clinical pharmacology ninth lecture (infectious diseases) (dr.noha nagah) (27!11!10)

8/2/2019 Clinical Pharmacology Ninth Lecture (Infectious Diseases) (Dr.noha Nagah) (27!11!10)

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Usually when the nature of theUsually when the nature of the

microorganism is unknown and a lifemicroorganism is unknown and a life-- threatening condition exists, anthreatening condition exists, anempiricempiric antimicrobial regimen isantimicrobial regimen isbegun before the offending organismbegun before the offending organismis identified and sometimes prior to theis identified and sometimes prior to the

documentation of the presence ofdocumentation of the presence of

infectioninfection

AA definitivedefinitive regimen is institutedregimen is institutedwhen the causative organism iswhen the causative organism isknown.known.


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CONFIRMING THE PRESENCECONFIRMING THE PRESENCE

OF INFECTIONOF INFECTION

FEVERFEVER

Elevation of body temperature above the normal range of 36.7 toElevation of body temperature above the normal range of 36.7 to

37.037.0C (98.1 to 98.6C (98.1 to 98.6F)F)

Pyrogens are substances that cause feverPyrogens are substances that cause fever

Induction of fever following infection is initiated by interleukInduction of fever following infection is initiated by interleukins byins by

acting on thermoregulatory neurons to elevate the internalacting on thermoregulatory neurons to elevate the internal

thermostatthermostat

Many drugs have been identified as causes of fever.Many drugs have been identified as causes of fever.

Hypersensitivity reactionHypersensitivity reaction

DrugDrug--induced fever is defined as persistent fever in the absence ofinduced fever is defined as persistent fever in the absence ofinfection or other underlying condition.infection or other underlying condition.

The fever must coincide temporally with the administration of thThe fever must coincide temporally with the administration of thee

offending agent and disappear promptly upon its withdrawal, afteoffending agent and disappear promptly upon its withdrawal, afterr

which the temperature remains normal.which the temperature remains normal.


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CONFIRMING THECONFIRMING THE

PRESENCE OF INFECTIONPRESENCE OF INFECTION

FeverFever False positivesFalse positives False negativesFalse negatives

Absence of fever in a patient with signs andAbsence of fever in a patient with signs and

symptomssymptoms

AntipyreticAntipyretic

Obtain careful historyObtain careful history

Partial effective therapyPartial effective therapy

BacteriostaticBacteriostatic


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CONFIRMING THE PRESENCE OFCONFIRMING THE PRESENCE OF

INFECTIONINFECTION

White Blood Cell CountWhite Blood Cell Count

Most infections result in elevated white blood cellMost infections result in elevated white blood cell(WBC) counts (leukocytosis) because of the(WBC) counts (leukocytosis) because of themobilization of granulocytes and/or lymphocytes tomobilization of granulocytes and/or lymphocytes to

destroy invading microbes.destroy invading microbes.

Bacterial infections are associated with elevatedBacterial infections are associated with elevated

granulocyte counts (neutrophils,basophils)granulocyte counts (neutrophils,basophils)

Lymphocytosis increases with viral infectionsLymphocytosis increases with viral infections

Many types of infections, however, may beMany types of infections, however, may be

accompanied by a completely normal WBC count andaccompanied by a completely normal WBC count and

differential.differential.


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CONFIRMING THECONFIRMING THE

PRESENCE OF INFECTIONPRESENCE OF INFECTION

Pain and InflammationPain and Inflammation Swelling, erythema, tenderness, andSwelling, erythema, tenderness, andpurulent drainagepurulent drainage Elevation of ESRElevation of ESRNegative result does not rule outNegative result does not rule out

infectioninfection

CC--reactive proteinreactive protein CytokinesCytokines


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Conf irm ing the presenceConf irm ing the presence

of an infect ionof an infect ion

Colonization versus infectionColonization versus infection ColonizationColonization

Presence of an organism without production of a disease in aPresence of an organism without production of a disease in ahosthost

Many body tissues are colonized with normal floraMany body tissues are colonized with normal flora

These bacteria are considered normal flora in their site,These bacteria are considered normal flora in their site,however, when introduced to other areas , they may becomehowever, when introduced to other areas , they may becomeinfectious when introduced to other body sites; e.g strepinfectious when introduced to other body sites; e.g strepepidermis is a skin flora, however, it is a pathogen in the CSFepidermis is a skin flora, however, it is a pathogen in the CSF

InfectionInfection

Presence of an organism within the tissue with invasivenessPresence of an organism within the tissue with invasivenessthat often results in a responsethat often results in a response


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VERIFICATION OF INFECTIONVERIFICATION OF INFECTION

Direct examinationDirect examination

Gram stainGram stain

Infected body materials must be sampled, if at all possibleInfected body materials must be sampled, if at all possibleor practical, before the institution of antimicrobial therapy,or practical, before the institution of antimicrobial therapy,for two reasonsfor two reasons..

FirstFirst , a Gram stain of the material may reveal bacteria, or, a Gram stain of the material may reveal bacteria, oran acidan acid--fast stain may detect mycobacteria orfast stain may detect mycobacteria oractinomycetes.actinomycetes.

SecondSecond , a delay in obtaining infected fluids or tissues until, a delay in obtaining infected fluids or tissues until

after therapy is started may result in false negative cultureafter therapy is started may result in false negative cultureresults or alterations in the cellular and chemicalresults or alterations in the cellular and chemicalcomposition of infected fluids.composition of infected fluids.

Abscesses and cellulitic areas should also be aspirated.Abscesses and cellulitic areas should also be aspirated.


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VERIFICATION OFVERIFICATION OF

INFECTIONINFECTION

CulturesCultures

MediaMedia

BactecBactec,, 1414 C labeled carbohydrates andC labeled carbohydrates andamino acidsamino acids

Early growth determined by radiolabelledEarly growth determined by radiolabelled

CO2CO2

InoculateInoculate

Aseptically collected sampleAseptically collected sample

AntigenAntigenantibody detectionantibody detection RapidRapid

SensitiveSensitive

SpecificSpecific


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CHOICE OF THE PROPERCHOICE OF THE PROPER

ANTIMICROBIALANTIMICROBIAL

HOST FACTORSHOST FACTORS

Local susceptibility dataLocal susceptibility data

External data may be misleadingExternal data may be misleading

Allergy or history of adverse drug reactionsAllergy or history of adverse drug reactions

Age of patientAge of patient

Identifying the etiology of pathogenIdentifying the etiology of pathogen

MeningitisMeningitis

DetoxificationDetoxification

NeonatesNeonates

MetabolismMetabolism

Drug selectionDrug selection

Dru dosinDrug dosing


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ANTIMICROBIALANTIMICROBIALAgeAge

Kernicterus in neonates when given sulphonamidesKernicterus in neonates when given sulphonamides

Replacement of bilirubin from plasma binding proteinsReplacement of bilirubin from plasma binding proteins

Grey baby when given chloramphenicolGrey baby when given chloramphenicol

PregnancyPregnancy

TeratogenicityTeratogenicity

Kinetics of drug absorptionKinetics of drug absorption

Metabolic abnormalitiesMetabolic abnormalities

G6PDH deficiencyG6PDH deficiency Sulphonamides, nitrofurantoin, nalidixic acid, dapsoneSulphonamides, nitrofurantoin, nalidixic acid, dapsone------etcetc

Slow acetylaors and INH (peripheral neuropathy, vit b supplementSlow acetylaors and INH (peripheral neuropathy, vit b supplement))

Hepatic and renal problemsHepatic and renal problems

Concomitant drug therapyConcomitant drug therapy

INH and phenytoin results in phenytoin toxicityINH and phenytoin results in phenytoin toxicity

Concomitant disease states.Concomitant disease states.

Diabetes and soft tissue infectionDiabetes and soft tissue infection

Immunosupressed patientsImmunosupressed patients



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DRUG FACTORSDRUG FACTORS

Importance of tissue penetration varies with the site ofImportance of tissue penetration varies with the site of

infection. The CNS is one body site where the importanceinfection. The CNS is one body site where the importanceof antimicrobial penetration is relatively well defined andof antimicrobial penetration is relatively well defined and

correlations with clinical outcomes are establishedcorrelations with clinical outcomes are established

Drugs that do not reach significant concentrations inDrugs that do not reach significant concentrations incerebrospinal fluid should either be avoided or instilledcerebrospinal fluid should either be avoided or instilleddirectly when treating meningitis.directly when treating meningitis.

Pharmacokinetic parameters such as area under thePharmacokinetic parameters such as area under theconcentrationconcentration--time curve (AUC) and maximal plasmatime curve (AUC) and maximal plasmaconcentration can be predictive of treatment outcome whenconcentration can be predictive of treatment outcome when

specific ratios of AUC or maximal plasma concentration tospecific ratios of AUC or maximal plasma concentration to

the minimum inhibitory concentration (MIC) are achievedthe minimum inhibitory concentration (MIC) are achieved


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Drug ToxicityDrug Toxicity

CostCost Dramatic increaseDramatic increase

BiotechnologyBiotechnology

Total economic impact of antimicrobial therapyTotal economic impact of antimicrobial therapy Drug acquisition costDrug acquisition cost

Storage/inventory costStorage/inventory cost

PreparationPreparation

DistributionDistributionAdministrationAdministration

MonitoringMonitoring

Adverse effectsAdverse effects

Impact on length of stayImpact on length of stay Cost of control systemsCost of control systems

Cost benefit ratiosCost benefit ratios


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COMBINATIONCOMBINATION

ANTIMICROBIAL THERAPYANTIMICROBIAL THERAPY

Combinations of antimicrobials are generally used to broadenCombinations of antimicrobials are generally used to broaden

the spectrum of coverage forthe spectrum of coverage for

empiric therapyempiric therapy

achieve synergistic activity against the infecting organism,achieve synergistic activity against the infecting organism,

prevent the emergence of resistanceprevent the emergence of resistance

Increasing the coverage of antimicrobial therapy is generallyIncreasing the coverage of antimicrobial therapy is generally

necessary in mixed infections where multiple organisms arenecessary in mixed infections where multiple organisms are

likely to be present, such as intraabdominal and female pelviclikely to be present, such as intraabdominal and female pelvic

infections in which a variety of aerobic (aminglycosides)andinfections in which a variety of aerobic (aminglycosides)and

anaerobic bacteria (metronidazole) may produce disease.anaerobic bacteria (metronidazole) may produce disease.

Another clinical situation in which increased spectrum ofAnother clinical situation in which increased spectrum of

activity is desirable is with nosocomial infection.activity is desirable is with nosocomial infection.

Prevent emergence of resistancePrevent emergence of resistance


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SYNERGISMSYNERGISM

GramGram--negative bacilli in immunosuppressed patients.negative bacilli in immunosuppressed patients.

Traditionally, combinations of aminoglycosides andTraditionally, combinations of aminoglycosides and --lactamslactams

have been used since these drugs together generally acthave been used since these drugs together generally act

synergistically against a wide variety of bacteria.synergistically against a wide variety of bacteria.

Weak supportive dataWeak supportive data

Synergistic combinations may produce better results inSynergistic combinations may produce better results in

infections caused . byinfections caused . by Pseudomonas aeruginosaPseudomonas aeruginosa, in certain, in certaininfections caused byinfections caused by EnterococcusEnterococcusspp.spp.

The use of combinations to prevent the emergence ofThe use of combinations to prevent the emergence of

resistance is widely applied but not often realized.resistance is widely applied but not often realized.

The only circumstance where this has been clearly effective isThe only circumstance where this has been clearly effective is

in the treatment of tuberculosis.in the treatment of tuberculosis.


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DISADVANTAGES OFDISADVANTAGES OF

COMBINATION THERAPYCOMBINATION THERAPY

Increased costIncreased cost

Greater risk of drug toxicityGreater risk of drug toxicity

Superinfection with even more resistantSuperinfection with even more resistant

bacteria.bacteria.

Some combinations of antimicrobials areSome combinations of antimicrobials are

potentially antagonistic. For example, agentspotentially antagonistic. For example, agents

that are capable of inducingthat are capable of inducing --lactamaselactamaseproduction in bacteria (such as cefoxitin) mayproduction in bacteria (such as cefoxitin) may

antagonize the effects of enzymeantagonize the effects of enzyme--labile drugslabile drugssuch as penicillins or imipenem.such as penicillins or imipenem.


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MONITORING THERAPEUTICMONITORING THERAPEUTIC

RESPONSERESPONSE White blood cell countWhite blood cell count

TemperatureTemperature

Signs and symptoms of infectionSigns and symptoms of infection

Physical complaints from the should diminish (i.e., decreasedPhysical complaints from the should diminish (i.e., decreasedpain, shortness ofpain, shortness ofbreath,coughbreath,cough, or sputum production)., or sputum production).

AppetiteAppetite

Radiologic studies as appropriate,Radiologic studies as appropriate,

Antimicrobial concentrations in body fluidsAntimicrobial concentrations in body fluids

Volume of distributionVolume of distribution

Low volume of distribution DehydrationLow volume of distribution Dehydration

High volume of distribution edema,,High volume of distribution edema,, acitisacitis

As the patient improves the route of antibiotic administrationAs the patient improves the route of antibiotic administrationshould be reshould be re--evaluated. Switch to oral therapy is an acceptedevaluated. Switch to oral therapy is an acceptedractice for man infections.ractice for man infections.


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CRITERIA FAVORING SWITCHCRITERIA FAVORING SWITCH

TO ORAL THERAPY INCLUDE:TO ORAL THERAPY INCLUDE:

Overall clinical improvementOverall clinical improvement

Lack of fever for 8 to 24 hoursLack of fever for 8 to 24 hours

Decreased WBCDecreased WBC

A functioning GI tractA functioning GI tract


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FAILURE OF ANTIMICROBIALFAILURE OF ANTIMICROBIAL

THERAPYTHERAPY

Failures Caused by Drug Select ionFailures Caused by Drug Select ion Inappropriate selection of drug, dosage, or route of administratInappropriate selection of drug, dosage, or route of administration.ion.

MalabsorptionMalabsorption of a drug product because ofof a drug product because ofGI diseaseGI disease (e.g., short(e.g., short--

bowel syndrome) or abowel syndrome) or a drug int eract iondrug int eract ion (e.g.,(e.g., complexationcomplexation ofof

fluoroquinolonesfluoroquinolones with multivalentwith multivalent cationscations resulting in reduced absorption)resulting in reduced absorption)

may lead to potentially submay lead to potentially sub--therapeutic serum concentrationstherapeutic serum concentrations

Accelerated drug elimination is also a possible reason for failuAccelerated drug elimination is also a possible reason for failure and mayre and may

occur in patients with cystic fibrosis or during pregnancy, whenoccur in patients with cystic fibrosis or during pregnancy, when moremore

rapid clearance or larger volumes of distribution may result inrapid clearance or larger volumes of distribution may result in low serumlow serum

concentrations, particularly forconcentrations, particularly for aminoglycosidesaminoglycosides..

A common cause of failure of therapy is poor penetration into thA common cause of failure of therapy is poor penetration into the site ofe site ofinfection. This is especially true for the soinfection. This is especially true for the so--called privileged sites such ascalled privileged sites such as

the CNS, the eye, and the prostate gland.the CNS, the eye, and the prostate gland.


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FAILURES CAUSED BY HOSTFAILURES CAUSED BY HOST

FACTORSFACTORS

immunosuppressedimmunosuppressed (e.g.,(e.g., granulocytopeniagranulocytopenia fromfrom

chemotherapy,chemotherapy,

acquired immune deficiency syndrome) may respondacquired immune deficiency syndrome) may respondpoorly to therapy because their own defenses arepoorly to therapy because their own defenses areinadequate to eradicate the infection despite seeminglyinadequate to eradicate the infection despite seemingly

adequate drug regimens.adequate drug regimens.

Other host factors are related to the necessity forOther host factors are related to the necessity for

surgical drainage of abscesses or removal of foreignsurgical drainage of abscesses or removal of foreign

bodies and/or necrotic tissue. If these situations are notbodies and/or necrotic tissue. If these situations are not

corrected, they result in persistent infection and,corrected, they result in persistent infection and,occasionally,occasionally, bacteremiabacteremia, despite adequate antimicrobial, despite adequate antimicrobial

therapy.therapy.


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FAILURES CAUSED BYFAILURES CAUSED BY

MICROORGANISMSMICROORGANISMS

Factors related to the pathogen include theFactors related to the pathogen include the

development of drug resistance during therapy.development of drug resistance during therapy.Primary resistance refers to the intrinsic resistance ofPrimary resistance refers to the intrinsic resistance of

the pathogens producing the infection. However,the pathogens producing the infection. However,

acquisition of resistance during treatment hasacquisition of resistance during treatment has

become a major problem as well.become a major problem as well.

The increase in resistance among pathogenicThe increase in resistance among pathogenic

organisms is believed to be due, in large part, toorganisms is believed to be due, in large part, to

continued overuse of antimicrobials in thecontinued overuse of antimicrobials in thecommunity, as well as in hospitals, and thecommunity, as well as in hospitals, and the

increasing prevalence ofincreasing prevalence ofimmunosuppressedimmunosuppressed patientspatients

receiving longreceiving long--term suppressive antimicrobials forterm suppressive antimicrobials forthe prevention of infections.the prevention of infections.


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clinical pharmacology ninth lecture (infectious diseases) (dr.noha nagah) (27!11!10)

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