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

Classifying Classifying Antimicrobial AgentsAntimicrobial Agents

Peptidoglycan Peptidoglycan SynthesisSynthesis

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

Peptidoglycan Cross-links

Beta Lactam Beta Lactam AntibioticsAntibiotics– PenicillinsPenicillins– CephalosporinsCephalosporins– CarbapenemsCarbapenems– MonobactamsMonobactams

VancomycinVancomycin

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

AminopenicillinsAminopenicillins– AmpicillinAmpicillin– AmoxicillinAmoxicillin

CarboxypenicillinsCarboxypenicillins– TicarcillinTicarcillin– CarbenicillinCarbenicillin

Penicillinase-Penicillinase-Resistant PenicillinsResistant Penicillins– CloxacillinCloxacillin– DicloxacillinDicloxacillin– MethicillinMethicillin– NafcillinNafcillin– OxacillinOxacillin

UreidopenicillinsUreidopenicillins– MezlocillinMezlocillin– PiperacillinPiperacillin

Beta Lactam Beta Lactam Antibiotics: Antibiotics: The PenicillinsThe Penicillins

First First GenerationGeneration– CephalothiCephalothi

nn– CefazolinCefazolin– CephalexinCephalexin– CephapirinCephapirin– CefadroxilCefadroxil– CephradinCephradin

ee

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.

CarbapenemsCarbapenems– Imipenem/CilastatinImipenem/Cilastatin– MeropenemMeropenem– ErtapenemErtapenem

MonobactamsMonobactams– AztreonamAztreonam

Beta Lactam Antibiotics: Beta Lactam Antibiotics: The Carbapenems and The Carbapenems and MonobactamsMonobactams

Beta lactam AntibioticsBeta lactam Antibiotics– Hepatic dysfunctionHepatic dysfunction– Acute interstitial nephritisAcute interstitial nephritis

azotemia, hematuria, proteinuria, fever, azotemia, hematuria, proteinuria, fever, rash, eosinophiliarash, eosinophilia

– 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

ErythromycinErythromycin ClarithromycinClarithromycin Azithromycin Azithromycin

– ClindamycinClindamycin

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

– ClarithromycinClarithromycin MACMAC

– AzithromycinAzithromycin MACMAC

ClindamycinClindamycin– aerobic gram-aerobic gram-

positive bacteria positive bacteria – anaerobes, especially anaerobes, especially

B. fragilis B. fragilis – used in combination used in combination

with aminoglycosides with aminoglycosides to treat intra-to treat intra-abdominal and abdominal and gynecologic gynecologic infections infections

ChloramphenicolChloramphenicol– Gray syndromeGray syndrome– Dose-dependent Dose-dependent

bone marrow bone marrow suppressionsuppression

– Aplastic anemia, Aplastic anemia, pancytopeniapancytopenia

MacrolidesMacrolides– GI complaintsGI complaints– RashRash

ClindamycinClindamycin– DiarrheaDiarrhea– Pseudomembranous Pseudomembranous

colitiscolitis– Rash, urticariaRash, urticaria– Hypotension Hypotension

Side Effects and Side Effects and Adverse Reactions Adverse Reactions

Disrupters of Nucleic Disrupters of Nucleic Acid MetabolismAcid Metabolism MetronidazoleMetronidazole Quinolones: Quinolones:

– CiprofloxacinCiprofloxacin– LevfloxacinLevfloxacin– Moxifloxacin Moxifloxacin – NorfloxacinNorfloxacin– OfloxacinOfloxacin– TrovafloxacinTrovafloxacin– GatifloxacinGatifloxacin– GrepafloxacinGrepafloxacin

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

MetronidazoleMetronidazole– dizzinessdizziness– paresthesiasparesthesias– peripheral peripheral

neuropathyneuropathy– disulfiram-like disulfiram-like

reactionreaction– blood dyscrasiasblood dyscrasias

QuinolonesQuinolones– headacheheadache– rash, photosensitivityrash, photosensitivity– GI complaintsGI complaints– arthralgiasarthralgias– confusionconfusion– liver dysfunctionliver dysfunction

Side Effects and Side Effects and Adverse Reactions Adverse Reactions

AntimetabolitesAntimetabolites

TrimethoprimTrimethoprim SulfonamidesSulfonamides

– SulfamethoxazSulfamethoxazoleole

– SulfisoxazoleSulfisoxazole

Inhibition of folate metabolism by sulfonamides and trimethoprim

SulfonamidesSulfonamides– Dizziness, headacheDizziness, headache– RashRash– Blood dyscrasiasBlood dyscrasias– CrystalluriaCrystalluria– Acute nephropathyAcute nephropathy– Bilirubin displacementBilirubin displacement

Side Effects and Side Effects and Adverse Reactions Adverse Reactions

Identity of infecting Identity of infecting organismorganism

Susceptibility of infecting Susceptibility of infecting organismorganism

Host FactorsHost Factors

Proper Antimicrobial Proper Antimicrobial Selection: FSelection: Factors to actors to

ConsiderConsider

Major Mechanisms Major Mechanisms of Antimicrobial of Antimicrobial ResistanceResistance

BypassBypass(TMP/SMX)(TMP/SMX)

EffluxEfflux(macrolides, (macrolides, quinolones)quinolones)

DecreasedDecreased permeabilitypermeability

((-lactams)-lactams)

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))

XX

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

Gram PositiveGram Positive– Staphylococcus Staphylococcus

S. aureusS. aureus S. epidermidisS. epidermidis

– 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

ConcentrationsConcentrations– Post-antibiotic Leukocyte EffectPost-antibiotic Leukocyte Effect– Inoculum EffectInoculum Effect

Other Important Factors: Other Important Factors:

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

Tobramycin

1 /

log

CF

U p

er m

L

1

2

3

4

5

6

7

8

0

Time (hours)

1 2 3 4 5 6

control

1/4 MIC

1 MIC

4 MIC

16 MIC

64 MIC

Antibiotic conc

NON-Concentration-Dependent Killing

9

1 /

log

CF

U p

er m

L

1

2

3

4

5

6

7

8

0

Time (hours)

1 2 3 4 5 6

control

1/4 MIC

1 MIC

4 MIC

16 MIC

64 MIC

Antibiotic conc

Pharmacodynamic Properties by Antibiotic

Class

CONCENTRATION dependent killing

TIME dependent killing

Aminoglycosides β-lactamsFluoroquinolones GlycopeptidesAzithromycin? Metronidazole

Macrolides (except Azithromycin) Chloramphenicol Rifampin Tetracyclines Clindamycin

Pharmacodynamic Relationships between Antibiotic Concentration and Antibacterial Effect

Time

Plasma Conc

MBC

MIC

CIDAL activity PAE

Bacterial REGROWTH

STATIC activity

Site Conc

Pharmacodynamic Relationships between Antibiotic

Concentration and Antibacterial Effect

Time

Plasma Conc

T > MIC PAE

AUC > MICAUC > MIC

MICMIC

Cmax

AUC

Pharmacokinetics

Susceptibility

MIC / MBC Serum / Tissue Concentrations

Pharmacodynamics

Time > MIC

Peak / MIC

AUC > MIC

Eradication / Cure

Antibiotic Pharmacodynamics Antibiotic Pharmacodynamics in Otitis Media: T>MICin 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: 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.

Antibiotic Antibiotic PharmacodynamicsPharmacodynamics

MIC = minimum inhibitory concentration

MBC = minimum bactericidal concentration

From: Levinson ME. Infect Dis Clin North Amer. 1995; 483-95.

Antibiotic 1

Antibiotic 2

Additive EffectsAdditive Effects Synergistic EffectsSynergistic Effects Antagonistic EffectsAntagonistic Effects

Antibiotic Antibiotic Combinations:Combinations:Rationale and IndicationsRationale and Indications

Antibiotic Synergy Antibiotic Synergy and Antagonismand Antagonism

Prevent emergence of Prevent emergence of resistanceresistance

Polymicrobial infectionsPolymicrobial infections Empiric therapyEmpiric therapy Reduced drug toxicityReduced drug toxicity SynergismSynergism

Antibiotic Antibiotic Combinations:Combinations:Rationale and IndicationsRationale and Indications

AntagonismAntagonism Increased drug costsIncreased drug costs Adverse drug Adverse drug

reactionsreactions

Antibiotic Combinations:Antibiotic Combinations: Disadvantages of Inappropriate Disadvantages of Inappropriate Combination TherapyCombination Therapy