Chemotherapy and antibiotic resistance - Kozel Flashcards
1
Q
What are antibiotics?
A
Chemical substances produced by various species of microorganisms that are capable of inhibiting in small amounts, the growth of other microorganisms.
2
Q
Name some characteristics of the ideal antimicrobial.
A
- selective toxicity so it kills microbe not host.
- bacteriosidal (kills bacterial) rather than bacteriostatic (inhibits bacterial growth).
- Absence of genetic or phenotypic resistance.
- Broad vs. narrow spectrum.
- Non-allergenic.
- Minimal adverse side effects.
- Remains active in body.
- Water soluble.
- Bacteriocidal levels can be reached in vivo.
3
Q
What are the 5 general categories for site of antibiotic action?
A
- Cell wall synthesis
- Membrane function or synthesis
- Nucleic acid synthesis
- Protein synthesis
- Metabolic pathways
** cell wall and protein synthesis are the big targets**
4
Q
What are some categories of mechanisms used by bacteria to resist antibiotics?
A
- enzymatic inactivation
- decreased permeability - i.e. gram-neg bacteria are intrinsically less permeable due to outer membrane
- efflux - production of pumps that pump antibiotic out of cell
- failure to convert an inactive precursor to its active form - a couple of antibiotics are pro-drugs and are only activated inside bacteria
- modification of susceptible molecular target
5
Q
Name some ways that bacteria modify susceptible molecular targets as a means of antibiotic resistance.
A
- alteration of antibiotic binding site
- protection of target site
- overproduction of target
- binding-up of antibiotic
6
Q
Describe the parameters of pharmacokinetics.
A
Pharmacokinetics describe how a certain drug is absorbed, distributed in the body and how it is eliminated from the body. To be effective a drug needs to be absorbed at the site of administration, transferred from the plasma to site of infection, and eliminated from plasma and site of infection when infection is cleared.
7
Q
Describe the parameters of pharmacodynamics.
A
Pharmacodynamics describes the relationship between concentration and pharmacologic or toxic effects. It also describes the relationship between concentration and antimicrobial effects.
8
Q
What is MIC?
A
Minimum inhibitory concentration - the minimum concentration of antibiotics that inhibits the growth of bacteria.
9
Q
What is MBC?
A
Minimum bactericidal concentration - the minimum concentration of antibiotics that kills bacteria.
10
Q
How are antibiotics that lead to the killing of bacteria described?
A
These are called bactericidal. Examples include B-lactams, vancomycin, fluorquinolones, metronidazole, and aminoglycosides.
11
Q
How are antibiotics that lead to inhibited growth of bacteria described?
A
These are called bacteriostatic and they rely on the host for clearance of microbes. Examples include tetracyclines, clindamycin, macrolides and sulfonamides.
12
Q
What is synergy?
A
This term describes the case where a combination of antibiotics leads to a 2-log10 increase in action relative to each agent alone.
13
Q
Give an example of synergy.
A
Penicillin helps gentamycin get into gram-pos bacteria so they are often prescribed together - ie for treatment of viridans streptococcal meningitis.
14
Q
Would a bacteriostatic antibiotic be the best choice for an immune compromised bacteria?
A
No because bacteriostatic antibiotics only inhibit growth of bacteria and they rely on the host to clear the infection and this process is not intact in an immune compromised person.
15
Q
What is the postantibiotic effect (PAE)?
A
This refers to the persistent suppression of growth following exposure to antimicrobials. This can occur via the slowing of growth at sub-MIC concentrations and/or via the altering of bacterial morphology such that defense mechanisms are inhibited.
16
Q
What is postantibiotic leukocyte enhancement (PALE)?
A
This refers to the increased susceptibility to phagocytosis and phagocytic killing that can also occur in the period right after the use of antibiotics has stopped.
17
Q
Describe the pharmacodynamic outcome parameters.
A
- Time above MIC - refers to how long a drug stays above the MIC, this is important for antibiotics that have time-dependent killing mechanisms.
- AUC/MIC - this parameter refers to the ratio of the 24-hour serum concentration curve to MIC. It describes the total exposure of the microbe to the antimicrobial agent.
- Cmax/MIC - this parameter refers to the maximum serum concentration with respect to the MIC. It is important for concentration dependent killing.
18
Q
Describe some characteristics of antimicrobials that have concentration-dependent mechanisms of killing.
A
- Higher drug concentrations have higher rate and extent of bactericidal activity.
- Cmax/MIC and AUC/MIC are the pharmacodynamic predictors of outcome.
- Examples are aminoglycosides, fluoroquinolones, and metronidazole.
19
Q
Describe some characteristics of antimicrobials that have time-dependent mechanisms of killing.
A
- They are concentration independent.
- Bactericidal action is relatively slow.
- Time above MIC is the pharmacodynamic predictor of outcome.
- Examples are B-lactams and vancomycin.
20
Q
Describe some characteristics of antimicrobials that are bacteriostatic agents.
A
- Typically produce prolonged post antibiotic effects.
- AUC/MIC is the pharmacodynamic predictor of outcome.
- Examples are tetracyclines, clindamycin, macrolides and sulfonamides.
21
Q
Which antibiotics target cell wall synthesis?
A
- B-lactam drugs
- vancomycin
- Bacitracin
- Cycloserine
22
Q
Name the different types of B-lactam antibiotics.
A
- Natural penicillins
- Penicillin derivatives such as Penicillinase-resistant drugs and Broad spectrum drugs
- Cephalosporins
- Carbapenems
- B-lactamase inhibitors
23
Q
What are the 2 types of natural penicillins?
A
- Penicillin G (Benzyl)
2. Penicillin V (phenoxymethyl)
24
Q
What part of the penicillin molecule has antimicrobial activity? antigenic activity?
A
The Beta lactam ring is the structure in penicillin that is reactive. If the penicillin forms a hapten then the thiazolidine ring is what is recognized and leads to sensitization.
25
What are some characteristics of natural penicillins?
1. Have a narrow spectrum - work mostly on gram- pos bacteria.
2. Widely used, inexpensive, drug of choice if sensitive.
3. provide starting material for semisynthetic penicillins.
4. Penicillin G is sensitive to gastric juice (can't give orally) but Penicillin V is not.
26
What are penicillin binding proteins?
These are proteins that can bind to B-lactam antibiotics. Their function is the construction of the pentapeptide-pentaglycine bridges that cross-link peptidoglycan.
27
Name some examples of penicillin binding proteins.
1. carboxypeptidases
2. endopeptidases
3. transglycosylases
4. transpeptidases
28
What is the mechanism of action of penicillins and B-lactam antibiotics?
1. bind to penicillin binding proteins - binds to the active site via covalent bonding
2. block peptidoglycan cross-linking system
3. Bactericidal action - eventual lysis due to autolytic enzymes
29
What are some mechanisms of resistance to penicillins/B-lactam antibiotics?
1. inactivation of the B-lactam ring via Beta lactamase enzyme, which is encoded usually on a plasmid or on a transposable chromosomal gene. This involves cleavage of the ring.
2. prevent the antibiotic from binding to Penicillin binding proteins. In gram-neg bacteria this is due to the intrinsic resistance inherent in the outer membrane and in N. gonorrheae it is due to an altered porin.
3. Alteration in binding site - reduction in number or affinity of penecillin binding proteins. Examples of bacteria that use this mechanism are some strains of S. pneumonia, N. gonorrheae, and MRSA.
30
Describe Penicillinase resistant penicillins.
These are synthetically made to be resistant to penicillinase via the introduction of a bulky group near the normal site of hydrolysis. These antibiotics are 1/10th as potent as penicillin G. Examples are Methicillin and Nafcillin.
31
Name 2 broad spectrum penicillins and some characteristics.
1. ampicillin
2. Carbenicillin
These are synthetically made so that they can get through the outer membrane of gram-neg bacteria. They are able to do this because charged groups are added to increase hydrophilicity so that they can penetrate the outer membrane porins. They are susceptible to penicillinases.
32
What is the pharmacology penicillins/B-lactam antibiotics?
1. Acid labile (susceptible to gastric juice, do not take orally) - Penicillin G and methicillin.
2. Acid Stable - Penicillin V and most semi-synthetic penicillins.
3. Rapid renal secretion.
4. Well distributed to most tissues.
5. Little to no penetration to intact blood-brain barrier (BBB).
6. Have time-dependent killing mechanism - use dosing strategy to maximize exposure to drug.
33
What are the side effects and toxicities of penicillin/ B-lactam antibiotics?
1. Allergic reactions via Haptenization (opening of B-lacatam ring to bind to host proteins). This results in making the thiazolidine ring more available and it acts as an antigen inducing sensitization.
2. May disturb normal GI flora so can cause GI issues (most prominent with ampicillin).
34
What is Cephalosporin?
A Beta lactam antibiotic.
35
Describe some characteristics of Cephalosporin.
1. Limited immunological cross-reactivity with penicillin because they do not have a thiazolidine ring.
2. Are generally resistant to beta lactamases.
3. There are generations of cephalosporins.
4. Some may be given orally and some should only be given parenterally (by injection).
36
What are the different generations of cephalosporins?
1st Gen. - narrow spectrum, mainly effective against gram-pos bacteria.
2nd Gen. - Expanded spectrum, work on gram-pos and some gram-neg bacteria.
3rd Gen. - Broad spectrum, work on gram-pos bacteria, have improved effect on gram-neg bacteria - especially pseudomonas.
4th Gen. - Extended spectrum, work gram positives and have increased gram negative activity over 3rd generation.
MRSA-active cephalosporins - have high affinity for Penecillin binding protein 2a.
37
What are the pharmacodynamics of Cephalosporins?
1. Oral and parenteral formulations are available for most generations.
2. distribution and metabolism varies widely - some have good CNS penetration.
3. Excreted primarily via kidney - so dosage is altered in patients with renal insufficiency.
38
Describe the toxicity and side effects of Cephalosporin.
1. Safety profile is generally favorable.
2. Cross-reaction frequency with penicillin is generally low.
3. GI effects most common - nausea, diarrhea.
4. Superinfections possible with broad spectrum cephalosporins since the GI flora is disturbed.
39
Describe the resistance of bacteria to broad spectrum cephalosporins?
1. new strains of Ceftriaxone-resistant N. gonorrhoeae have now emerged.
2. Resistance to broad spectrum cephalosporins is typically multifactorial involving altered penicillin binding proteins, overexpression of efflux pumps and mutation in porins so that uptake is reduced.
40
Describe Carbapenems.
1. Beta-lactam antibiotics with a modified alpha ring (eliminates sulfur).
2. Have high affinity for essential penicillin binding proteins of most gram pos and gram neg bacteria.
3. exceptionally broad spectrum with good penetration of the outer membrane of gram-negatives via a specific porin.
4. highly resistant to beta lactamase due to a hydroxyethyl group at C6.
5. Not effective against MRSA.
41
Describe the clinical use of Carbapenems?
1. empirical antibacterial therapy
| 2. useful for a wide array of infections due to broad spectrum
42
Describe the pharmacodynamics of Carbapenems.
1. administered parenterally due to poor absorption when taken orally.
2. rapidly hyrolyzed by peptidase in renal tubule.
3. May be given with Cilastatin which is a peptidase inhibitor that blocks renal degradation of imipenem.
43
Describe the toxicity and side effects of Carbapenems.
1. generally well tolerated
| 2. susceptible to allergic reactions
44
Give some examples of Carbapenems.
1. Imipenem
| 2. Muropenem
45
What are beta lactamase inhibitors?
These are drugs that do not have antimicrobial action even though they have a B-lactam ring. They are used in conduction with B-lactam antibiotics because they can form a covalent bond with beta lactamase thus allowing penicillins to work.
46
What are some examples of B-lactamase inhibitors.
1. Clavulanic acid
| 2. Sulbactam
47
How are Beta lactamase inhibitors used clinically?
They are given in combination with penicillinase-sensitive beta lactams. Examples are:
1. Augmentin - a mix of amoxicillin wit clavulanate.
2. Unasyn - a mix of Ampicillin with sulbactam.
48
What is vancomycin?
A glycopeptide antibiotic that inhibits cell wall synthesis.
49
Describe some characteristics of Vancomycin.
1. a large molecule.
2. works on gram-positives
3. Is an alternative to penicillin and is often the drug of last resort
50
What is the mechanism of action of Vancomycin?
1. Binds to the terminal alanines that are part of the cell wall synthesis so it blocks transpeptidation and is bactericidal.
51
Describe the resistance to vancomycin.
1. plasmid mediated and involves multiple genes.
2. both enterococcus species and staph aureus species may be resistant.
3. VRE - vancomycin resistant enterococcus and rarely vancomycin resistant staph aureus (VRSA) use the mechanism of altering the target via substituting lactate for a terminal alanine so that vancomycin cannot bind.
4. VISA - vancomycin intermediate staph aureus use a different mechanism. They make many free terminal alanine groups so that they are a decoy and they bind vancomycin leaving the real alanine bonds untouched.
52
Describe the pharmacodynamics of vancomycin.
1. typically given intravenously due to poor adsorption when taken orally. This does however make it useful for C. diff infections.
2. Excreted primarily via the kidney so dosage is altered in patients with renal insufficiency.
53
Describe the toxicity and side effects of vancomycin.
1. ototoxicity at high doses
2. nephrotoxicity at high doses
3. may cause infusion-related reactions
54
What are polymyxins?
A class of antibiotic that acts on membrane function.
55
What is the mechanism of action of polymyxins?
1. structure includes a fatty acid tail. This fatty acid tail can penetrate the phospholipid bilayer.
2. Penetration of the lipid bilayer leads to leakage of metabolites and disruption of membrane function.
3. Bactericidal - disruption of the membrane leads to cell death
56
What is the clinical use of polymyxin?
This class of antibiotics works on gram negative bacteria. It is also mostly used topically due to its toxicity however, it is used perenterally against highly resistant strains of Pseudomonas, Klebsiella or Acinetobacter where no other alternative exists.
57
Is polymyxin given orally?
No, it is used topically and in rare occasions it can be given via IV (not orally because it is not absorbed well).
58
What is the main adverse affect of polymyxin?
Dose-related nephrotoxicity.
59
Give an example of a polymyxin.
Colistin.
60
Name two antibiotics that work by inhibiting DNA synthesis.
1. quinolones/fluoroquinolones
| 2. metronidazole
61
What is the basic structure of quinolones?
They are made up of 2 fused rings and if there is a fluorine attached then they are called a fluoroquinolone.
62
What is the mechanism of action of quinolones?
They inhibit DNA gyrase and are bactericidal.
63
What mechanism is used in resistance to quinolones?
Bacteria that are resistant have a mutated form of DNA gyrase - so this target of quinolones has now been altered.
64
What is the clinical use of quinolones?
They work on both gram-neg and gram-pos bacteria. They are used to treat UTI's and a variety of other bacterial infections.
65
What are the pharmacodynamics of quinolones?
1. good absorption following oral administration.
2. are excreted in renally in high concentrations so they are good for treating UTI's and dosage must be altered in patients with renal insufficiency.
66
What are some adverse effects of quinolones?
1. GI effects -can cause nausea, vomiting and abdominal discomfort.
2. CNS effects - mild headache, dizziness.
3. may cause achilles tendon damage.
4. may cause C. diff infections since it disturbs normal GI flora.
67
Give an example of a fluoroquinolone.
Ciprofloxacin.
68
What is Metronidazole?
A synthetic antibiotic that targets DNA synthesis.
69
What is the mechanism of action of Metronidazole?
This antibiotic is prescribed as a prodrug that is reduced to its active form by an electron transport protein in anaerobic bacteria. It works by producing cytotoxic compounds that damage DNA, it is bactericidal.
70
What are the clinical uses of Metronidazole?
1. works against obligate anaerobes and many protozoa but does not work on facultative anaerobes and obligate aerobes.
2. used to treat anaerobic infections and given as prophylaxis in colorectal surgery.
3. has good absorption following oral administration with similar blood levels whether given orally or via IV.
71
Why does Metronidazole work against protozoans and what is the name of the form that is prescribed for these infections?
Some protozoa such as Trichomonas vaginalis have a protein that is capable of reducing metronidazole to activate it to active form. The drug prescribed for protozoan infections is called Flagyl.
72
Describe the toxicity and side effects of Metronidazole.
1. Generally well tolerated but with numerous relatively uncommon side effects.
2. Most common side effects are GI in origin - nausea, diarrhea.
3. Has possible (but largely unproven ) mutagenic effects.
73
What is Rifampin?
An antibiotic that works via the inhibition of RNA synthesis.
74
What is the mechanism of action of Rifampin?
This drug binds to DNA-dependent, RNA polymerase and blocks chain initiation. It is ineffective against eukaryotic polymerases but is bactericidal or bacteriostatic (depending on concentration of bacteria) towards bacteria.
75
What mechanism has bacteria evolved to resist Rifampin?
A rapid, single step mutation in the Beta subunit of the polymerase so that Rifampin cannot bind.
76
What are the pharmacodynamics of Rifampin?
1. given orally - good absorption.
2. good distribution throughout body - limited in CNS.
3. majority is eliminated fecally but is also eliminated in the urine.
77
What is the clinical use of Rifampin?
Used to treat TB, leprosy, and given prophylactically for N. meningitidis along with many other applications.
78
Describe the toxicity and side effects of Rifampin.
1. excreted in mucous membranes and has a chromofore so will cause orange discoloration of tears, sweat and urine.
2. GI effects most common - cramping, nausea, diarrhea.
3. causes hepatic toxicity because it is a powerful up-regulator of hepatic cytochrome P-450 enzymes. This leads to altered hepatic metabolism of hormones and drugs by decreasing their half-life.
79
Name the antibiotics that are inhibitors of translation by inhibiting the 30S subunit of bacterial ribosomes.
1. Aminoglycosides
| 2. Tetracyclines
80
Name the antibiotics that are inhibitors of translation by inhibiting the 50S subunit of bacterial ribosomes.
1. Chloramphenicol
2. Lincosamides - lincomycin and clindamycin
3. Oxazolidinones
4. Macrolides - erythromycin
81
What is the mechanism of action of the amino glycosides?
Aminoglycoside structure includes amino sugars and an aminocyclitol group. This group of antibiotics works by irreversibly binding to the 30S subunit of bacterial ribosomes. This causes depletion of the ribosomal pool, misreading of the transcript, and premature release of the ribosome so that bacterial proteins cannot be made properly.
82
What are the clinical uses of aminoglycosides?
These drugs have broad spectrum and work against gram-pos and gram-neg bacteria. They are commonly used to treat TB. They also exhibit synergy with antimicrobials that target the cell wall such as the penicillins. The cell wall active antimicrobials facilitate the uptake of aminoglycosides by gram pos. bacteria.
83
By what mechanism do bacteria resist aminoglycosides?
1. The primary mechanism is by plasmid-mediated enzymatic alteration of the drugs' binding site on the 30S subunit such as acetylation, phosphorylation and adenylation.
2. reduced uptake
3. intrinsic resistance of anaerobes.
84
Describe the pharmacodynamics of aminoglycosides.
1. minimally absorbed in GI tract - given IM or IV.
2. excreted primarily via the kidney so dosage is altered in patients with renal insufficiency.
3. concentration dependent effect so Cmax/MIC is the predictor of efficacy.
85
Describe the adverse effects of aminoglycosides.
1. high rates of nephrotoxicity
2. high rates of reversible ototoxicity
3. acts as a neuromuscular blockade - rare
86
Name some clinically important aminoglycosides.
1. Streptomycin
2. Gentamycin
3. Neomycin
4. tobramycin
5. amikacin
87
What is the clinical use of streptomycin?
Used as a second line drug for resistant TB , primary drug used for tularemia and plague and used to treat empirically because of its broad spectrum. Is more toxic than newer agents.
88
What is the clinical use of neomycin?
Neomycin is given as a topical ointment and is less effective with gram-positives so it is given in combination with cell wall-active agents.
89
What is the clinical use of gentamycin, tobramycin and amikacin?
These drugs are given as empiric therapy for suspected aerobic, gram-neg infections. They are also used as specific therapy once cultures and sensitivities are known.
90
What is Tetracycline?
An antibiotic that works by blocking the 30S subunit of bacterial ribosomes.
91
Describe the mechanism of action of tetracycline.
This drug blocks the binding of aminoacyl tRNA to the A site of the bacterial ribosome. The binding is reversible so the drug is bacteriostatic rather than bactericidal.
92
Describe the mechanisms of resistance of bacteria to tetracycline.
Bacteria produce an active efflux mechanism - a pump that removes tetracycline from the cell. It also produces cytoplasmic proteins that bind to the ribosome to protect it from tetracyclines.
93
What is the clinical use of tetracycline?
It is a very broad spectrum drug- works against gram pos, gram neg, spirochetes, mycoplasma, rickettsiae, chlamydia and many anaerobes. It is the first line drug prescribed for chlamydia, rickettsia and spirochete infection but more often given as second line defense due to toxicity and resistance.
94
Describe the pharmacodynamics of tetracycline.
1. given orally
2. impaired by ingestion of divalent and trivalent cations such as those in milk.
3. excretion is via kidney and bile
95
Describe the toxicity and side effects of tetracycline.
1. photosensitivity in skin
2. GI disturbances
3. nephrotoxicity
4. stains teeth and bones in early development (8 years and under)
5. predisposes to superinfection (especially via Staph aureus) because it can linger in GI tract and disturb normal flora.
96
What is Chloramphenicol?
An antibiotic that works by blocking the 50S subunit of bacterial ribosomes. No longer used in US but sold OTC in Mexico so may see patients with it.
97
What are Lincosamides?
Antibiotics that work by inhibiting the 50S bacterial ribosomal subunit.
98
What is an example of an Lincosamide?
Clindamycin.
99
What is the mechanism of action of Clindamycin?
This drug works by blocking the peptidyl transferase activity of the 50S ribosomal subunit of bacteria. It is bacteriostatic.
100
Describe bacterial resistance to Clindamycin.
Bacteria are resistant by altering the target of the antibiotic. Specifically the plasmid mediated methylation of the ribosome to reduce binding of Clindamycin.
101
What is the clinical use of Clindamycin?
This drug works against aerobic gram-pos cocci and anaerobes. Most gram-negatives are resistant. It is an alternative to penicillin if patient is hypersensitive. Also given for MRSA since many strains are susceptible.
102
Describe the pharmacodynamics of Clindamycin.
1. given orally and sometimes parenterally
2. excretion is via urine and feces
3. half-life increases with renal failure so dosage changes are required
103
What are the adverse effects of Clindamycin?
1. GI disturbances - diarrhea, nausea, vomiting, cramps
| 2. Can cause Pseudomembranous colitis mainly via C. diff infection due to disturbance of normal GI flora
104
What are Oxazolidinones?
A class of antibiotics that work by inhibiting the 50S ribosome of bacteria.
105
What is an example of an Oxazolidinone?
Linezolid.
106
What is the mechanism of action of the Oxazolidinones such as Linezolid?
They bind to the 50S bacterial ribosomal subunit and prevent its binding to the 30S subunit to form the 70S complex. This unusual mechanism is bacteriostatic and is effective against many resistant bacteria.
107
What is the clinical use of Linzolid?
1. Active against most clinically important gram positives and limited activity with gram negatives.
2. Used to treat MRSA, multi drug resistant Strep pneumoniae and vancomycin resistant enterococci.
3. Used as a reserve antibiotic for use with difficult bacteria that are resistant to other antibiotics.
108
What are the pharmacodynamics of Linezolid?
1. given orally or via IV
2. outstanding bioavailability
3. broken down in vivo and excreted in urine
109
Describe the toxicity and side effects of Linezolid.
1. generally well tolerated
2. GI effects - diarrhea, nausea, vomiting
3. Myelosuppression (suppression of bone marrow production of RBC's and platelets) with long term use
4. weak nonspecific inhibitor of monoamine oxidase so should not be given with SSRI's (antidepressants)
110
What are macrolides?
A class of antibiotics that inhibit the 50S ribosomal subunit.
111
Name some common Macrolides.
Erythromycin, azithromycin and clarithromycin.
112
What is the mechanism of action of macrolides?
These antibiotics work by binding to the 50S bacterial ribosomal subunit and blocking peptidyl transferase and translocation. Its actions are bacteriostatic.
113
What mechanism of resistance do bacteria have against macrolides?
They exhibit plasmid mediated methylation of the 50S subunit so that antibiotics cannot bind to it. If a bacteria is resistant to clindamycin/lincomycin then they are most likely resistant to macrolides too.
114
What are the clinical uses of Macrolides?
1. have generally broad spectrum - most active against aerobic, gram-positives.
2. are the primary antibiotic used for mycoplasma and legionella infections and is an alternative if allergic to penicillins.
115
Describe the pharmacodynamics of the Macrolides?
1. Erythromycin is acid labile so oral doses given as enteric-coated or as more stable salts or esters.
2. Azithromycin is acid stable.
3. Are well distributed in body except brain and CSF.
4. excretion varies with antibiotic but is primarily biliary excretion.
116
Describe the toxicity and side effects of Macrolides.
1. cause hepatotoxicity
2. GI - stimulate motility, nausea, diarrhea, abdominal pain
3. can cause cardiac arrhythmias
4. inhibitor of cytochrome P450 system so can cause significant drug interactions
117
Name the class of antibiotics that are metabolite analogs.
1. sulfonamides
2. trimethoprim
3. isoniazid
118
What bacterial metabolic pathway do sulfonamides and trimethoprim interupt?
The production of Folic acid. Folic acid is needed by the bacterium to make DNA and RNA.
119
What is the mechanism of action of the sulfonamides?
In Folic acid metabolism, dihydrofolic acid is produced from an intermediate called PABA (p-aminobenzoic acid). Sulfonamides act as a structural analog of PABA, competitively inhibiting the synthesis of dihydrofolic acid by binding to the enzyme that forms it - dihydropteroate synthetase. Its actions are bacteriostatic.
120
What is the bacterial mechanism of resistance to sulfonamides?
They exhibit plasmid mediated production of dihydropteroate synthetase with a decreased affinity to sulfonamides and they also overproduce the enzyme so that plenty of dihydrofolic acid is formed.
121
Describe the clinical use of sulfonamides.
1. broad spectrum including gram-pos, gram-neg, nocardia, chlamydia.
2. used to treat UTI's and many other special applications.
122
Describe the pharmacodynamics of sulfonamides.
1. given orally - rapidly absorbed in GI tract
| 2. largely excreted in urine
123
Describe the toxicity and side effects of sulfonamides.
1. Rarely causes disorders of the hematopoietic system such as hemolytic anemia, agranulocytosis, aplastic anemia.
2. Commonly causes hypersensitivity reactions - rashes, hives.
3. associated with an immune reaction called Steven-Johnson syndrome - presents with confluent epidermal necrosis and is considered a dermatological emergency.
124
What is the mechanism of action of Trimethoprim?
Trimethoprim is a structural analog of a portion of dihydrofolic acid so it competitively inhibits the synthesis of tetrahydrofolic acid. It works synergystically with sulfonamides.
125
Describe the clinical use of Trimethoprim.
1. broad spectrum similar to sulfonamides.
2. used in conjunction with sulfamethoxazole and cotrimoxazole (Bactrim and Septra).
3. used to treat UTI's
4. works in some gram-neg infections
5. drug of choice for pneumocystis jirovecii (fungal infection but Trimethoprim works for it)
6. used to treat MRSA along with sulfamethoxazole
126
Describe the pharmacodynamics of Trimethoprim.
1. given orally
| 2. high levels in urine - why it is use to treat UTI's
127
Describe the toxicity and side effects of Trimethoprim.
1. impaired folate usage
| 2. hypersensitivity
128
What is the mechanism of action of Isoniazid (INH)?
This drug is taken in the prodrug form which is activated by catalase in the bacterium. It inhibits the synthesis of mycolic acids (in cell wall of mycoplasma).
129
What is the clinical use of Isoniazid?
1. only effective against mycobacteria
| 2. the primary drug of choice for low-grade TB infections
130
Bacteria are resistant to Isoniazid through what mechanism?
Resistance is very common and is primarily acheived through bacterial deletion of the gene that codes for the catalase that activates the prodrug form of Isoniazid.
131
Describe the pharmacology of Isoniazid.
1. given orally and IM
| 2. well absorbed
132
Describe the toxicity and side effects of Isoniazid.
1. Hepatitis
| 2. inhibitor of Cytochrome P450 system so causes drug interactions
133
What are some mechanisms that bacteria use to resist antibiotics?
1. Enzymatic inactivation of antibiotic
2. Decreased permeability
3. Efflux of antibiotic
4. Modification of susceptible molecular target
5 failure to convert an inactive precursor agent to its active form
134
What are some methods of enzymatic inactivation of an antibiotic?
1. Destruction of the antibiotic by bacterium
| 2. modification of the antibiotic so that it fails to reach or bind to target
135
What are some ways that bacteria reduce permeability to antibiotic?
1. outer membrane is intrinsically less permeable
| 2. inner cytoplasmic membrane is less permeable
136
What are some ways that bacteria modify the susceptible molecular target of bacteria?
1. they alter the binding site for antibiotic
2. they protect the binding site
3. they overproduce the target
4. they bind up the antibiotic
137
Which antibiotics are primarily enzymatically altered by bacteria as a means of resistance?
B- lactams, aminoglycosides
138
Which antibiotics are primarily taken out via efflux by bacteria as a means of resistance?
Tetracyline
139
Which antibiotics primarily have their target binding sites altered by bacteria as a means of resistance?
B-lactams, glycopeptides, quinolone, Rifampin, macrolides, lincosamides, sulfonamides, trimethoprim
140
What are the Ten commandments of antibiotic use?
1. Use antibiotics only when needed – teach the patient how to manage symptoms of non-bacterial infections
2. Use the right antibiotic – precise targeting is better than shotgun
3. Consider pharmacokinetics and pharmacodynamics – use the shortest course that has clinical efficacy
4. Encourage patient compliance
5. Use antibiotic combinations only in specific situations – reduces resistance, costs and side effects due to drug interactions
6. Avoid low quality and sub-standard drugs
7. Discourage self-prescription
8. Follow evidence-based guidelines – beware those sponsored by drug companies
9. Rely on the clinical microbiology lab
10. Prescribe empirically – but intelligently – know local susceptibility trends
141
Name some antibiotic sensitivity tests.
1. diffusion tests
2. dilution tests
3. automated tests
142
How do diffusion tests work?
1. spread patient isolate on agar plate
2. place antibiotic disc on plate
3. incubate and measure the diameter of inhibition zone if present
4. use zone diameter and standard tables to estimate MIC
143
What are the advantages of diffusion tests?
1. simple and inexpensive
| 2. mostly widely used assay
144
What are the disadvantages of diffusion tests?
1. non-quantitative interpretation
2. does not measure bactericidal activity
3. innappropriate for slow growers such as TB and for slow diffusing antibiotics such as vancomycin
145
How do dilution tests work?
1. prepare serial dilutions of antibiotics.
2. inoculate with standardized inoculum of clinical isolate.
3. calculate MIC needed to inhibit growth.
146
What are the advantages of dilution tests?
1. provides quantitative results
2. not influenced by growth rate
3. avoids problems with diffusion properties of antibiotics
4. allows for determination of MBC
147
What are the disadvantages of dilution tests?
1. expensive, time consuming
| 2. requires rigid quality control
