Pharmacology of Antimicrobials
1
ANTIMICROBIALS--PART I
I. Therapeutics
II. Classification by Organism
III. Classification by Mechanisms of Action
IV. Important Antimicrobial Concepts
V. Antimicrobial Resistance
VI. Principles of Selection and Administration
VII. Adverse Effects of Antibiotic Therapy
VIII. Nursing Implications
2
Therapeutic Goal
3
Therapeutic Goal
• The infecting organisms may be bacteria, viral,
protozoa
• Therapeutic goal
– To clear the tissue of the infecting organisms
• There are a lot of chemicals that will destroy
microbes
– The problem is that they may also destroy the host
4
Requirements to Achieve the
Therapeutic Goal
5
Requirements to Achieve the Therapeutic Goal
• Organism be susceptible to concentrations of
drug at infected site
• Dose and route of administration result in
adequate levels of drug at infected site for a
sufficient time in order to rid the organisms
• Local factors do not interfere with drug activity
• Host defenses facilitate microbial clearance
• Adjunctive therapies such as drainage or relief of
obstruction be used when necessary
6
Classification of Drugs by
Microorganism Affected
7
Classification of Drugs by Microorganism
Affected
A. Antibacterial Drugs
1. Narrow spectrum: target few types
2. Broad spectrum: target many types
3. Anti-mycobacterial drugs
B. Antifungal drugs
C. Antiviral drugs
1. Other antivirals
2. Antiretroviral
8
Classification of Antibiotics by
Mechanism of Action
9
Classification of Antibiotics by Mechanism of
Action
•
•
•
•
•
Inhibits bacterial cell wall synthesis
Inhibits protein synthesis
Inhibits nucleic acid synthesis
Interrupts metabolic pathways
Disrupts cell membrane permeability
– Cause the cell to drown
• Inhibits enzymes important in microorganism’s
function
10
Important Antimicrobial Drug
Concepts
Bacteriocidal vs. Bacteriostatic
Effects
11
Important Antimicrobial Drug Concepts
Bacteriocidal vs. Bacteriostatic Effects
•
Bacteriocidal: drug actually kills bacteria
•
Bacteriostatic: drug inhibits bacteria
reproduction so host defenses can kill
–
Ex. neomyosin that is put on a cut
12
Important Antimicrobial Drug
Concepts
Selective Toxicity
13
Important Antimicrobial Drug
Concepts
Selective Toxicity
•
Selective toxicity: Drug is toxic to the
microorganism but not to the human host.
14
Important Antimicrobial Drug
Concepts
Organism Sensitivity
15
Important Antimicrobial Drug
Concepts
Organism Sensitivity
•
Organism Sensitivity: drug is toxic to the
microorganism causing the infection.
–
A laboratory test will determine this.
16
Antimicrobial Resistance
17
Antimicrobial Resistance
• Antimicrobial resistance:
–The microorganism is no longer affected by
a particular antimicrobial that was once
effective against that microorganism
• Determined via the culture and sensitivity
testing
18
Antimicrobial Resistance
Culture and Sensitivity Testing of
Bacteria
19
Antimicrobial Resistance
Culture and Sensitivity Testing of Bacteria
• Bacteria isolated from the site of infection are cultured on a
plate.
– Some bacteria cannot be cultured on a plate
• Ex. leprosy must be cultured in an armadillo or on the foot plate of a mouse
• Paper discs soaked with various antibiotics are applied to the
plate.
– If the bacteria is affected by the antibiotic (is sensitive to it), a clear area
will develop around the antibiotic-soaked disc.
• Indicates that the antibiotic killed or prevented the bacteria from growing
• The extent of the clear area is a measure of how well the
antibiotic works against that particular bacterium.
20
21
Mechanisms of Antimicrobial
Resistance
22
Mechanisms of Antimicrobial Resistance
• Production of a drug-inactivating enzyme
– Produced by the microorganism
• Change in receptor structure of the organism
• Change in structural features of the
microorganism that affect drug permeability
• Development of alternative metabolic pathways
• These abilities can be conferred on a particular
bacterium by a spontaneous mutation or
conjugation (a sort of bacterial sex).
23
Factors Promoting Development
of Antimicrobial Resistance
24
Factors Promoting Development of
Antimicrobial Resistance
I. Administration of antimicrobials when not needed.
- Antibiotics are not effective against viruses
II. Lack of /improper adherence to regimens.
- Do not take the antibiotics at the correct time or for the
correct amount of time
III. Dosing that does not maintain adequate drug levels.
- Drug levels may be too low
- The correct dose may be given but then the absorption is
negatively affected
- Ex. when drugs are taken with tums or antacids
25
Common Resistant Microbes
26
Common Resistant Microbes
• Methicillin-resistant Staphylococcus aureus
(MRSA)
• Penicillin-resistant Streptococcus pneumoniae
• Vancomycin-resistant Enterococci (VRE)
• Multi-drug resistant tuberculosis
• HIV
27
Principles of Antimicrobial
Selection and Administration
28
Principles of Antimicrobial Selection
and Administration
• I. Match “drug with bug” principle
• II. Consider Drug Spectrum
• III. Consider Combination Therapy
• IV. Consider Site of Infection
• V. Maintain Adequate Blood Levels
• VI. Antibiotic Combinations
29
Principles of Antimicrobial
Selection and Administration
Match the Drug with the Bug
30
Principles of Antimicrobial Selection and
Administration
Match the Drug with the Bug
A. Identify pathogen: culture, gram stain (positive vs.
negative), common cause
-
In Africa, physicians look at the symptoms and treat the person
based on them because of the lack of medical care
B. Determine microbial susceptibility to drug: culture and
sensitivity, genotype and phenotype, literature
- This can be done even before the drug is given to the
person
C. Role of infectious disease consultant
1. Suggest appropriate therapy
2. Prevent overuse or inappropriate use of
antimicrobials
31
Principles of Antimicrobial
Selection and Administration
Spectrum, Therapy, Site of Infection
32
Principles of Antimicrobial Selection and Administration
Spectrum, Therapy, and Site of Infection
II. Consider Drug Spectrum
• Narrow vs. Broad Spectrum drug
III. Consider Combination therapy
IV. Consider Site of Infection
• Skin
• Lung
• Meninges/brain
• Abscess
33
Abscess
34
Abscess
35
Principles of Antimicrobial
Selection and Administration
Maintain Adequate Blood Levels
36
Principles of Antimicrobial Selection and
Administration
Maintain Adequate Blood Levels
• Many antibiotics should be administered around-theclock, i.e. every six hours for 4 times per day, every
eight hours for 3 times per day, etc.
– This depends on the half-life of the medication
– Also depends on how fast the medication is excreted through
the liver or the feces
• Oral antibiotics should be administered on an empty
stomach and should not be co-administered with other
oral medications.
– Ex. antacids and other forms of calcium can many times
inactivate the antibiotics
37
Principles of Antimicrobial
Selection and Administration
Antibiotic Combinations
38
Principles of Antimicrobial Selection and
Administration
Antibiotic Combinations
• Combinations of antibiotics that work by different
mechanisms may be synergistic or they may work against
each other.
• In the case of mixed infections with more than one
bacterial species, a combination may be required.
• In some instances, antibiotic resistance is discouraged by
combinations.
• Combinations should be used only when indicated.
39
Which of the following promote
antimicrobial resistance?
Administering antimicrobials when needed
Maintaining adequate drug levels
Non-adherence to regimen
Using antimicrobial to which the organism is
sensitive
40
Which of the following promote
antimicrobial resistance?
ce
t..
.
U
si
ng
an
re
n
-a
dh
e
on
N
tim
ic
ro
b
to
qu
ad
e
ng
ia
l
re
...
at
e
ic
...
tim
an
ai
nt
ai
ni
in
is
te
r
in
g
M
A
...
25% 25% 25% 25%
dm
1. Administering
antimicrobials when
needed
2. Maintaining adequate
drug levels
3. Non-adherence to
regimen
4. Using antimicrobial to
which the organism is
sensitive
41
Patient Variables in
Administering Antimicrobials
42
Patient Variables in Administering
Antimicrobials
A.
Health status: comorbidities, immunosuppressive therapy, etc.
- Can affect the choice of what antibiotic to use
B.
Life span and gender: appropriateness of dose and agent
- Decreased kidney function can affect doses
- Advanced liver disease may present a problem
C.
Ethnicity/culture: belief about medications may hinder
compliance
- Herbal remedies may cause a problem when mixed with
prescribed medications
D.
Environment: access to refrigeration, running water, etc.
- In some places, the hospitals and clinics turn off the
electricity over night
43
Adverse Effects of Antibiotic
Therapy
44
Adverse Effects of Antibiotic Therapy
• Normal gut flora are killed, which produces diarrhea
and can pave the way for colonization with pathogenic
bacteria, possibly even leading to death.
– Ex. E. Coli and other organisms help to maintain normal gut
function
• Suprainfection – infection with a second (antibiotic
resistant) organism that occurs during antibiotic
therapy.
– In pseudomembranous colitis, the bowel is colonized with
Clostridium difficile, producing a severe diarrhea that is
sometimes fatal.
• Allergy – most common with the penicillins.
45
Pseudomembranous colitis
46
Pseudomembranous colitis
47
Nursing Implications for
Antimicrobial Therapy
48
Nursing Implications for Antimicrobial
Therapy
I. Assess history carefully for hypersensitivity (allergic) reactions, possible
pregnancy and lactation
II. Assess kidney and/or liver function, especially in hypertensives,
diabetics, and the elderly.
- the kidney and the liver are the two locations where the majority of
antibiotics are excreted
III. Review culture and sensitivity reports.
IV. Monitor for response to therapy.
V. Patient Education
VI. Intravenous Administration of Antibiotics
49
Nursing Implications for
Antimicrobial Therapy
Patient Education
50
Nursing Implications for Antimicrobial Therapy
Patient Education
• Patient should complete full course of
antibiotics
• Take missed doses as soon as remembered
• Teach signs and symptoms of hypersensitivity
reaction. Can develop hypersensitivity AT ANY
TIME. (See following photos)
• May need a backup method of birth control
– Ex. rifampin used to treat TB decrease the effectiveness
of birth control pills
51
Stevens Johnsons Syndrome
52
Stevens Johnsons Syndrome
Note extensive sloughing of epidermis from Stevens-Johnson
syndrome. Courtesy of David F. Butler, MD.
http://emedicine.medscape.com/article/756523-overview
53
Nursing Implications
Intravenous Administration of
Antibiotics
54
Nursing Implications
Intravenous Administration of Antibiotics
• Many antibiotics are easy to give IV – they can be given in
small volumes of fluid over short infusion times.
• A few antibiotics have stringent requirements for IV
administration – they require large volumes of fluid and
lines in large veins, and/or they must be administered
slowly.
• Erythromycin and other macrolides – large volumes and
large veins.
• Vancomycin and clindamycin – administer slowly.
• If you don’t know – LOOK IT UP!
55
Antimicrobials: PART II
CATEGORIES
OF
ANTIMICROBIALS
56
Outline of Anti-infectives
57
Outline of Anti-infectives
Cell Wall
I. Beta-Lactams
I. Penicillin
II. Cephalosporins
III. Carbepenems
IV. Azetronam
II. Vancomycin
58
Outline of Anti-infectives
Protein Synthesis
III. Bacteriostatic inhibitors of protein synthesis
I. Tetracyclines
II. Macrolides
III. Clindamycin
IV. Chloramphenicol
V. Others
IV. Bacteriocidal inhibitors of protein synthesis
I. Aminoglycosides
59
Outline of Anti-infectives
DNA
V. Sulfamethoxazole-trimethroprime (Bactrim)
VI. Fluoroquinones (Floxacin)
VII. Metronidazole (Flagyl)
60
Outline of Anti-infectives
Antifungals and Antivirals
VIII. Antifungals
I. Amphtericin B
II. Ketoconazole
IX. Antivirals
I. Acyclovir
II. Ganciclovir
III. Drugs for Influenza
I. Amantadine
II. Rimantadine
III. Neurominidase Inhibitors – Tamiflu, Relenza
61
Outline of Anti-infectives
TB Drugs
X. TB drugs
I. Isoniazid
II. Rifampin
III. Pyrazinamide
IV. Ethambutol
62
Outline of Anti-infectives
HIV Drugs
XI. HIV drugs
I. Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
II. Non-nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
III. Protease Inhibitors (PIs)
IV. Entry Inhibitors
I. Fusion Inhibitors (Enfuvirtide)
II. Attachment Inhibitors (Selenztry)
V. Integrase Inhibitors (Raltegravir)
63
I. Antibiotics Affecting the Bacterial
Cell Wall: Beta-Lactam Antibiotics
64
I. Antibiotics Affecting the Bacterial Cell
Wall: Beta-Lactam Antibiotics
• The standard antibiotics that everyone has heard of
• Beta-lactam antibiotics penetrate the cell wall and bind
to targets on cytoplasmic membrane
• Disrupt synthesis/maintenance of the cell wall
– Bacterium is killed by an increase in osmotic pressure
• The bacteria kind of drowns
• Can be inactivated by beta-lactamases: enzymes that
degrade the drug.
• Gram-negative organisms have an additional
component to their cell wall that most beta-lactam
antibiotics cannot penetrate. Therefore, most of these
agents are not effective against gram-negative bacteria.
65
Types of Beta-Lactam Antibiotics
66
Types of Beta-Lactam Antibiotics
1.
2.
3.
4.
Penicillins
Cephalosporins
Carbapenems
Azetronam
Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier,67
p. 963
1. Penicillins
Pharmacotherapeutics
68
1. Penicillins
Pharmacotherapeutics
• Therapeutic: used for gram-positive bacteria such as
Strep and Staph and a few gram-negatives such as
Neisseria, and syphilis (Treponema).
• Some, but not all, will cover anaerobes such as
Enterobacter and also Pseudomonas, and Klebsiella.
• Prophylactic: used to prevent bacteremia in selected
populations at risk for endocarditis, such as people with
artificial or damaged heart valves.
• Individual penicillins have varying resistance to betalactamases (bacterial enzymes that break apart the
beta-lactam ring).
69
Pharmacokinetics of Penicillins
70
Pharmacokinetics of Penicillins
• Different penicillins are orally active or not.
• Most have a short half-life.
• Depot forms: benzathine penicillin G and procaine penicillin
G are administered by deep IM injection and released over
a long time.
• Distribution
– Bound to plasma proteins and do not cross blood-brain barrier
well except when it is compromised as in infection.
• Excretion
– Kidneys
71
Blood Levels of Different
Formulations of Penicillin G
72
Blood Levels of Different Formulations of
Penicillin G
Lehne, 2007,
Pharmacology for
Nursing Care, 6th
ed., Elsevier, p. 966
73
Penicillin Allergy
74
Penicillin Allergy
• As with any drug allergy, penicillin allergy involves the
immune system and antibodies that bind to the drug or
its degradation products.
• Can be as mild as rash or severe as anaphylaxis.
• Can occur with first or repeated exposure.
• Cross-allergy to other beta-lactam antibiotics.
• Skin testing may not be dependable and may cause an
anaphylactic reaction in sensitive individuals.
75
Adverse Effects of Penicillins
76
Adverse Effects of Penicillins
• Adverse effects include gastrointestinal symptoms and
suprainfections related to loss of normal flora.
– Nausea, vomiting, diarrhea, and constipation are some of
the most common adverse effects of antibiotics
• Overdose can cause neurologic problems, including
seizures.
– Has to be a pretty big overdose in order to cause seizures
• Most often happens in patients who are attempting to commit
seizures
77
Drug Interactions of Penicillins
78
Drug Interactions of Penicillins
• Synergistic with aminoglycoside antibiotics,
but can not be administered in the same IV
line.
– Need to have two lines running into the person
79
Beta-Lactamases (Penicillinases)
80
Beta-Lactamases (Penicillinases)
• Enzymes that cut the
beta-lactam ring,
inactivating beta
lactam antibiotics
• Bacteria that
manufacture betalactamases may be
resistant to all or most
beta lactam
antibiotics.
Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier,
p. 964
81
Beta-Lactamase Inhibitors
82
Beta-Lactamase Inhibitors
• Drugs that bind to the active site of beta-lactamases,
preventing these enzymes from cutting the beta-lactam
ring of the antibiotic.
– This prevents resistance of the bacteria to these antibiotics.
• Many beta-lactamase inhibitors are irreversible.
• Beta-lactam antibiotics can be administered along with
beta-lactamase inhibitors.
• Ex. augmentin
83
Penicillin-Beta-Lactamase
Inhibitor Combinations
84
Penicillin-Beta-Lactamase Inhibitor
Combinations
Drugs that combine a penicillin drug and the
inhibitor:
• Amoxicillin + clavulanic acid = Augmentin
• Ampicillin + sulbactam = Unasyn
• Ticarcillin + clavulanic acid = Timentin
• Piperacillin + tazobactam = Zosyn
85
Penicillin works by...
86
Penicillin works by:
m
e
nt
..
en
zy
sy
iti
n
g
an
n
In
hi
b
pr
ot
ei
rin
g
lte
A
.
n.
..
sy
in
pr
ot
e
g
iti
n
hi
b
In
A
ffe
c
tin
g
th
e
ba
ct
er
ia
l
...
1. Affecting the bacterial
cell wall
2. Inhibiting protein
synthesis
3. Altering protein
synthesis
4. Inhibiting an enzyme
in bacterial DNA
replication
..
25% 25% 25% 25%
87
2. Cephalosporins
88
2. Cephalosporins
• Similar to penicillins in structure and activity.
• Four generations, each with its own spectrum of
activity, susceptibility to beta-lactamases, and uses.
– Have gotten better with each generation
Pharmacokinetics:
• Widely distributed to body fluids including bone
• 1st and 2nd generation cephalosporins do not cross
blood-brain barrier.
• Most eliminated by the kidney: may need decreased
dose with decreased renal function
89
Major Differences between
Cephalosporin Generations
90
Major Differences between Cephalosporin
Generations
Activity against Resistance to
Gram Negative BetaLactamase
enzymes
Distribution to
CSF
1st (e.g.,
cephalothin)
2nd (e.g.,
cefamandole)
3rd (e.g.
cefotaxime)
Low
Low
Poor
Higher
Higher
Poor
Higher
Higher
Good
4th (e.g.
cefepime)
Highest
Highest
Good
Generation
Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 973
91
Possible Problems with
Cephalosporins
92
Possible Problems with Cephalosporins
• Chance of increased bleeding with warfarin because
of interference with Vitamin K metabolism –
cefmetazole, cefoperazone, and cefotetan.
• The same three can trigger a disulfiram-like reaction if
used with alcohol (Lehne, p. 411).
– Will cause the person to throw up if given alcohol
• To avoid the development of resistant populations of
bacteria, third and fourth generations should be
reserved for serious infections!
93
3. Carbapenems
94
3. Carbapenems
• Imipenem, meropenem, and ertapenem
• Beta-lactam antibiotics with extremely broad spectrum
• Gram positive cocci
• Gram negative cocci and bacilli
• Anaerobes
• IV administration is required
– Not absorbed from the GI tract
• Cross allergy with penicillins
• Suprainfection is a problem
• Especially valuable in mixed infections
95
II. Non-Beta-Lactam Antibiotic
Affecting the Bacterial Cell Wall:
Vancomycin
96
II. Non-Beta-Lactam Antibiotic Affecting the
Bacterial Cell Wall: Vancomycin
• A potentially toxic antibiotic used to treat serious
infections.
• Not a beta-lactam, but interferes with cell wall synthesis.
• Can be used in treating gram+ infections in penicillin-allergic
patients
• Synergism with aminoglycosides
• Poor penetration into CSF
– Cannot be used for encephalopathy or meningitis
• Oral preparation can be used for bowel infections,
particularly Clostridium difficile (a suprainfection).
– In this use, the drug isn’t absorbed into the bloodstream.
97
Adverse Effects of Vancomycin
98
Adverse Effects of Vancomycin
• Ototoxicity
• Nephrotoxicity
• Multiple drug interactions with hyperlipidemic
drugs, muscle relaxants, and ototoxic drugs
• Rapid infusion causes a severe reaction of
flushing, tachycardia, and hypotension which can
be fatal (infuse over 60 minutes).
• Irritating to the vein, causing thrombophlebitis
(use large, central vein and change IV site often).
99
III. Bacteriostatic Inhibitors of
Protein Synthesis
100
III. Bacteriostatic Inhibitors of Protein
Synthesis
1. Tetracyclines
2. Macrolides
3. Clindamycin
4. Chloramphenicol
5. Others
101
Protein Synthesis
102
Protein Synthesis
Porth,
Pathophysiology,
Concepts of
Altered
Health
States, 7th
ed., 2005,
Lippincott,
p. 123.
103
1.Tetracyclines
104
1.Tetracyclines
• Tetracycline, doxycycline, minocycline and others
• Bind to the 30S ribosomal subunit and prevent
elongation of the peptide chain.
• Broad spectrum but resistance has developed in
many bacterial species, limiting their use.
• Agents of choice for rickettsial diseases (Rocky
Mountain spotted fever) and for Chlamydia.
• Used in acne, periodontal disease.
• Mainly oral use, rare IV.
• Poor CSF penetration
105
Problems with Tetracyclines
106
Problems with Tetracyclines
• Poor absorption of some: all form insoluble
compounds with calcium, iron, magnesium,
aluminum and zinc. So don’t give with
antacids/laxatives, milk/dairy, iron.
• Bind to calcium in developing teeth and form a
discolored area.
– So don’t give to pregnant women (will only affect baby
teeth) or children below 8 years.
• Suprainfection with bowel organisms or Candida
107
Tetracycline-Stained Teeth
108
Tetracycline-Stained Teeth
http://www.wisconsinreconstructiveimplantdentist.com/images/tetracycline4.jpg
The patient was treated with tetracycline while the permanent teeth
were developing. Dark staining is present in the parts of the teeth that
were forming during treatment.
109
110
2. Macrolides
111
2. Macrolides
• Erythromycin, clarithromycin, azithromycin.
• Inhibit protein synthesis by inhibiting the 50 S
ribosomal subunit.
• Erythromycin is commonly used for grampositive and some gram-negative bacteria.
• Drug of choice for Legionella (Legeneir’s
disease) and Chlamydia
• An alternative to penicillin in allergic patients.
• Poor CSF penetration
112
Adverse Effects of Macrolides
113
Adverse Effects of Macrolides
• Some forms of erythromycin are corrosive to the GI
tract and can cause erosive esophagitis. Other
formulations have fewer problems and can be taken
with food.
• IV erythromycin is corrosive to veins and must be
diluted in large quantities of fluid and infused
slowly into a large vein.
• Hepatotoxicity is a concern.
114
WARNING with Erythromycin
and Clarithromycin!
115
WARNING with Erythromycin and
Clarithromycin!
• Erythromycin and clarithromycin are strong
inhibitors of cytochrome P450 – administer
with caution in patients taking drugs
metabolized by these enzymes.
• A lot of the anti-virals are broken down in the
liver by the p450 enzyme system
116
3. Clindamycin
117
3. Clindamycin
• Inhibits 50S ribosomal subunit: shouldn’t be used with a
macrolide.
• Good for anaerobes and gram-positive aerobes.
• Poor penetration of the brain.
• Suprainfection with Clostridium difficile.
• IV infusion must be SLOW.
• Reserve for serious infections
118
IV. Bacteriocidal Antibiotics that
Alter Protein Synthesis
Aminoglycosides
119
IV. Bacteriocidal Antibiotics that Alter Protein Synthesis
Aminoglycosides
• Tobramycin, gentamycin, amakacin and others
• Bind to the 30S ribosomal subunit. They are bacteriocidal
because they promote the formation of abnormal
proteins whose abnormal functioning kills the cell.
• No activity against anaerobes.
• Good coverage of gram-negative bacteria including
Pseudomonas, Klebsiella, and Serratia.
• Charged drugs that are not absorbed— used IV.
• Can be used topically to sterilize the gut or on the skin
(neomycin) or eye.
120
• Ototoxic and nephrotoxic— adjust for renal impairment
Aminoglycoside Administration
121
Aminoglycoside Administration
• For many patients, once daily infusion is as
good as divided doses because it produces
very high levels that kill bacteria even after
the blood level declines.
• Low levels in between the daily dose allows
washout from body cells in between doses
and lowers the risk of toxicity.
122
Aminoglycoside
Gentamicin Levels
123
Aminoglycoside
Gentamicin Levels
Lehne, RA, Pharmacology for Nursing Care, 5th ed., 2004, Saunders, p. 922
124
V. Sulfamethoxazoletrimethroprim (Bactrim)
125
V. Sulfamethoxazole-trimethroprim (Bactrim)
• Bactrim blocks bacterial enzymes that are
important for the synthesis of the building
blocks of DNA, RNA and proteins.
• This is a combination of a sulfa drug
(sulfamethoxazole) and an inhibitor of a
bacterial enzyme called dihydrofolate
reductase (trimethoprim).
• The two drugs that combine to form bactrim
block different steps in the pathway and
therefore are synergistic in their activity.
• Broad spectrum, including many gram
negative and gram positive microorganisms
• Used extensively for UTI and for
Pneumocystis carinii pneumonia of AIDS
126
Lehne, RA, Pharmacology for Nursing Care,
5th
ed., 2004, Saunders, p. 927
Adverse Effects of
Sulfamethoxazole-trimethroprim
(Bactrim)
127
Adverse Effects of Sulfamethoxazoletrimethroprim (Bactrim)
• Hypersensitivity reactions are most concerning
• Rash, including rare Stevens-Johnson syndrome.
• The trimethoprim component can cause blood dyscrasias
– Abnormal amounts of the components of blood
• Crystalluria (kidney/bladder stones) – patient should remain
well-hydrated.
• CNS effects – headaches are relatively common, sudden
psychosis
128
VI. Fluoroquinones
129
VI. Fluoroquinones
• Ciprofloxacin, levofloxacin, oxofloxacin and others
• Inhibit an enzyme (DNA gyrase) important in
bacterial DNA replication
• Active against aerobic organisms, most gram
negative and some gram positive.
• Should not be taken with aluminum, iron, calcium,
or zinc supplements.
• Can increase plasma levels of theophylline and
warfarin.
130
Adverse Effects of
Fluoroquinones
131
Adverse Effects of Fluoroquinones
• Can cause irreversible joint disease in
children <18.
• Rarely, tendon rupture in adults.
• Photosensitivity.
• Candida suprainfections, especially of the
oropharynx.
• Infrequent but serious CNS effects.
132
Sjogren’s Syndrome
133
An 81-year-old woman with rheumatoid arthritis, Sjogren's syndrome, and
hypertension presented with swelling and pain in the area of the left heel, which
had developed suddenly a week after a short course of levofloxacin for acute
bronchitis
Vyas H and Krishnaswamy G. N Engl J Med
2007;357:2067
134
VII. Metronidazole (Flagyl)
135
VII. Metronidazole (Flagyl)
• Targets anaerobic organisms, including parasites
and bacteria
• C. difficile, Bacteroides, Entameba histolytica
(amoebic dsysentery)
• A prodrug that is activated only in anaerobic cells.
• Darkening of the urine
• CNS adverse effects
• Caution during pregnancy, avoid during lactation
• Cytochrome P450 interactions
136
VIII. Antibiotics for Tuberculosis
Target Mycobacteria
137
VIII. Antibiotics for Tuberculosis Target
Mycobacteria
• TB is Mycobacterium Tuberculosis
• TB is always treated with 2 or more drugs to avoid
the emergence of resistant strains.
• Treatment is prolonged (6-10 months) because the
bacteria grow very slowly.
– Compliance is a huge issue.
• The sensitivity of the bacterium to the proposed
regimen must be determined ahead of time.
• Treatment is evaluated for efficacy.
138
Mycobacteria Infection
139
Mycobacteria Infection
• Patients with HIV infection or who are
immunocompromised are very susceptible to TB and
other mycobacteria and are treated differently than
other patients.
• A reactive skin test in a previously negative patient
indicates a new exposure. The patient should be treated.
• TB infection can be followed by a latent phase where the
disease is inactive. Persons in the latent phase should be
treated to avoid the re-emergence of active disease.
• Patients with newly reactive skin tests and patients in the
latent phase can be treated with monotherapy,
frequently isoniazid but sometimes rifampin (the one
that if given to the woman during child-bearing years,
need to back it up with another type of birth control).
VIII. Tuberculosis Drug
Isoniazid
141
VIII. Tuberculosis Drug
Isoniazid
• Inhibits the formation of the mycobacterial cell wall – highly specific
for TB.
• Pharmacokinetics- distributed to all body tissues and fluids, crosses
blood-brain barrier to achieve therapeutic levels.
• Used alone to treat latent TB and with at least one other drug for
active TB.
• Risk of peripheral neuropathy is decreased by giving with pyridoxine
(vitamin B6).
• Hepatotoxic, especially in older people. Contraindicated for people
with pre-existing liver disease. Monitor liver enzymes.
• Alcohol consumption increases the risk of hepatotoxicity.
• Increases levels of phenytoin – draw phenytoin levels and decrease
the dose if necessary.
142
VIII. Tuberculosis Drug
Rifampin
143
VIII. Tuberculosis Drug
Rifampin
•
•
•
•
Used with at least one other drug for active TB
Distributed to the CSF.
Hepatic metabolism.
Hepatotoxic and increases the hepatotoxicity of
isoniazid and pyrazinamide.
• Induces cytochrome P450 enzymes – decreases
levels of birth control pills, seizures meds, and
others.
• Turns body fluids red! (Warn the patient)
144
VIII. Tuberculosis Drug
Pyrazinamide
145
VIII. Tuberculosis Drug
Pyrazinamide
• Often combined with isoniazid, rifampin,
and ethambutol.
• Hepatotoxic – follow liver enzymes.
146
VIII. Tuberculosis Drug
Ethambutol
147
VIII. Tuberculosis Drug
Ethambutol
• Distributed widely but doesn’t penetrate the
brain
• Can cause optic neuritis. Need eye exam by
ophthalmologist
• Allergic reactions
• NOT hepatotoxic!
148
Antifungals
Amphotericin B
149
Antifungals
Amphotericin B
• A fungus is considered a plant without chlorophyll in it
• Nickname – Amphoterrible!
• Binds to sterols in the fungal membrane and increases
permeability – the fungal cell swells and bursts
• Toxic to mammalian cells (human) because of the
cholesterol in cell membranes.
• Used for systemic fungal infections.
• Infusion reactions – phlebitis and systemic symptoms
(fever, chills, rigors, nausea, and headache).
• Nephrotoxic – use with caution with other nephrotoxic
drugs (aminoglycosides)
• Dose reduction when used with flucytosine – a highly
synergistic combination.
150
Antifungals
Ketoconazole
151
Antifungals
Ketoconazole
• Inhibits the synthesis of a sterol component of the
fungal cell membrane.
– Could interfere with the cholesterol in your own cells
• Oral alternative to amphotericin B for systemic
fungal infections.
• Can be used topically for fungal skin infections.
• Strong inhibitor of cytochrome P450 enzymes –
use with extreme caution in hepatically
metabolized drugs – Table 91-3 Lehne.
• Rare hepatic necrosis.
152
Antivirals
Acyclovir
153
Antivirals
Acyclovir
• Active against all herpes viruses: herpes simplex, herpes zoster, and
cytomegalovirus (CMV)— although most strains of CMV are
resistant.
– CMV is an infection that often occurs as CMV retinitis early in the HIV process
• Many patient used to go blind early because of it but do not as much now because of
prophylaxis
• Suppresses synthesis of viral DNA – but must be activated by a viral
enzyme, thymidine kinase.
• Resistance is commonly due to thymidine kinase deficiency.
• Topical, oral, and IV.
• Nephrotoxic – maintain high hydration to dilute drug in renal
tubules.
• Valacyclovir (Valtrex) is a prodrug of acyclovir – but it is more
bioavailable.
• NOTE – immunization for chicken pox and shingles (both are
manifestations of herpes zoster) is available
– Immunizations would prevent the need to receive acyclovir
154
Herpes Zoster (Shingles)
155
Herpes Zoster (Shingles)
http://www.healthline.com/channel/herpeszoster_images?id=1507
156
Antivirals
Ganciclovir
157
Antivirals
Ganciclovir
• Active against all herpes viruses, including CMV – but has
serious toxicities.
• Reserved for treatment of CMV in immunocompromised
patients, including HIV-infected and transplant patients.
• Poor oral bioavailability is slightly increased by food.
• Excreted unchanged in the urine – decrease dose for
patients with renal impairment.
• Granulocytopenia and thrombocytopenia are prominent
adverse effects – monitor blood counts.
• Teratogenic and embryotoxic – birth control should be in
place.
158
Antivirals
Prevention
159
Antivirals
Prevention
• First line of defense is immunization!!!
– Practically everyone should be immunized
– Traditional injected vaccine is approved for everyone
– Live inhaled vaccine (Flu-Mist) is approved for people
2-49 years old
• The flu mist is not nearly as effective as the injection
• The seasonal flu vaccine for this season (20102011) will include H1N1.
160
Drugs for Influenza
161
Drugs for Influenza
• Amantadine and rimantadine – work as prophylaxis
during epidemics and as treatment.
– Only effective against influenza A
• Neuraminidase inhibitors
– Oseltamivir (Tamiflu) is an oral drug that can be used as
prophylaxis or to shorten the duration of flu
– Zanamivir (Relenza) is inhaled but works similarly to
oseltamivir – not approved for prophylaxis.
– Both must be taken very soon after the first flu symptoms
appear to be effective in shortening the duration of the flu.
Amphotericin B is an
163
Amphotericin B is an
Antibacterial
Antifungal
Antiviral
Antiseptic
Antimycobacterial
ob
a
ct
er
ia
l
tic
nt
im
yc
nt
is
ep
A
A
nt
iv
ir
al
A
l
ng
a
nt
ifu
A
ac
te
ria
l
20% 20% 20% 20% 20%
nt
ib
A
1.
2.
3.
4.
5.
164
Human Immunodeficiency Virus
165
Human Immunodeficiency Virus
Photo: Hardin MD/University of Iowa and CDC
http://www.lib.uiowa.edu/HARDIN/MD/cdc/948.html
166
Warning with HIV Drugs!
167
Warning with HIV Drugs!
• HIV drugs have many overlapping toxicities and many
interactions with each other and other drugs.
• When administering these drugs – LOOK THEM UP!
– Medications are very complex
• Do not depend on physicians or other nurses to
prevent your mistakes!
• Need a specialist in order to properly manage the
disease (not just the primary care practitioner)
168
Of Particular Note with HIV
Drugs!
169
Of Particular Note with HIV Drugs!
• HIV is always treated with combinations of drugs. The current
combinations are collectively referred to as ART (Anti-Retroviral
Therapy), ARV (Anti-Retrovirals) or HAART (highly active
antiretroviral therapy). To avoid development of viral resistance, it
is very important that patients receiving HAART take their
medications reliably and on time.
• Skipping doses can have devastating results, both for the individual
patient and for society if the patient infects someone else with a
resistant strain of virus.
– Increases the risk of developing a resistance against the drugs
– Should not begin a treatment program for patients who are not expected to
be coherent
• Because the medications have a variety of side effects that can be
very bothersome, it may be tempting to patients to discontinue
treatment when they feel better.
170
Types of HIV Drugs
171
Types of HIV Drugs
Five classes currently on the market:
1. Nucleoside reverse transcriptase inhibitors (NRTIs)
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
3. Protease inhibitors (PIs)
4. Attachment inhibitors
–
Fusion (subq and costs $2680/month)
– CCR5 antagonist
5. Integrase inhibitors
172
ART, ARV, or HAART Therapy
173
ART, ARV, or HAART Therapy
• A combination of three or four drugs that target
different aspects of the viral life-cycle.
• Can reduce viral load so that it is undetectable in
blood, but does not cure HIV infection.
• Controversy: when to begin ART, ARV or HAART?
Currently wait until CD4+ cells drop below 500
cells/mm3 but some recommend earlier
treatment.
– In most African countries, because of the costs
associated with HIV, many will wait until the CD4
count goes down to 200 or 350
174
HIV Drugs
Diagram
175
HIV Drugs
Diagram
Lehne, 2007, Pharmacology for Nursing
Care, 6th ed., Elsevier, p. 1067
176
Pregnant HIV-Infected Patients
177
Pregnant HIV-Infected Patients
• Pregnant patients who would otherwise receive treatment should receive it
while pregnant, although particular drugs might have to be avoided.
• Treatment of the patient’s infection will reduce viremia and thereby reduce
the risk of transmission to the fetus.
• In women who have not received therapy during pregnancy, RT inhibitors can
be given during labor, and to both mother and child after delivery.
– This strategy reduces maternal to fetal transmission dramatically.
• In the US, can determine if the child has HIV almost immediately
• In Africa, need to wait 1.5 years because it takes this long for the antibodies
against HIV (from the mother) to leave the body
• PMTCT programs = Prevention of Mother to Child Transmission.
– The mother needs to know not to breast feed her child because of the risk of
transmission
• It is best to do either all breast feeding or all formula feeding, rather than mixed feedings
178
179
I. and II. Reverse Transcriptase
Inhibitors
180
I. and II. Reverse Transcriptase Inhibitors
• Nucleoside Reverse
Transcriptase
Inhibitors (NRTIs)
• Non-Nucleoside
Reverse Transcriptase
Inhibitors (NNRTIs)
• Work at same stage
in the replication
cycle but in different
ways
181
I. Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)
182
I. Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
• Inhibit viral enzyme, reverse transcriptase, that converts viral RNA
into DNA, by terminating the growing DNA strand. This activity
can also inhibit human DNA polymerases so these drugs are toxic
to dividing cells.
• Zidovudine (AZT), ddi, ddc, 3tc, d4t and others were some of the
early drugs.
– We still use AZT but rarely use d4t in the United States
• Can cause mitochondrial toxicity in liver (hepatomegaly and fatty
liver) and elsewhere leading to lactic acidosis.
– Early on, the majority of people who developed lactic acidosis dies quickly
• Bone marrow depression, anemia, neutropenia.
– This is when erythropoietin was first researched
• All have GI toxicity – stomatitis, nausea, diarrhea, etc.
• Peripheral lipoatrophy (particularly d4t)
• Peripheral neuropathy
183
Facial Lipoatrophy
184
Facial Lipoatrophy
http://img.thebody.com/legacyAssets/09/64/ellen.jpg
185
II. Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
186
II. Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
• Bind to the active site of the reverse transcriptase
enzyme.
• More specific for the viral reverse transcriptase and do
not affect human DNA polymerases the way the
nucleoside RT inhibitors do.
• Nevirapine, delavirdine, efavirenz
• All have cytochrome P450 interactions but of different
kinds (nevirapine is an inducer, delavirdine and efavirenz
can inhibit).
• Many drug interactions.
• Rash can be severe – Stevens-Johnson syndrome.
• Severe hepatotoxicity.
• Avoid St. John’s wort.
187
III. Protease Inhibitors (PIs)
188
III. Protease Inhibitors (PIs)
• Inhibit viral protease,
which is responsible for
the final step in
maturation of an
infective virus.
• Because of the inability
to cut the long viral
proteins into functional
units, the virus remains
immature and noninfective.
• Affect the budding off
of the drugs
• Tend to cause the
central obesity
Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 1067
189
III. Protease Inhibitors (PIs)
190
III. Protease Inhibitors (PIs)
• Indinavir, ritonavir, saquinavir, nelfinavir, amprenavir, fosamprenavir,
atazanavir, tipranavir and lopinavir
• Several dosage forms and one combination (lopinaver +ritonavir).
• All cause significant adverse effects:
1. Hyperglycemia/diabetes
2. Fat redistribution from the periphery to the central areas of the
body
3. Hyperlipidemia
4. Increased bleeding in patients with hemophilia.
5. Reduced bone mineral density.
6. Elevation of serum transaminases (liver enzymes).
7. ECG changes with atazanavir (prolonged QT)
- more likely to develop heart disease
• Despite plethora of bad effects, these drugs are so important in
managing HIV infected patients that they are rarely discontinued
because of bad effects.
191
Buffalo Hump
192
Buffalo Hump
http://www.righthealth.com/topic/Buffalo%20Hump?as=clink&ac=143
7&afc=2168586466&p=
193
Enlarged Abdomen
194
Enlarged Abdomen
195
III. Protease Inhibitors
196
III. Protease Inhibitors
• All are metabolized by cytochrome P450 enzymes.
Concurrent administration with inducers or inhibitors of
cytochrome P450 can affect half-lives and drug levels
(recall that the non-nucleoside RT inhibitors have
varying effects on the cytochrome P450 enzymes). See
table 93-6 in Lehne.
• St. John’s wort and garlic preparations should be
avoided.
• Most have GI side effects similar to the nucleoside and
non-nucleoside RT inhibitors.
197
IV. Entry Inhibitors
198
IV. Entry Inhibitors
• Inhibits entry of HIV
into CD4 positive
cells.
• Two types:
– Fusion Inhibitors
– Attachment Inhibitors
199
Lehne, RA, Pharmacology for Nursing Care,
5th
ed., 2004, Saunders, p. 986
Fusion Inhibitor
Enfuvirtide (Fuzeon)
200
Fusion Inhibitor
Enfuvirtide (Fuzeon)
• The drug binds to gp41, a viral envelope
protein.
• Resistance occurs when the viral gene
encoding gp41 mutates to alter its shape so
the drug can not bind.
201
Fusion Inhibitor
Enfuvirtide
202
Fusion Inhibitor
Enfuvirtide
• The only fusion inhibitor currently on the market.
• Must be given by subcutaneous injection twice a day.
– This is why it is considered one of the deep salvage drugs
• Reserved for patients who have failed more standard
HAART with RT inhibitors and protease inhibitors.
• Extremely expensive.
• Injection-site reactions (pain and tenderness) are
common and may persistent for days.
• Risk of bacterial pneumonia is increased.
• Hard to manufacture – supply is limited.
203
Attachment Inhibitors
204
Attachment Inhibitors
• Blocks the CCR5 receptor so HIV does not
attach to the CD4 cell
– A.k.a. CCR5 antagonist
• Maraviroc (Selzentry™) only approved CCR5
antagonist
• Need to have tropism testing (only works for
CCR5 receptor not other receptor types)
205
IV. Attachment Inhibitors
Maraviroc
206
IV. Attachment Inhibitors
Maraviroc
• Dosage is adjusted depending on whether it is
combined with a CYP 450 inducer or inhibitor
• Pregnancy Category B
• Side effects include:
– Cough, fever, rash, muscle and joint pain, stomach
pain, dizziness, liver toxicity
– Use with caution in people with cardiovascular
disease
207
V. Integrase Inhibitors
208
V. Integrase Inhibitors
• A critical step in the HIV life
cycle is the integration of viral
genetic information into the
host cell DNA which then turns
into a viral factory.
• The enzyme integrase aids in
this task.
• Integrase inhibitors block this
enzyme.
• There is one opportunity for
this to be effective. If it fails,
there is no other opportunity
since the genetic information
from the virus is already
incorporated
209
Lehne, RA, Pharmacology for Nursing Care,
5th
ed., 2004, Saunders, p. 986
V. Integrase Inhibitors
Raltegravir
210
V. Integrase Inhibitors
Raltegravir
• Currently one approved drug –raltegravir
(Isentress)
• Given twice daily (a compliance issue)
• Diarrhea, nausea, and headache are possible
adverse effects.
• Eliminated by metabolism – plasma
concentrations may be reduced by enzyme
inducers, particularly rifampin.
• Pregnancy category C
211
All of the following are classes
of HIV medications EXCEPT:
1.
2.
3.
4.
Protease Inhibitor
Integrase Inhibitor
Beta-Lactamase Inhibitor
Reverse Transcriptase Inhibitor
212
All of the following are classes of HIV
medications EXCEPT:
...
er
se
Tr
an
sc
ri
pt
as
...
hi
b
In
e
ev
R
B
et
aLa
ct
am
as
ra
s
te
g
In
P
ro
te
a
se
e
In
h
In
h
ib
i
ib
ito
to
r
r
25% 25% 25% 25%
1. Protease Inhibitor
2. Integrase Inhibitor
3. Beta-Lactamase
Inhibitor
4. Reverse
Transcriptase
Inhibitor
213
Resistance and Adherence
214
Resistance and Adherence
• Replication rate of HIV is between 1 and 10 billion
virions/day
– Once the virus gets into the host’s DNA, they spit out more
viruses
• There is a high probability of introducing base-pair
errors by HIV reverse transcriptase
• HIV can mutate into a drug-resistant form very
quickly
– Combining antiretroviral drugs that work at different
points in the replication cycle minimizes resistance.
• Recommend > 95% adherence to antiretroviral
medications to prevent resistance.
215
Conclusion
216
Conclusion
• Therapy for HIV infection is complicated and drugs have
significant toxicity and interactions with other drugs.
• Management of HIV-infected patients is best done by
health care providers who are very experienced with
these drugs and their side effects.
• When HIV-infected patients are hospitalized on general
medical or surgical floors, nurses must become
knowledgeable about the patient’s regimen and how it
might interact with other drugs the patient might be
given as part of his/her hospital treatment.
217
218