical uses:
trichomonal infections
amebiasis
Giardiasis
Clostridium difficile****(most important use for this drug) and C. tetani
anaerobic bacterial infections (bacteriodes)
H. pylori (with other drugs)
rosacea (topical gel)
```
107
What are some ways to inhibit bacterial protein synthesis?
- Inhibitors of amino acid t-RNA synthetase
- Inhibitors of the initiation complex – binding of the aminoacetyl t-RNA to Site A
- Inhibitors of peptide bond formation and elongation
108
What is the mechanism of action for Linezolid and Mupirocin?
They both inhibit amino acid t-RNA synthetase.
Linezolid binds to the 50s subunit and inhibits formation of fmet-tRNA Also binds to 50S near chloramphenicol site
Mupirocin inhibits isoleucyl t-RNA synthetase
109
What are the pharmacokinetics of Linezolid?
- Oral absorption excellent - 100% bioavailability
| - T1/2 4-6 hours
110
What is the clinical use of Linezolid?
```
Gram positive cocci
Used in bacteria resistant to the usual antibiotics - given p.o. and i.v.
- E. fecium, E. fecalis (VREF)
- methicillin resistant S. aureus (MRSA)
- resistant pneumococci
```
111
How is mupirocin used and what does it treat?
Used only topically for skin infections caused by gram positive organisms:
pyoderma or impetigo
- S. aureus
- S. pyogenes (β hemolytic strep)
112
How do aminoglycosides work?
they inhibit the initiation complex!
- Inhibit binding of the aminoacyl t-RNA to the 30s subunit thus disruption formation of the functional initiation complex, which blocks initiation of protein synthesis and/or blocks further translation and elicits premature termination
- Binding also causes misreading of the genetic code, so there is incorporation of the incorrect amino acid
113
Does resistance develop quickly with aminoglycosides?
Yes
114
List the aminoglycosides? When was the last aminoglycoside developed?
```
Streptomycin 1944
Neomycin 1949
Kanamycin 1957
Gentamicin 1963
Tobramycin 1967
Spectinomycin 1967
Amikacin 1972
Netilmicin 1983
```
*There has not been a new amionglycoside in 30 years (there have been new penicllins and cephalosporins)
115
What are the pharmacokinetics of aminoglycosides?
Polar drug hence:
- Little or no absorption after oral dosing
Distributed to extracellular space; poor penetration to CSF (except neonates)
- Renal elimination by glomerular filtration.
- T 1/2 = 2-3 hrs; prolonged by renal insufficiency
116
What are the clinical uses of aminoglycosides?
- Major clinical use: gram negative infections
- Endocarditis
- In serious infections, usually used with other antibiotics
- Topical forms available; avoid use on skin because of sensitization.
- Oral forms may be used to “sterilize” gut before surgery or as adjuvant to treating hepatic coma
- Spectinomycin used only for gonorrhea (not first line)
- Gentamicin drops and ointment used for eye infections
117
What are the toxicities of aminoglycosides?
Toxicity may be related to serum levels
- ear - cochlear and vestibular - irreversible
- renal - especially with pre-existing renal disease). - reversible
- Neuromuscular blockade - large doses intra-abdominally during intraperitoneal dialysis. Reversed by calcium.
118
What is the mechanism of action for tetracyclines?
Inhibitor of Binding of Aminoacetyl t-RNA to the A Site
- Binds to 30s bacterial ribosome and prevents attachment of the aminoacyl tRNA to the A
119
What are the pharmacokinetics of tetracyclines?
- May be used p.o.(usual) and i.v.(rarely)
- Oral absorption decreased with food and dairy products (binds to calcium)
- Wide distribution in the body
- Wide range of T1/2 :
2-4 hrs for tetracycline
16-18 hrs for doxycycline and minocycline
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What is the clinical use of tetracyclines?
Most Common Use - Acne and Lyme Disease
Broad spectrum: gram positive, gram negative, rickettsia, mycoplasma, chlamydia
Initially widely used. Mostly replaced by more effective and safer antibiotics
rickettsial disease, gonorrhea, chlamydia group, resistant UTI, tularemia, brucellosis, cholera, mycoplasma
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What are the toxicities of tetracyclines?
- Chelates to bone - teeth staining
- Phototoxicity (especially with teens with acne)
- Bone marrow
- Renal disease
- Liver disease
- Increased intracranial pressure in infants
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What are the inhibitors of peptide bond formation and elongation?
- Chloramphenicol
- Clindamycin
- Macrolides
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What is the mechanism of action of Chloramphenicol?
- Binds to the 50s subunit; wide spectrum
- Inhibits peptidyl synthetase (prevents amino acid in A site from joining elongating chain in P site)
(rarely ever used anymore - replaced by safer antibiotics)
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How does clindamycin work?
This drug causes dissociation of peptidyl-tRNA from the ribosome.
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What is the pharmacology of clindamycin?
- Excellent p.o. absorption
I.V. form available for serious infections
- Widely distributed
- T1/2 = 3 hrs.
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What is the clinical use for clindamycin?
- Gram positive organisms; also anaerobes especially bacteriodes
- Gram positive infections in β-lactam allergic patients
adjuvant therapy of invasive streptococcal infections
- Bacteriodes; other susceptible anaerobes
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What are the side effects of clindamycin?
- Skin rashes – 10%
- Pseudomembranous colitis with C. Difficile infection. Incidence varies from 2- 20%. May be lethal.
- 5-20% diarrhea; may cause pseudomembranous colitis
