Transcript The Drugs to Kill the Bugs: Part 1

Antimicrobial
Pharmacotherapy in Children
Paul C. Walker, Pharm.D.
Manager, Clinical Pharmacy Services
Detroit Medical Center
and
Clinical Assistant Professor
College of Pharmacy and School of Nursing
University of Michigan
Classifying
Antimicrobial Agents
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Inhibition of cell wall synthesis
Altering cell membrane permeability
Reversibly inhibiting protein synthesis
Irreversibly disrupting protein synthesis
Disruption of nucleic acid metabolism
Blocking essential metabolic events
Peptidoglycan Synthesis
Peptidoglycan is composed of chains of peptidoglycan monomers (NAG-NAMtetrapeptide). These monomers join together to form chains and the chains
are then joined by cross-links between the tetrapeptides to provide strength.
Peptidoglycan Synthesis
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•
•
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New peptidoglycan synthesis
occurs at the cell division plane by
way of a collection of cell division
machinery known as the divisome.
Bacterial enzymes called
autolysins, located in the divisome,
break both the glycosidic bonds at
the point of growth along the
existing peptidoglycan, as well as
the peptide cross-bridges that link
the rows of sugars together.
Transglycosidase enzymes then
insert and link new peptidoglycan
monomers into the breaks in the
peptidoglycan.
Finally, transpeptidase enzymes
reform the peptide cross-links
between the rows and layers of
peptidoglycan to make the wall
strong
Structure of
Bacterial Cell Walls
Peptidoglycan
Cross-links
Comparison of the structure and composition of
gram positive and gram negative bacterial cell walls
Inhibitors of Cell Wall
Synthesis
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Beta Lactam
Antibiotics
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–
–
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Penicillins
Cephalosporins
Carbapenems
Monobactams
Vancomycin
The beta lactam ring of penicillin
How Penicillins Inhibit
Peptidoglycan Synthesis
During normal bacterial growth,
bacterial enzymes called autolysins put
breaks in the peptidoglycan in order to
allow for insertion of peptidoglycan
building blocks (monomers of NAG-NAMpeptide). These monomers are then
attached to the growing end of the
bacterial cell wall with transglycosidase
enzymes. Finally, transpeptidase
enzymes join the peptide of one
monomer with that of another in order
to provide strength to the cell wall.
Penicillins and other -lactam antibiotics
bind to the transpeptidase enzyme and
block the formation of the peptide crosslinks. This results in a weak cell wall and
osmotic lysis of the bacterium.
Beta Lactam Antibiotics:
The Penicillins
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Natural Penicillins
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– Penicillin G
– Penicillin V
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–
–
–
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Aminopenicillins
– Ampicillin
– Amoxicillin
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Carboxypenicillins
– Ticarcillin
– Carbenicillin
Penicillinase-Resistant
Penicillins
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Cloxacillin
Dicloxacillin
Methicillin
Nafcillin
Oxacillin
Ureidopenicillins
– Mezlocillin
– Piperacillin
Beta Lactam Antibiotics:
The Cephalosporins
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First
Generation
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–
–
–
–
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Cephalothin
Cefazolin
Cephalexin
Cephapirin
Cefadroxil
Cephradine
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Second
Generation
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–
–
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–
–
–
Cefaclor
Cefoxitin
Cefuroxime
Cefotetan
Cefpoxodime
Cefprozil
Cefonicid
Cefmetazole
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Third
Generation
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–
–
–
–
–
–
–
–
–
Cefotaxime
Ceftriaxone
Cefoperazone
Cefipime*
Cefmenoxime
Ceftizoxime
Ceftazidime
Cefdinir
Cefixime
Ceftibutin
* This is classified as a “fourth” generation agent; it has gram negative activity similar to other third
generation agents, but better gram positive coverage.
Beta Lactam Antibiotics:
The Carbapenems and Monobactams
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Carbapenems
– Imipenem/Cilastatin
– Meropenem
– Ertapenem
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Monobactams
– Aztreonam
Side Effects and Adverse
Reactions
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Beta lactam Antibiotics
– Hepatic dysfunction
– Acute interstitial nephritis
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azotemia, hematuria, proteinuria, fever,
rash, eosinophilia
– Neurotoxicity
– Transient blood dyscrasias
– Allergic or hypersensitivity reactions
– Coagulopathy
Vancomycin
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Indications: serious gram positive
infections where -lactams are
inappropriate (MRSA, MRSE, allergy,
etc.)
Toxicities and Side Effects
– Nephrotoxicity
– Ototoxicity
– Red Man Syndrome
Prokaryotes vs. Eukaryotes:
Ribosomes
Disrupters of Protein
Synthesis
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Bind to the ribosomal
subunits to impair
protein synthesis
– Aminoglycosides
– Chloramphenicol
– Macrolides
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Erythromycin
Clarithromycin
Azithromycin
– Clindamycin
The Aminoglycosides
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Kanamycin
Gentamicin
Tobramycin
Amikacin
Netilmicin
Sisomycin
Structure of the
antibiotic gentamicin
C1a bound to its RNA
target. Aminoglycoside
antibiotics cause
misreading of the
genetic code.
Blocks initiation of
protein synthesis
Blocks translation to cause
premature termination
Causes incorporation
of incorrect amino acid
Aminoglycosides bind to the 30s subunit to
impair protein synthesis.
Agents that Bind to the
50S Ribosome
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Chloramphenicol
– spectrum of activity
 S. pneumonia
 H. influenza
 Neisseria spp.
 Salmonella
 Bordetella
 Enterobacteriaceae
 some anaerobes
Agents that Bind to the
50S Ribosome
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Macrolides
– Erythromycin

S. pneumonia, S.
pyogenes, Legionella,
Chlamydia trachomatis,
M. catarrhalis, H.
influenza, Mycoplasma
pneumonia
– Clarithromycin
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MAC
– Azithromycin
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MAC
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Clindamycin
– aerobic gram-positive
bacteria
– anaerobes, especially B.
fragilis
– used in combination
with aminoglycosides to
treat intra-abdominal
and gynecologic
infections
Side Effects and Adverse
Reactions
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Chloramphenicol
– Gray syndrome
– Dose-dependent bone
marrow suppression
– Aplastic anemia,
pancytopenia
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Macrolides
– GI complaints
– Rash
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Clindamycin
– Diarrhea
– Pseudomembranous
colitis
– Rash, urticaria
– Hypotension
Disrupters of Nucleic Acid
Metabolism
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Metronidazole
Quinolones:
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Ciprofloxacin
Levfloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Trovafloxacin
Gatifloxacin
Grepafloxacin
Disrupters of Nucleic Acid
Metabolism
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Metronidazole
Participates in redox reactions; it is activated by a reduction of the nitro
group to an anion radical. In the case of metronidazole, reduced
ferredoxin appears to be the primary electron donor responsible for its
reduction The anion radical is highly reactive and will form adjuncts with
proteins and DNA leading to a loss of function. In particular, the reactions
with DNA result in strand breakage and inhibition of replication and will
lead to cell death.
Disrupters of Nucleic Acid
Metabolism
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Quinolones: inhibit
DNA-gyrase and
topoisomerase II
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Ciprofloxacin
Levfloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Trovafloxacin
Gatifloxacin
Grepafloxacin
Side Effects and Adverse
Reactions
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Metronidazole
– dizziness
– paresthesias
– peripheral
neuropathy
– disulfiram-like
reaction
– blood dyscrasias
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Quinolones
– headache
– rash,
photosensitivity
– GI complaints
– arthralgias
– confusion
– liver dysfunction
Antimetabolites
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Trimethoprim
Sulfonamides
– Sulfamethoxazole
– Sulfisoxazole
Inhibition of folate metabolism by
sulfonamides and trimethoprim
Side Effects and Adverse
Reactions
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Sulfonamides
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Dizziness, headache
Rash
Blood dyscrasias
Crystalluria
Acute nephropathy
Bilirubin displacement
Proper Antimicrobial
Selection: Factors to Consider
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Identity of infecting organism
Susceptibility of infecting
organism
Host Factors
Major Mechanisms
of Antimicrobial Resistance
Target site modification
(intracellular or extracellular;
-lactams, macrolides,
quinolones, glycopeptides)
Enzymatic
degradation
(intracellular or
extracellular;
-lactams,
aminoglycosides)
Decreased
permeability
(-lactams)
X
Bypass
(TMP/SMX)
Efflux
(macrolides,
quinolones)
Enzyme Inactivation of
Penicillins
2
1
1 = Site of action of penicillinase
2 = Site of action of amidase
A = Thiazolidine ring
B = -lactam ring
Structure of penicillins and interaction
with beta lactamase
Resistance to Penicillin in N.
gonorrhea
Beta lactamase
Bacterial Resistance:
What Problems are We Seeing?
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Gram Negative
Organisms
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H. Influenza
M. Catarrhalis
Enterobacter
Klebsiella
Citrobacter
Serratia
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Gram Positive
– Staphylococcus
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S. aureus
S. epidermidis
– Streptococcus
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S. pneumoniae
Vancomycin
– Enterococci
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E. faecalis
E. faecium
– S. aureus
Other Important Factors:
MICs and MBCs Fail to Tell the Whole Story
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Antimicrobial Pharmacodynamics
– attempt to characterize the relationship
between ANTIMICROBIAL EXPOSURE
(concentration, dose, AUC) and
ANTIMICROBIAL EFFECT (eg., rate, extent,
and duration of antimicrobial activity)
Other Important Factors:
MICs and MBCs Fail to Tell the Whole Story
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Antibiotic Pharmacodynamics
– Rate and Extent of Bactericidal
Action
– Post-antibiotic Effect
– Effects of Sub-inhibitory
Concentrations
– Post-antibiotic Leukocyte Effect
– Inoculum Effect
Classification Based on
Pharmacodynamic Characteristics
– Concentration-Dependent Agents
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Bactericidal activity is dependent on
concentration above the MIC achieved,
increasing with increasing concentration
– Time-Dependent Agents
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Bactericidal activity is dependent on how long
the concentration exceeds the MIC
– Bacteriostatic Agents
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Abort bacterial growth and allow host defenses
to eradicate organisms
Concentration-Dependent Killing of
Pseudomonas aeruginosa with Tobramycin
1 / log CFU per mL
8
Antibiotic
conc
7
6
control
5
1/4 MIC
1 MIC
4
4 MIC
3
16 MIC
2
64 MIC
1
0
1
2
3
Time (hours)
4
5
6
NON-Concentration-Dependent Killing
9
Antibiotic
conc
1 / log CFU per mL
8
7
control
6
1/4 MIC
5
1 MIC
4
4 MIC
3
16 MIC
2
64 MIC
1
0
1
2
3
Time (hours)
4
5
6
Pharmacodynamic Properties
by Antibiotic Class
CONCENTRATION
dependent killing
Aminoglycosides
Fluoroquinolones
Azithromycin?
TIME
dependent killing
β-lactams
Glycopeptides
Metronidazole
Macrolides (except
Azithromycin)
Chloramphenicol
Rifampin
Tetracyclines
Clindamycin
Pharmacodynamic Relationships between Antibiotic
Concentration and Antibacterial Effect
CIDAL
activity
STATIC
activity
Plasma
Conc
PAE
Bacterial
REGROWTH
Site
Conc
MBC
MIC
Time
Pharmacodynamic Relationships between Antibiotic
Concentration and Antibacterial Effect
Cmax
Plasma
Conc
AUC
AUC > MIC
MIC
PAE
T > MIC
Time
Pharmacokinetics
Susceptibility
MIC / MBC
Serum / Tissue Concentrations
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Pharmacodynamics
Time > MIC
Peak / MIC
AUC > MIC
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Eradication / Cure
Antibiotic Pharmacodynamics in
Otitis Media: T>MIC
Average percentage of time drug concentration exceeds the minimum inhibitory concentration
(%T>MIC) for pediatric dosages of oral ß-lactam agents against penicillin-sensitive (black bars) and
penicillin-intermediate (hatched bars) Streptococcus pneumoniae. Rodvold. Pharmacoatherapy.
2001; 21(11s) :319s-330s.
Antibiotic Pharmacodynamics:
Ciprofloxacin AUC0-24:MIC and Clinical Outcomes
Percentage of bacteriologic (black bars) and clinical (hatched bars) cures as a function of
AUC0-24:MIC in 68 patients with gram-negative infections treated with ciprofloxacin. Note
that the bacteriologic and clinical outcomes are better with AUC > 125.
Clinical Breakpoints
Clinical breakpoints are supposed to indicate at which MIC
the chance of eradication or even clinical success of
antimicrobial treatment prevails significantly over failure,
given the dosing schedule of the drug. The breakpoint thus
is not only dependent on the antimicrobial activity of the
drugs itself, but also on its pharmacokinetics and
pharmacodynamics.
Postantibiotic effect
 The
period of time where there is
persistent suppression of bacterial
growth following exposure to an
antimicrobial agent, despite removal of
the antimicrobial agent.
Antibiotic Pharmacodynamics
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MIC = minimum
inhibitory
concentration
MBC = minimum
bactericidal
concentration
Antibiotic 1
Antibiotic 2
From: Levinson ME. Infect Dis Clin North Amer. 1995; 483-95.
Antibiotic Combinations:
Rationale and Indications
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Additive Effects
Synergistic Effects
Antagonistic Effects
Antibiotic Synergy
and Antagonism
Antibiotic Combinations:
Rationale and Indications
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Prevent emergence of
resistance
Polymicrobial infections
Empiric therapy
Reduced drug toxicity
Synergism
Antibiotic Combinations:
Disadvantages of Inappropriate
Combination Therapy
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Antagonism
Increased drug costs
Adverse drug reactions