CHEMOTHERAPY Antimicrobial chemotherapy Antiviral chemotherapy Antiparasitic Drugs Cancer...

CHEMOTHERAPYCHEMOTHERAPY

Antimicrobial chemotherapyAntimicrobial chemotherapy

Antiviral chemotherapyAntiviral chemotherapy

Antiparasitic DrugsAntiparasitic Drugs

Cancer ChemotherapyCancer Chemotherapy

CHEMOTHERAPYCHEMOTHERAPY

Concepts easy to understand.Concepts easy to understand.

Many distinct diseases so less Many distinct diseases so less prototype drugs.prototype drugs.

ANTIBIOTICSANTIBIOTICS

General PrinciplesGeneral Principles

Mechanism of Action Mechanism of Action

Pharmacokinetics/Therapeutic UsesPharmacokinetics/Therapeutic Uses

Adverse effectsAdverse effects

STUDY AIDSSTUDY AIDS

ObjectivesObjectives

Summary tablesSummary tables

STUDY AIDSSTUDY AIDS

Review questions on web: Review questions on web: http://info.unmc.edu/scholarchemo1/http://info.unmc.edu/scholarchemo1/AntiBio/AntibioTestframe.htmAntiBio/AntibioTestframe.htm

STUDY AIDSSTUDY AIDS

http://dev1.unmc.edu/JeopardyGame/Antibiotics.htm

http://dev1.unmc.edu/JeopardyGame/AntibioticsDouble.htm

ANTIMICROBIAL ANTIMICROBIAL CHEMOTHERAPYCHEMOTHERAPY

Selective ToxicitySelective Toxicity

CHEMOTHERAPYCHEMOTHERAPY

Allows the normal host-Allows the normal host-defense mechanisms to defense mechanisms to gain control.gain control.

CLASSIFICATION OF CLASSIFICATION OF CHEMOTHERAPEUTIC CHEMOTHERAPEUTIC AGENTSAGENTS

TimeTime

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ControlControl

Bacteriostatic agentBacteriostatic agent

Bactericidal agentBactericidal agent

BACTERIOSTATIC DRUGSBACTERIOSTATIC DRUGS

SulfonamidesSulfonamides

ErythromycinErythromycin

TetracyclinesTetracyclines

BACTERICIDAL DRUGSBACTERICIDAL DRUGS

Trimethoprim +SulfamethoxazoleTrimethoprim +Sulfamethoxazole

AminoglycosidesAminoglycosides

ββ-lactams-lactams

TT

AntimetabolitesCell Wall Synthesis

Inhibit Protein SynthesisNucleic acid synthesis

XXXXXXXX

Cell membrane Permeability

CHOICE OF THE CHOICE OF THE ANTIBIOTICANTIBIOTIC

First determine etiology of the First determine etiology of the infection.infection.

CHOICE OF THE CHOICE OF THE ANTIBIOTICANTIBIOTIC

Sensitivity pattern of the infecting Sensitivity pattern of the infecting organism must be determined.organism must be determined.

Consider pharmacokinetics and host Consider pharmacokinetics and host factors.factors.

PHARMACOKINETIC PHARMACOKINETIC FACTORSFACTORS

Location of Infection.Location of Infection.

Route of Administration.Route of Administration.

Pattern of excretion, metabolism, and Pattern of excretion, metabolism, and degree of protein binding.degree of protein binding.

HOST FACTORSHOST FACTORS

Host defense (Immunocompetence).Host defense (Immunocompetence).

Local factors.Local factors.

Age. Age.

Genetic factors.Genetic factors.

Drug Allergy.Drug Allergy.

HOST FACTORSHOST FACTORS

Renal disease and liver disease.Renal disease and liver disease.

AIDSAIDS

Pregnancy.Pregnancy.

USES OF ANTIBIOTICSUSES OF ANTIBIOTICS

Empirical antimicrobial therapy- Empirical antimicrobial therapy- before the pathogen is known.before the pathogen is known.

Infections with known etiology.Infections with known etiology.

MISUSES OF ANTIBIOTICSMISUSES OF ANTIBIOTICS

Treatment of nonresponsive Treatment of nonresponsive infections.infections.

Therapy of fever of unknown originTherapy of fever of unknown origin

Fever of short durationFever of short durationFever persisting for 2 or more weeks.Fever persisting for 2 or more weeks.

MISUSES OF ANTIBIOTICSMISUSES OF ANTIBIOTICS

Dosing errorsDosing errorsWrong frequencyWrong frequencyExcessive or subtherapeutic dosesExcessive or subtherapeutic doses

MISUSES OF ANTIBIOTICSMISUSES OF ANTIBIOTICS

Inappropriate reliance on Inappropriate reliance on chemotherapy alone (e.g. chemotherapy alone (e.g. abscesses).abscesses).

MISUSES OF ANTIBIOTICSMISUSES OF ANTIBIOTICS

Lack of adequate bacteriological Lack of adequate bacteriological information.information.

• Absence of supporting dataAbsence of supporting data

• Agents selected by habitAgents selected by habit

• Doses are routine, rather than individualizedDoses are routine, rather than individualized

COMBINATION COMBINATION CHEMOTHERAPYCHEMOTHERAPY

Separate but simultaneous Separate but simultaneous administration.administration.

Combination Chemotherapy- Combination Chemotherapy- AdvantagesAdvantages

Treatment of polymicrobial Treatment of polymicrobial infections.infections.

Prevent or delay resistance.Prevent or delay resistance.

Synergy.Synergy.

Combination Chemotherapy- Combination Chemotherapy- AdvantagesAdvantages

Severe infections of unknown Severe infections of unknown etiology-empirical therapy.etiology-empirical therapy.

DISADVANTAGESDISADVANTAGES

Increased risk of toxicity.Increased risk of toxicity.

Increased likelihood of Increased likelihood of superinfections.superinfections.

Increased cost.Increased cost.

Antagonism of an antibacterial effect.Antagonism of an antibacterial effect.

FIXED DOSE FIXED DOSE COMBINATIONSCOMBINATIONS

Ratio and dose of antibiotics are Ratio and dose of antibiotics are determined based on determined based on in vitroin vitro studies. studies.

Encourages inadequate treatment.Encourages inadequate treatment.

PROPHYLAXIS OF INFECTIONPROPHYLAXIS OF INFECTION

This should be used only in This should be used only in circumstances in which efficacy has circumstances in which efficacy has been demonstrated and the benefits been demonstrated and the benefits outweigh the risks.outweigh the risks.

PROPHYLAXIS OF PROPHYLAXIS OF INFECTIONINFECTION

Effective when a single drug is used Effective when a single drug is used to prevent infection from a specific to prevent infection from a specific microorganism. microorganism.

In patients undergoing organ In patients undergoing organ transplantation or receiving cancer transplantation or receiving cancer chemotherapy.chemotherapy.

PROPHYLAXIS OF INFECTIONPROPHYLAXIS OF INFECTION

Primary and 2ndary prevention of Primary and 2ndary prevention of opportunistic infections in AIDS opportunistic infections in AIDS patients when CD4 counts are below patients when CD4 counts are below certain threshholds.certain threshholds.

PROPHYLAXIS OF INFECTIONPROPHYLAXIS OF INFECTION

To prevent wound infections after To prevent wound infections after various surgical procedures.various surgical procedures.

Complications of Antimicrobial Complications of Antimicrobial TherapyTherapy

Drug ResistanceDrug Resistance

SuperinfectionsSuperinfections

ToxicityToxicity

DRUG RESISTANCEDRUG RESISTANCE

Involves a stable genetic change in Involves a stable genetic change in the bacteria.the bacteria.

DRUG RESISTANCEDRUG RESISTANCE

Mutation and selection with passage Mutation and selection with passage vertically.vertically.

Horizontal transfer from a donor cell Horizontal transfer from a donor cell by transduction, transformation or by transduction, transformation or conjugation. conjugation.

MUTATION-SELECTIONMUTATION-SELECTION

Occurs in many different genes.Occurs in many different genes.

Random events that confer a survival Random events that confer a survival advantage when a drug is present.advantage when a drug is present.

CHROMOSOMAL MUTATIONSCHROMOSOMAL MUTATIONS

Antibiotics are acting as selecting Antibiotics are acting as selecting agents.agents.

+ Antibiotic+ Antibiotic

Resistant PopulationResistant Population

HORIZONTAL GENE HORIZONTAL GENE TRANSFERTRANSFER

Mobile genetic elements (plasmids, Mobile genetic elements (plasmids, transposable elements, integrons, transposable elements, integrons, gene cassettes).gene cassettes).

TransductionTransduction

TransformationTransformation

CONJUGATIONCONJUGATION

Direct cell to cell contact through a sex Direct cell to cell contact through a sex pilus or bridgepilus or bridge

Very important for the spread of Very important for the spread of resistance because multiple resistance resistance because multiple resistance genes can be transferred genes can be transferred simultaneously.simultaneously.

Enzyme Inactivation

Altered Permeability

Mod. of target siteand reduced affinity

CROSS-RESISTANCECROSS-RESISTANCE

e.g. sulfonamides, penicillinse.g. sulfonamides, penicillins

PREVENTION OR DELAY OF PREVENTION OR DELAY OF RESISTANCERESISTANCE

Judicious (appropriate) or careful Judicious (appropriate) or careful use of antibioticsuse of antibiotics

Adequate DosageAdequate Dosage

Combination ChemotherapyCombination Chemotherapy

SUPERINFECTIONSSUPERINFECTIONS

A new infection appearing during the A new infection appearing during the chemotherapy of a primary one.chemotherapy of a primary one.

Caused by removing inhibitory Caused by removing inhibitory influence of the normal flora.influence of the normal flora.

+ Antibiotic + Antibiotic (Broad spectrum)(Broad spectrum)

Resistant pathogenResistant pathogen

Secondary infection from Secondary infection from resistant organismsresistant organisms

TREATMENT OF THE TREATMENT OF THE SUPERINFECTIONSUPERINFECTION

Stop present therapy.Stop present therapy.

Culture infected area.Culture infected area.

Treat against the offending Treat against the offending microorganism.microorganism.

TOXICITYTOXICITY

HypersensitivityHypersensitivity

Direct Toxicity- GIDirect Toxicity- GI

BACTERICIDAL AGENTSBACTERICIDAL AGENTS

Drugs whose killing action is time Drugs whose killing action is time dependent don’t show increased dependent don’t show increased killing above MBC; bactericidal killing above MBC; bactericidal activity continues as long as the activity continues as long as the serum concns. exceed MBC.serum concns. exceed MBC.

GramGram++

GramGram__

GramGram++

GramGram

__

RickettsiaRickettsia

AmoebaAmoeba

Drug Concentration on Drug Concentration on microbial killingmicrobial killing

AUC:MIC (area under the serum AUC:MIC (area under the serum concentration time curve: minimal concentration time curve: minimal inhibitory concentration).inhibitory concentration).

Peak serum concentration:MICPeak serum concentration:MIC

Appropriate Dose of Appropriate Dose of Antimicrobial AgentAntimicrobial Agent

Principles of pharmacokinetics and Principles of pharmacokinetics and pharmacodynamics are used to pharmacodynamics are used to determine this.determine this.

Appropriate Dose of Antimicrobial Appropriate Dose of Antimicrobial AgentAgent

Pharmacodynamic factors include Pharmacodynamic factors include cidal vs static activity and cidal vs static activity and postantibiotic effects.postantibiotic effects.

CIDAL VS STATIC CIDAL VS STATIC

For primarily static agents inhibitory For primarily static agents inhibitory drug concn’s are much lower than drug concn’s are much lower than cidal concn’s.cidal concn’s.

Usually cell wall active drugs are Usually cell wall active drugs are cidal and protein synthesis inhibitors cidal and protein synthesis inhibitors are static.are static.

CIDAL VS STATICCIDAL VS STATIC

Some agents that are considered to Some agents that are considered to be static may be cidal vs selected be static may be cidal vs selected organisms.organisms.

CIDAL VS STATICCIDAL VS STATIC

Static and cidal agents are equivalent Static and cidal agents are equivalent for immunocompetent hosts.for immunocompetent hosts.

Cidal agents should be used when Cidal agents should be used when host defenses are impaired.host defenses are impaired.

CIDAL VS STATICCIDAL VS STATIC

Bactericidal agents can be divided Bactericidal agents can be divided into 2 groups (1) concentration into 2 groups (1) concentration dependent e.g. aminoglycosides and dependent e.g. aminoglycosides and quinolones and (2)time dependent quinolones and (2)time dependent killing e.g. beta lactams and killing e.g. beta lactams and vancomycin.vancomycin.

POSTANTIBIOTIC EFFECTPOSTANTIBIOTIC EFFECT

Persistent suppression of bacterial Persistent suppression of bacterial regrowth after brief exposure.regrowth after brief exposure.

Mechanism is likely multifactorial Mechanism is likely multifactorial and may vary with the specific and may vary with the specific antimicrobial drug and organism antimicrobial drug and organism combination.combination.

HoursHours

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Postantibiotic effectPostantibiotic effect

Drug addedDrug added Drug removedDrug removed

00 8844

POSTANTIBIOTIC EFFECTPOSTANTIBIOTIC EFFECT

With aminoglycosides it has allowed With aminoglycosides it has allowed once daily dosing and less once daily dosing and less monitoring.monitoring.