Paul C. Walker, Pharm.D. Paul C. Walker, Pharm.D. Manager, Clinical Pharmacy Services Manager, Clinical Pharmacy Services Detroit Medical Center Detroit Medical Center and and Clinical Assistant Professor Clinical Assistant Professor College of Pharmacy and School of Nursing College of Pharmacy and School of Nursing University of Michigan University of Michigan Antimicrobial Antimicrobial Pharmacotherapy in Pharmacotherapy in Children Children
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Paul C. Walker, Pharm.D. Manager, Clinical Pharmacy Services Detroit Medical Center and Clinical Assistant Professor College of Pharmacy and School of.
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Paul C. Walker, Pharm.D.Paul C. Walker, Pharm.D.Manager, Clinical Pharmacy ServicesManager, Clinical Pharmacy Services
Detroit Medical CenterDetroit Medical Centerandand
Clinical Assistant ProfessorClinical Assistant ProfessorCollege of Pharmacy and School of NursingCollege of Pharmacy and School of Nursing
University of MichiganUniversity of Michigan
Antimicrobial Antimicrobial Pharmacotherapy in Pharmacotherapy in ChildrenChildren
Inhibition of cell wall synthesisInhibition of cell wall synthesis Altering cell membrane permeabilityAltering cell membrane permeability Reversibly inhibiting protein synthesisReversibly inhibiting protein synthesis Irreversibly disrupting protein synthesisIrreversibly disrupting protein synthesis Disruption of nucleic acid metabolismDisruption of nucleic acid metabolism Blocking essential metabolic eventsBlocking essential metabolic events
Peptidoglycan is composed of chains of peptidoglycan monomers (NAG-NAM-tetrapeptide). These monomers join together to form chains and the chains are then joined by cross-links between the tetrapeptides to provide strength.
Peptidoglycan Peptidoglycan SynthesisSynthesis
• 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 Structure of Bacterial Cell Bacterial Cell WallsWalls
Comparison of the structure and composition of gram positive and gram negative bacterial cell walls
Inhibitors of Cell Wall Inhibitors of Cell Wall SynthesisSynthesis
The beta lactam ring of penicillin
How Penicillins Inhibit How Penicillins Inhibit Peptidoglycan Peptidoglycan SynthesisSynthesis 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-NAM-peptide). 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 cross-links. This results in a weak cell wall and osmotic lysis of the bacterium.
Natural PenicillinsNatural Penicillins– Penicillin GPenicillin G– Penicillin VPenicillin V
Second Second GenerationGeneration– CefaclorCefaclor– CefoxitinCefoxitin– CefuroximeCefuroxime– CefotetanCefotetan– CefpoxodimeCefpoxodime– CefprozilCefprozil– Cefonicid Cefonicid – CefmetazoleCefmetazole
Beta Lactam Beta Lactam Antibiotics: Antibiotics: The CephalosporinsThe Cephalosporins
Third Third Generation Generation – CefotaximeCefotaxime– CeftriaxoneCeftriaxone– CefoperazoneCefoperazone– Cefipime*Cefipime*– CefmenoximeCefmenoxime– Ceftizoxime – CeftazidimeCeftazidime– CefdinirCefdinir – 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.
– NeurotoxicityNeurotoxicity– Transient blood dyscrasiasTransient blood dyscrasias– Allergic or hypersensitivity reactionsAllergic or hypersensitivity reactions– CoagulopathyCoagulopathy
Side Effects and Side Effects and Adverse Reactions Adverse Reactions
VancomycinVancomycin
Indications: serious gram positive Indications: serious gram positive infections where infections where -lactams are -lactams are inappropriate (MRSA, MRSE, allergy, inappropriate (MRSA, MRSE, allergy, etc.)etc.)
Toxicities and Side EffectsToxicities and Side Effects– NephrotoxicityNephrotoxicity– OtotoxicityOtotoxicity– Red Man SyndromeRed Man Syndrome
Prokaryotes vs. Prokaryotes vs. Eukaryotes: RibosomesEukaryotes: Ribosomes
Bind to the Bind to the ribosomal subunits ribosomal subunits to impair protein to impair protein synthesissynthesis– AminoglycosidesAminoglycosides– ChloramphenicolChloramphenicol– MacrolidesMacrolides
Disrupters of Protein Disrupters of Protein SynthesisSynthesis
KanamycinKanamycin GentamicinGentamicin TobramycinTobramycin AmikacinAmikacin NetilmicinNetilmicin SisomycinSisomycin Aminoglycosides bind to the 30s subunit to
impair protein synthesis.
The The AminoglycosidesAminoglycosides
Blocks initiation of protein synthesis
Blocks translation to cause premature termination
Causes incorporation of incorrect amino acid
Structure of the antibiotic gentamicin C1a bound to its RNA target. Aminoglycoside antibiotics cause misreading of the genetic code.
Agents that Bind to the Agents that Bind to the 50S Ribosome50S Ribosome ChloramphenicolChloramphenicol
– spectrum of activityspectrum of activity S. pneumoniaS. pneumonia H. influenzaH. influenza Neisseria spp.Neisseria spp. SalmonellaSalmonella BordetellaBordetella EnterobacteriaceaeEnterobacteriaceae some anaerobessome anaerobes
Agents that Bind to Agents that Bind to the 50S Ribosomethe 50S Ribosome MacrolidesMacrolides
– ErythromycinErythromycin SS. pneumonia, S. . pneumonia, S.
pyogenes, Legionella, pyogenes, Legionella, Chlamydia Chlamydia trachomatis, M. trachomatis, M. catarrhalis, H. catarrhalis, H. influenza, influenza, Mycoplasma Mycoplasma pneumoniapneumonia
Disrupters of Nucleic Disrupters of Nucleic Acid MetabolismAcid Metabolism MetronidazoleMetronidazole
Participates in redox reactions; it is activated by a reduction of Participates in redox reactions; it is activated by a reduction of the nitro group to an anion radical. In the case of metronidazole, the nitro group to an anion radical. In the case of metronidazole, reduced ferredoxin appears to be the primary electron donor reduced ferredoxin appears to be the primary electron donor responsible for its reduction The anion radical is highly reactive responsible for its reduction The anion radical is highly reactive and will form adjuncts with proteins and DNA leading to a loss of and will form adjuncts with proteins and DNA leading to a loss of function. In particular, the reactions with DNA result in strand function. In particular, the reactions with DNA result in strand breakage and inhibition of replication and will lead to cell death.breakage and inhibition of replication and will lead to cell death.
Disrupters of Nucleic Disrupters of Nucleic Acid MetabolismAcid Metabolism Quinolones: inhibit Quinolones: inhibit
DNA-gyrase and DNA-gyrase and topoisomerase IItopoisomerase II– CiprofloxacinCiprofloxacin– LevfloxacinLevfloxacin– Moxifloxacin Moxifloxacin – NorfloxacinNorfloxacin– OfloxacinOfloxacin– TrovafloxacinTrovafloxacin– GatifloxacinGatifloxacin– GrepafloxacinGrepafloxacin
Target site modificationTarget site modification((intracellular or extracellular; intracellular or extracellular; -lactams, macrolides, -lactams, macrolides, quinolones, glycopeptides)quinolones, glycopeptides)
Enzymatic Enzymatic degradationdegradation(intracellular or (intracellular or extracellular; extracellular; -lactams, -lactams, aminoglycosidesaminoglycosides))
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Enzyme Inactivation of Enzyme Inactivation of PenicillinsPenicillins
Structure of penicillins and interaction with beta lactamase
1
2
1 = Site of action of penicillinase2 = Site of action of amidaseA = Thiazolidine ringB = -lactam ring
Resistance to Penicillin Resistance to Penicillin in in N. gonorrheaN. gonorrhea
Beta lactamase
Gram Negative Gram Negative OrganismsOrganisms– H. InfluenzaH. Influenza– M. CatarrhalisM. Catarrhalis– EnterobacterEnterobacter– KlebsiellaKlebsiella– CitrobacterCitrobacter– SerratiaSerratia
– StreptococcusStreptococcus S. pneumoniaeS. pneumoniae
Vancomycin Vancomycin – EnterococciEnterococci
E. faecalisE. faecalis E. faeciumE. faecium
– S. aureusS. aureus
Bacterial Resistance: Bacterial Resistance: What Problems are We What Problems are We Seeing?Seeing?
Antimicrobial PharmacodynamicsAntimicrobial Pharmacodynamics– attempt to characterize the attempt to characterize the
relationship between relationship between ANTIMICROBIAL ANTIMICROBIAL EXPOSUREEXPOSURE (concentration, dose, AUC) (concentration, dose, AUC) and and ANTIMICROBIAL EFFECTANTIMICROBIAL EFFECT (eg., rate, (eg., rate, extent, and duration of antimicrobial extent, and duration of antimicrobial activity)activity)
Other Important Factors: Other Important Factors:
MICs and MBCs Fail to Tell the Whole MICs and MBCs Fail to Tell the Whole StoryStory
Antibiotic PharmacodynamicsAntibiotic Pharmacodynamics– Rate and Extent of Bactericidal Rate and Extent of Bactericidal
ActionAction– Post-antibiotic EffectPost-antibiotic Effect– Effects of Sub-inhibitory Effects of Sub-inhibitory
MICs and MBCs Fail to Tell the Whole MICs and MBCs Fail to Tell the Whole StoryStory
– Concentration-Dependent AgentsConcentration-Dependent Agents Bactericidal activity is dependent on concentration above Bactericidal activity is dependent on concentration above
the MIC achieved, increasing with increasing concentrationthe MIC achieved, increasing with increasing concentration
– Time-Dependent AgentsTime-Dependent Agents Bactericidal activity is dependent on how long the Bactericidal activity is dependent on how long the
concentration exceeds the MICconcentration exceeds the MIC
– Bacteriostatic AgentsBacteriostatic Agents Abort bacterial growth and allow host defenses to Abort bacterial growth and allow host defenses to
eradicate organismseradicate organisms
Classification Based on Classification Based on Pharmacodynamic Pharmacodynamic CharacteristicsCharacteristics
Concentration-Dependent Killing of Pseudomonas aeruginosa with
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: Antibiotic Pharmacodynamics: Ciprofloxacin AUCCiprofloxacin AUC0-240-24:MIC and Clinical :MIC and Clinical
Outcomes 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 BreakpointsClinical 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 effectPostantibiotic effect
The period of time where there is The period of time where there is persistent suppression of bacterial persistent suppression of bacterial growthgrowth following exposure to an following exposure to an antimicrobial agent, despite antimicrobial agent, despite removal of the antimicrobial removal of the antimicrobial agent.agent.