pharmacology: antibiotics

the pharm lecture on the conventional use of antibiotics. first, an introduction to the different terms and ideas in the world of antibiotics. there are a whole host of antibiotics, with a huge variety of structure and function depending on the microorganism targeted. bactericidal agents are drugs that actively kill microbes whereas bacteriostatic agents simply halt the growth and proliferation of microbes. minimum inhibitory concentration, or MIC, is the minimum concentration of an antibiotic required to have inhibitory action. besides low concentration, antibiotics can fail to work due to a number of factors, such as a failure to reach target, enzymatic inactivation, as well as specific ways that the microbe can develop resistance: conjugation (DNA that confers resistance passed from cell to cell), mutation (spontaneous), and transduction (DNA carried into microbe via bacteriophage). host conditions also play a factor-- pus, hematomas, abscesses all inactivate different classes of antibiotics.

the first class of antibiotics are the sulfonamides; an example is sulfamethoxazole. sulfonamides act by competitively antagonizing PABA in bacterial cells, blocking the synthesis of folic acid, required for DNA replication. since it halts reproduction of microbes it is considered a bacteriostatic, not bacteriocidal agent. it spreads everywhere in the body, including the CSF, and has a range of side effects: headache, skin changes (rashes and photosensitivity). it is sometimes combined with another folic acid inhibitor, trimethoprim, in a ratio of 5:1 sulfamethoxazole : trimethorpim. this combination might be indicated in more severe presentations and specifically for prophylaxis of pneumocystis carinii in patients with AIDS. the side effects are similar, but the combination creates more hypersensitivity, especially in the skin, which can be covered in papulomacular lesions that are pruritic and sandpaper like. general side effects from folic acid disruption are megaloblastosis, leukopenia, thrombocytopenia, and steven johnson's syndrome.

penicillins are another class of antimicrobials that work via beta-lactam rings that bind to penicillin proteins and disrupt the peptidoglycan layer in the bacterial cell walls. they are thus bactericidal, and are effective against a wide variety of gram positive bacteria. it is the antibiotic most commonly associated with allergies, although it is estimated that only about 20% of patients with reported allergies actually have them. "penicillin g" is an example, although it is not as widely used anymore due to widespread resistance in the form of microbes that produce beta lactamase. amoxicillin is a penicillin derivative with a beta lactam ring, thiazolaine ring, and side chains. being a penicillin drug, amoxicillin works to inhibit the peptidoglycan cross links in the bacterial cell walls, and it is spread through all tissues except for the CSF (as opposed to the sulfonamides). it is sometime prescribed in combination with clavulanate, which is an inhibitor of beta-lactamase, thus overcoming the microbes that are resistant to penicillin. side effects of this combination can include GI distress such as diarrhea, and pseudomembranous colitis is a severe diarrhea that is caused by clostridium difficile and associated with amoxicillin / clavulanate use.

cephalexin is in the cephalosporin drug class, which is similar to penicillin in that the mechanism involves a beta-lactam ring disrupting the peptidoglycan layer of the bacterial cell wall. due to the similar mechanisms, cephalosporins have similar side effect profiles to penicillin and also might need to be avoided in patients with penicillin allergies. another note: the first generation of cephalosporins are more specific for gram positive organisms while the second and third generations are more specific for gram negative organisms. drug resistance, as with penicillin, can occur via bacterial production of beta lactamase or modification of PDG. it is indicated in bronchitis, acute ENT infections.

macrolides are another class of antibiotics that work via a macrocytic lactone ring, which binds to the bacteria's 50S ribosomal subunit, making in an effective bacteriostatic agent as well as a bactericidal agent at higher concentrations. it has a similar coverage spectrum to penicillin, but covers more organisms such as chlamydia, mycobacterium, mycoplasma, and ricksettia. it also tends to be accumulated in leukocytes and thus transported to the site of infection. it is common to have GI upset (nausea and vomiting), which can be offset by an enteric coating that is sometimes available.

azithromax is another macrolide, having a multi-membered lactone ring that binds to the 50S ribosomal subunit. it is unique because of its long, 68 hour half life and easy dosing regimen-- a "z pack" has 6 pellets, 2 of which are taken on the first day, followed by 1 per day for the next 4 days. it is indicated for ENT infections, pneumonia, sinusitis, as well as for infection with atypical organisms such as mycoplasma and chlamydia. side effects are similar to erythromycin but with much less GI disturbances.

tetracyclines are another class of antibiotics (tetra because of the four hydrocarbon ring structure) that work by binding to the 16S part of the 30S bacterial ribosomal subunit, inhibiting protein translation. it is less effective these days due to widespread resistance and is mainly used for severe acne / rosacea. it is contraindicated in pregnancy and in children and can also permanently stain teeth. patients on tetracyclines should avoid dairy and calcium as they will interfere with absorption due to chelation. tetracycline specifically can be used in outpatient care for lyme's patients, and are also effective against organisms that have resistance to agents that work on the cell wall (ie penicillins), such as legionella, mycobacterium, chlamydia, ricksettia, plasmodium.

another drug class that binds to the 30S ribosomal subunit is the aminoglycoside class, of which gentamycin is a representative member. it has a relatively narrow coverage spectrum, mainly treating aerobic gram negative organisms-- in particular pseudomonas. it is also used mainly in severe, systemic conditions such as septicemia and is generally switched to a less toxic alternative once the causative organism is identified. side effects might include irreversible nephrotoxicity as well as ototoxicity.

quinolones such as ciproxin are another class that work by yet another mechanism-- this time by disrupting the microbial DNA gyrase enzyme, which is involved in uncoiling of DNA in the replication process. it has an affinity for intracellular organisms such as legionella and mycoplasma, and was also used as an anthrax treatment during the anthrax scares. quinolones chelate calcium and deposit into collagen and bone and thus are contraindicated in children and pregnancy. due to their collagen disruption they are associated with tendon injury, in particular the achilles tendon. it also reduces the breakdown of caffeine and affects the senses of taste and smell.

imidazoles are a class of drugs that are activated only upon intracellular processing by certain organisms: gram negative anaerobes (clostridium, bacteroids, fusobacterium), or protozoa. they work by disrupting the DNA helical structure and thus preventing reproduction. side effects might include GI upset, headache, thrush, and metallic taste in the mouth. it also interferes with alcohol metabolism by inhibiting acetaldehyde dehydrogenase, leading to a buildup of acetaldehyde in the body when alcohol is consumed (and thus a much amplified hangover feeling).

lincosamides-- derived from an actinomides species and is similar to macrolides but also works against actinomycetes, plasmodium, mycoplasma. it is rather toxic and is also associated with clostridium difficile related diarrhea. it is sometimes used topically for treatment of acne.

vancomycin is an glycopeptide antibiotic that is used as a "last resort" drug for severe conditions such as pseudomembranous colitis (only after metronidazole is shown to be ineffective) and against MRSA. like penicillin it works by disrupting the peptidoglycan layer of the bacterial cell walls, although it binds to a different site than the beta lactam in penicillin. it is usually given IV although may be given orally if treating c. difficile in the gut. side effects include "red man syndrome" and shock due to massive histamine release.

speaking of MRSA... MRSA are staph that are resistant to beta lactams (penicillins and cephalosporins) and come in two flavors-- community acquired, which can be treated with sulfas, tetracyclines, and clindamycin, and hospital acquired, which can only be treated with vancomycin.

muciprocin is another drug used against MRSA's which are originally derived from pseudomonas flourescens. it works by inhibiting incorporation of isoleucine into the cell walls of gram negative bacteria. it is used topically in such skin conditions as impetigo, boils, folliculitis.

some last notes on additional antibiotics: bacitracin targets gram positive organisms by inhibiting the transfer of cell wall precursors from the cell membrane to the cell wall. polymyxin kills gram negative bacteria by altering the cell membrane permeability, causing increased water uptake to the point of cell death. polysporin is the combination of polymyxin and bacitracin, while neosporin has both and adds neomycin, and aminoglycoside to the mix. this is the triple antibiotic cream that is used to treat superficial bacterial infections.


questions
1. difference between bactericidal vs. bacterioistatic agents?
2. classes of antibiotics that are naturally derived?
3. types of microbial resistance?
4. what are three categories of target inactivation? describe each mechanism.
5. what is the minimum inhibitory concentration?
6. pus might inactivate which antibiotics?
7. how might a hematoma inhibit antibiotics?
8. how might abscesses inhibit antibiotics?

sulfamethoxazole...
9. class?√√√√√
10. mechanism of action?√√√√√
11. bacteriostatic or bactericidal?√√√√√
12. spread throughout body?√√√√√
13. indicated in which conditions?X√XX†††
14. side effects?X√√√√√
15. sometimes combined with...X√√√√√
16. ratio of [15]?√√√√√√
17. when might [15] be specifically indicated?√√√√√√
18. how do the side effects of [15] compare to sulfamethoxazole?√√√√√√
19. skin morphology?√√√√√√
20. side effects associated with folic acid synthesis disruption?†√√√√√√

penicillins...
21. target which organisms?X√√
22. what type of antibiotics are penicillins? mechanism of action?√
23. is penicillin bactericidal or bacteriostatic?√
25. ∂escribe the prevalence of penicillin allergies.√
26. if a patient has true allergy to penicillin...√
27. penicillin g ineffective against...X√√
28. what is added to IM penicillin g?
29. side effects of penicillin g?X√X√

30. what is amoxicillin?√√√
31. mechanism of action?√√√
32. 2 mechanisms for bacterial resistance of amoxicillin?√√
33. distribution in the body?√√
34. indications for amoxicillin?XXX√XX
35. side effects?X†√†√
36. sometimes combined with what? mechanism of action?X√√√√
37. side effects?X√√√√
38. second of [37] caused by what microbe?√√

cephalexin...
39. bactericidal or bacteriostatic?X√√
40. mechanism?√X√
41. how do the generations of cephalosporins differ in their actions?√√√
42. the spectrum of coverage is similar to which other drug?X√√√
43. 2 mechanisms of resistance?√ √√
44. indications?XXX††
45. side effects?XXX√√

macrolides...
46. active constituent of macrolides?†√√
47. mechanism of action?√√√
48. bacteriostatic or bactericidal?√†√
49. unique transport mechanism within body?√√√
50. compare the coverage spectrum with penicillin.†X††√
51. indications for erythromycin?XXX
52. erythromycin needs to be dosed...√√√
53. common side effects?√√
54. most tablets are...√√

azithromax...
55. why is azithromax so popular?√√√√
56. active molecular constituent?XX√√√
57. mechanism of action?XX√√√
58. what is the half life of azithromax?√√√√√
59. typical dosing?√√√√√
60. indications?X√√√
61. compare the side effects of azithromax and erythromycin.X√√√√
62. helpful to dose concurrently with...√√√√√

tetracyclines...
63. molecular structure?√√
64. mechanism of action?√X√X√
65. usage is less effective due to...√√
66. most common use?XX√√√
67. all tetracyclines can do what in the oral cavity?X√
68. contraindicated in which populations?√√
69. shouldn't be given concurrently with...X√
70. reason for [69]?√√
71. is tetracycline bacteriostatic or bactericidal?XX√√√
72. effect on skin?XX√√
73. useful in outpatient care for...√√√
74. effective against organisms that are resistant to...àX
75. examples of [74]?X√X√

aminoglycosides...
76. mechanism of action?√√√X†√√
77. indicated for which organisms?√√√X√√
78. most frequently indicated for what condition?√√√X√X
79. what is the usual course of dosing for aminoglycosides?√√√√
80. gentamycin MOA?√√√√
81. what patients in particular are susceptible to [77]?√√√√
82. method of administration?√√√√
83. side effects?√√√X√X

quinolones...
84. mechanism of action?X√X√
85. has an affinity for which organisms?X√X√
86. most severe side effect?√√X√√
87. ciproxin associated with what disease?X√√
88. affinity for what body tissue?√√√
89. affinity for injury of what body part?√√√
90. reduces breakdown of...X√√√
91. affect on the senses?√√√

imidazoles...
92. mechanism of imidazoles?X√√√√
93. describe how metronidazole is activated.√√√√√
94. indications?X√X
95. examples of anaerobic bacteria?X†
96. side effects?X†
97. interaction with alcohol?√√

lincosamides...
98. what are these drugs derived from?X√√√
99. coverage spectrum? (similar to which drug class)X†√√
100. side effects?XX√X
101. clindamycin used topically for?X√√√

vancomycin...
102. indication?X√
103. which organisms in particular might this drug be indicated for?√√√
104. mechanism of action?X√√
105. what form of adminstration?√√√
106. alternate administration? why?√√√
107. side effects?X√
108. should only be used to treat pseudomembranous colitis after...√√

MRSA...
109. what are MRSA's?√
110. two categorizations?√
111. first category is susceptible to which drugs?√
112. second?√

mupirocin...
113. derived from...X√√
114. mechanism of action?XXX
115. administered...X√√
116. effective against which types of organisms?XXX
117. used in what conditions?X†

misc...
118. MAO of bacitracin?√√
119. bacitracin targets which organisms?X√
120. bacitracin used for what conditions?XX
121. polymyxin MAO?√√
122. polymyxin effective against which organisms?√√
123. polysporin is...√√
124. neosporin is...X√

name the drug or class with these characteristics...
125. beta lactam ring√√√√√
126. intracellularly activatedXXX√√√
127. altering bacterial cell membrane permeabilityX√√√
128. transported in leukocytesX√√√√√
129. outpatient care in lyme's diseaseXX√√√√
130. treatment of pneumocystis carinii in AIDSX√X√√
131. aerobic gram negativesXXX√
132. steven johnson's syndrome√√
133. severe acne / rosaceaX√X√
134. red man syndromeXX√
135. DNA gyrase√
136. folic acid synthesis inhibition√
137. causes pseudomembranous†
138. metallic taste in the mouth√
139. chelates calcium and stains teeth√
140. other medication to avoid if have penicillin √
141. last resort for pseudomembranous colitis√
142. blocks isoleucine incorporation into cell walls√
143. 50S ribosomal subunitX
144. irreversible nephrotoxicity√
145. drug with long half life√
146. 30S ribosomal subunitX

answers
1. bactericidal agents kill, while bacteristatic agents simply halt the growth.
2. penicillins
cephalosporins
macrolides
tetracyclines
aminoglycosides
3. failure to reach target
inactivated by enzyme
microbial target area inactivated
4. conjugation (genes from cell to cell), mutation, transduction (bacteriophage carries DNA into microbe).
5. the bare minimum concentration of the drug that is needed to inhibit the growth of the organism.
6. aminoglycosides. [squirting bragg's on pus]
7. hemoglobin can inhibit some drugs such as tetracyclines and penicillin. [heme tetracycline penicillin][H T P][blood on the toilet paper]
8. the low pH of abscesses inactivate some antibiotics such as the macrolides. [abscesses macrolides][looking at an abscess closely with the macro mode]

9. sulfonamide.
10. competitively inhibits PABA, which is used in the synthesis of folic acid, which is required in DNA replication.
11. bacteriostatic.
12. everywhere, including CSF.
13. UTI, otitis media, bronchitis,
14. GI upset
headache
skin changes-- rash, photosensitivity.
15. trimethoprim-- another folic acid inhibitor.
16. 5:1 sulf to tri
17. besides the indications in question 13, it might also be indicated for pneumocystiss carinii prophylaxis in HIV patients.
18. markedly increased hypersensitivity, especially of the skin.
19. raised papulomacular appearance, feels like sandpaper, pruritic.
20. megaloblastosis
leukopenia
thrombocytopenia
stevens johnson's syndrome

21. gram-positive bacteria.
22. beta-lactams.
23. inhibiting formation of peptidoglycan cross links in bacterial cell wall.
24. bactericidal.
25. penicillin is the drug that is most reported in relation to allergies, but it is estimated that only 20% actually have an allergy.
26. all the cillin's should be avoided, and maybe the cephalosporin group as well.
27. many gram negative anaerobes, all beta-lactamase producing organisms.
28. procaine.
29. neutropenia, nephrotoxicity.

30. penicillin derivative that contains thiazolaine ring, beta-lactam ring, side shains.
31. binds to penicillin binding protein and inhibits protein synthesis in cell wall.
32. beta-lactamase or modification of penicillin binding protein.
33. everywhere except CSF.
34. UTI's, lower respiratory infections, skin infections, ENT infections .
35. GI issues, although less than ampicillin.
36. clavulanic acid, in order to prevent beta-lactamase inhibition.
37. GI distress, pseudomembranous colitis.
38. clostridium difficile.

39. bactericidal.
40. same as penicillin; disrupting the PDG element in bacterial cell walls.
41. first generation-- gram positive. second and third generation-- gram negative. [turning to the dark side after the first generation]
42. amoxicillin.
43. beta lactamase production or modifications of PDG.
44. ENT infections
bronchitis
skin infections
prophylaxis
45. GI effects
yeast overgrowth.

46. macrocytic lactone ring.
47. inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit.
48. only bactericidal at high concentrations.
49. accumulate within leukocytes and therefore are carried to site of infection.
50. similar to but slightly wider than penicillin: includes chlamydia, mycoplasma, mycobacteria, ricksettia. [cmmr][come here!]
51. respiratory tract infx
syphilis
chlamydia
gonorrhea
52. 4 times a day.
53. GI distress-- N/V
54. enteric coated to offset GI side effects.

55. long half life and easy dosing schedule.
56. many membered lactone ring.
57. macrolides: lactone ring binds to 50S ribosomal subunit, blocking protein synthesis.
58. 68 hours.
59. two tablets day one, one tablet day 2-5.
60. ENT infections, sinusitis, pneumonia, bronchitis
mycoplasma, chlamydia
61. similar but with far less GI distress.
62. probiotics.

63. four hydrocarbon ring structure.
64. inhibits cell growth by binding to the 16S part of the 30S ribosomal subunit.
65. widespread bacterial resistance.
66. severe acne and rosacea.
67. permanently stain teeth.
68. children younger than 8-15, pregnant women.
69. calcium or dairy.
70. the tetracyclines chelate with calcium / dairy in the gut and markedly diminish absorption.
71. bactericidal.
72. photosensitivity.
73. lyme's disease.
74. agents with cell wall activity (ie penicillins).
75. mycoplasma
chlamydia
legionella
ricksettia
plasmodium
[mclrp][LaMe CRaP]

76. binds to the 30S bacterial ribosomal subunit and interferes with protein translation.
77. aerobic, gram negative bacteria such as pseudomonas.
78. serious infections such as septicemia.
79. once causal organism is identified therapy is switched to a less toxic drug.
80. binds to 30S and 50S ribosomal subunit, interfering with protein synthesis.
81. burn victims.
82. IV.
83. potentially irreversibly nephrotoxic and ototoxic.

84. inhibits bacterial DNA gyrase.
85. intracellular residing organisms such as legionella, mycoplasma.
86. tendon damage or rupture especially when used in combination with prednisone.
87. anthrax.
88. chelates calcium, deposited in bone and cartilage.
89. achilles tendon.
90. caffiene.
91. affects taste and smell.

92. disrupts the helical structure of DNA.
93. it is taken up into certain organisms that activate the pro-drug intracellularly into its active form.
94. infections of anaerobic bacteria or protozoa.
95. bacteroids, fusobacterium, clostridium. [bfc][big f...]
96. GI upset
headache
metallic taste in the mouth
thrush
97. inhibits acetaldehyde dehydrogenase, the enzyme that breaks down the breakdown product of alcohol.

98. species of actinomides.
99. similar to macrolides but also effective against actinomycetes, plasmodium, mycoplasma.
100. c. diff associated diarrhea, toxicity.
101. acne.

102. used in prophylaxis and treatment of severe gram positive bacterial infection. generally used as a last resort.
103. c. difficile and MRSA.
104. inhibition of peptidoglycan polymerization (distinct from penicillin mechanism)
105. IV, because not absorbed well orally.
106. oral if treating difficult case of pseudomembranous colitis.
107. red man or red neck syndrome.
108. metronidazole is shown to be ineffective.

109. multi-resistant staph aureus; staph that is resistant to beta lactams.
110. community acquired and healthcare acquired.
111. sulfa drugs (trimethorprim / sulfamethoxazole), tetracyclines, clindamycin.
112. vancomycin.

113. pseudomonas flourescens.
114. halts incorporation of isoleucine into bacterial proteins.
115. topically.
116. gram negative bacteria including MRSA.
117. impetigo, boils, folliculitis.

118. interferes with the transfer of cell wall precursors from the cell membrane to the cell wall.
119. gram positive.
120. superficial skin and eye infections.
121. binds to bacterial cell membrane and increases permeability, causing increased water uptake and death of bacteria.
122. gram negative.
123. bacitracin and polymyxin.
124. bacitracin and polymyxin and neomycin.

125. penicillins
126. metronidazole
127. polymyxin
128. macrolides
129. tetracyclines
130. sulfonamides
131. aminoglycosides
132. sulfonamides.
133. tetracycline
134. vancomycin
135. quinolones
136. sulfonamides
137. amoxicillin plus clavulanate
138. metronidazole.
139. tetracycline
140. cephalosporins
141. vancomycin
142. mupirocin
143. macrolides
144. gentamycin
145. azithromycin
146. tetracycline and aminoglycosides.