Antimicrobial Therapies (Intro) Flashcards
Principles of
Antimicrobial Therapy
Overview
Antimicrobials [also called antibiotics]—injure or kill an invading pathogen without harming the cells of the host
Selection requires knowledge of:
-The identity of the pathogen
-Susceptibility of the pathogen
-Site of infection
-Patient factors
-Safety and efficacy of the agent
-Cost
Most patient will require empiric therapy prior to bacterial identification
Identification of the Pathogen
Most of the time, we have to do a culture to know the culprit pathogen we are treating and determine susceptibility, so we went
to ensure all cultures are done before empiric therapy is started
If culture nonconfirmatory, or not an option—other avenues may be helpful—detection of antigens, DNA or RNA; detection of an
inflammatory response
Newest techniques PCR and matrix assisted laser desorption/ionization time of flight [MALDI-TOF] mass spectrometry to obtain accurate, rapid identification of the organism
Empiric Therapy
Timing
• Acutely ill patient with FUO
• Neutropenic patient
• Patient with meningitis
• Others that require immediate therapy
Selecting a Drug
• Choosing a drug without susceptibility is influenced by site, patient history, local
susceptibility patterns
• Broad spectrum indicated initially when pathogen unknown or polymicrobes are suspected
• Choice may also be guided by known association of particular organisms in a given clinical setting
Bacteriostatic vs. Bactericidal
Bacteriostatic
• Thought to arrest growth and replication of bacteria at drug levels achieved
• Most of these agents are able to effectively kill pathogens, but they are unable to meet the arbitrary cut-off value in the bacterial definition
Bactericidal
• Able to effectively kill
>/=99% within 18-24° of incubation
Other Considerations
• It is possible for a drug to be bacteriostatic for one microbe and bactericidal for another
• Other factors have to be considered—host immune system, drug concentration at the site of infection, underlying severity of the illness
MIC—Minimal Inhibitory Concentration
Lowest antimicrobial concentration that prevents visible growth of a microbe after 24° of incubation
Quantitative measure of in vitro susceptibility
MIC is most common approach used by clinical labs
MBC—Minimum Bactericidal Concentration
Lowest concentration of antimicrobial agent that results in a 99.9% decline in colony count after overnight broth dilution incubations
MBC is rarely determined in clinical practice
Effect of the
Site of
Infection
Therapy—The
Blood-Brain
Barrier
Levels of an antibiotic must reach the site of infection for the bacteria to be eradicated
Natural barriers to drug delivery are created by some bodily structures—prostate,
testicles, placenta, vitreous, CNS
Particularly important—blood-brain
barrier—this barrier is a single layer of
endothelial cells fused by tight junctions
that prevent entry from the blood to the
brain of virtually all molecules, except those
that are small and lipophilic
Other
Considerations
Lipid Solubility
• Major determinant of drug’s ability to penetrate the blood-brain barrier
• Lipid soluble drugs [Chloramphenicol, Metronidazole] have significant penetration into the CNS
• Those with low lipid solubility [Penicillin] have limited penetration through the intact blood-brain barrier
• Infections in which the brain becomes inflamed, this barrier does not function as well—and local permeability is increased
Other
Considerations
Molecular Weight
Drugs with low molecular weight have an enhanced ability to cross the blood-brain barrier, while compounds with high
molecular weights [Vancomycin] penetrate
poorly—even in the presence of brain/meningeal inflammation
Other
Considerations
Protein Binding
High degree of protein binding of a drug restricts its entry into the CSF
Amount of free [unbound] drug in the serum, rather then the total amount of drug
present, is important for CSF penetration
Other
Considerations
Susceptibility to
Transporters
or Efflux Pumps
Antibiotics that have an affinity for
transporter mechanisms or do not have an affinity for efflux pumps have better CNS penetration
Patient Factors
Immune System
Eliminating the pathogen from the body depends on an intact immune system
Alcoholism, DM, HIV, malnutrition,
autoimmune disease, pregnancy, older age, immunosuppressants drugs can affect immune status
High dose of bactericidal drugs may be needed to resolve infection in these individuals
Renal Dysfunction
Renal disease can cause accumulation of certain antibiotics—dose adjustment prevents drug accumulation and ADEs
Direct monitoring of serum levels of some antibiotics [Vancomycin, aminoglycosides] is preferred to know the maximum and/or minimum values in order to prevent toxicity
Hepatic Dysfunction
Drugs that are concentrated or eliminated by the liver [Erythromycin, Doxycycline] must be used carefully in patients with liver disease
Poor Perfusion
Decreased circulation to a body area or decreased perfusion to the GI tract can result in decreased absorption, making
getting to a therapeutic concentration difficult with enteral routes of administration
Age
Renal and liver elimination processes are
poorly developed in newborns—making
them high risk to toxic effects
[Chloramphenicol, sulfonamides]
Young children should not receive
Tetracyclines or Quinolones which can
affect teeth, bones and joints
Older patients may have decreased renal
or liver function, which can alter
pharmacokinetics of certain antibiotics
Pregnancy and Lactation
Many drugs cross the placental barrier or
get into the nursing baby via the breast
milk—check the product information
before prescribing
The concentration of an antibiotic in fetal
circulation or in breast milk is usually low,
but the total dose to the infant may be
enough to cause detrimental effects—for
instance—congenital abnormalities have
been seen after pregnant women have
taken tetracyclines—so should not be
prescribed
Risk Factors for Multidrug-Resistant
Organisms
Multidrug-resistant pathogens need broader
antibiotic coverage, when empiric therapy is
being chosen
• Many risk factors
Prior use of antibiotics in last 90 days
Hospitalization for >2 days within last 90
days
Current hospitalization exceeding 5 days
Admission from a NH
High frequency of resistance in the
community or local hospital [using hospital antibiograms]
Immunosuppressive disease and/or
therapies
Safety of the
Agent
PCNs are among least toxic of ALL
antibiotics because they interfere
with a site or function unique to the
growth of the bacteria
Other agents have less specificity
and are reserved for life-threatening
infections because of potential for
serious toxicities
Cost of Therapy
Not uncommon for several drugs to
show similar efficacy in treating
infection, but vary in cost
Choice of therapy usually centers on site
of infection, severity, ability to take oral
meds—and then important to consider
cost
Route of Administration
Oral route is appropriate for infections that can be treated outpatient
Parenteral route is used when the med is poorly absorbed from the GI tract and for those with serious infections that need high serum concentrations of the antibiotic
In hospitalized patients that need IV drugs, switch to oral meds should occur as soon as possible
Switching patients from IV to oral, when the
patient is stable decreases cost, shortens length of stay and decreases complications from IV catheters
Antibiotics such as Vancomycin and
aminoglycosides are poorly absorbed from the gut and do not achieve high enough serum levels via oral ingestion
Determinants
of Rational
Dosing
Dosing is based on pharmacodynamics
and pharmacokinetic properties—the
three important properties that greatly
influence the frequency of dosing;
-Concentration-dependent killing
-Time-dependent [concentration-
independent] killing
-Postantibiotic effect [PAE]
Concentration Dependent Killing
Certain drugs—such as aminoglycosides and Daptomycin show a large increase in the rate of bacterial killing as the concentration of the drug increases from 4 to 64 times the MIC of the drug for the causative pathogen
Giving drugs that exhibit this concentration-killing by a once a day bolus infusion obtains high peak levels—that cause rapid killing of the bug
Time-Dependent [Concentration-Independent] Killing
ß-lactams, Glycopeptides, Macrolides, Clindamycin Linezolid
• Do not exhibit concentration-dependent killing
• Clinical efficacy of these is best predicted by percentage of time that blood
levels of the drug remain above the MIC—this is time-dependent
[concentration-independent] killing
• Dosing for PCN and Cephalosporins should ensure that blood levels are >
than MIC 50% [PCN] and 60% [Cephalosporins] of the time to get best
clinical results
• Extended [3-4°] or continuous infusions can be used instead of intermittent
[30”] dosing—to get longer time above the MIC and killing more microbes
Fluoroquinolones, Vancomycin
• Work best by maximizing ratio of 24° area
under the concentration-time curve to MIC
[AUC24/MIC]
• AUC24 is overall exposure of a drug during the dosing interval and takes into account the concentration as well as time
Postantibiotic Effect [PAE]
Persistent suppression of microbial growth that occurs after levels of the drug have fallen below the MIC
Drugs that have a PAE often require one dose per day—especially against gram negative bacteria [aminoglycosides, fluoroquinolones]
Chemotherapeutic Spectra
Narrow Spectrum
• Agents acting on a single or limited group of microbes
• An example—INH is active only against
Mycobacterium tuberculosis
Extended Spectrum
• Drugs that are modified to be effective against gram + organisms and also against a number of gram –bacteria
• An example—Ampicillin
Broad Spectrum
• Drugs affect a wide variety of microbe
species
• These drugs can alter the nature of the
normal bacterial flora and lead to
superinfection from pathogens such as
C. difficile [the growth of which is normally kept in check by other colonizing bacteria]
• Examples—Tetracyclines, Fluoroquinolones, Carbapenems
Combinations of Antimicrobial Drugs
For the most part, it is advisable to treat patients with one antibiotic that is the most specific to the pathogen causing them to be ill
This will reduce the chance of superinfections, decreases emergence of resistant strains and minimizes toxicity
However, sometimes combinations of antibiotics are advantageous are may be mandated to get the patient well
Combinations of Antimicrobial Drugs
Advantages and Disadvantages
Advantages
Some combinations show synergy [ß-lactams + aminoglycosides]
Because synergism is pretty rare, we use these combinations in special
cases—enterococcal endocarditis
Combinations often used when infection is of unknown etiology or several organisms
with variable sensitivities—such as TB
Disadvantages
Many drugs work only when pathogens are multiplying, so when combinations are given, where one is bactericidal and other is
bacteriostatic—the 1st drug may interfere with the action of the 2nd agent
For example—bacteriostatic tetracyclines interfere with the bactericidal effects of PCN and cephalosporins
Another concern is development of
resistance from giving unneeded combinations
Drug
Resistance
Pathogens are resistant to a drug if the maximum level of the drug that can be tolerated by the host does not stop the bug from growing
Some pathogens are inherently resistant to an specific drug—gram negative bugs are resistant to Vancomycin
Microbes normally responsive to a particular drug may develop more virulent or resistant strains via spontaneous mutation, acquired resistance and selection
Some strains are resistant to more than one
antibiotic
Genetic Alterations Leading to Drug Resistance
Acquired antibiotic resistance requires the
temporary or permanent gain or alteration of bacterial genetic information
Resistance occurs due to the ability of DNA to change/mutate or to move from one organism to another
Altered Expression of Proteins in Drug-Resistant Organisms
Modification of Target Sites
Alteration of the target site of an antibiotic
through mutation
Decreased Accumulation
Decreased uptake or increased efflux of an
antibiotic can cause resistance because the
drug is not able to access the site of action in
enough concentration to maim or kill the
microbe
Gram – bugs can limit penetration of certain
ß-lactams antibiotics by altering number
and structure of porins in the outer
membrane
Efflux pumps can limit levels of tetracyclines
in certain microbes
Enzymatic Inactivation
• Ability to destroy or inactivate an antibiotic can cause resistance
• ß-lactamases [penicillinases] that
hydrolytically inactive the ß-lactam ring of Penicillins or Cephalosporins
• Acetyltransferases that transfer an acetyl
group to the antibiotic inactivating the
aminoglycoside
• Esterases that hydrolyze the lactone ring
of macrolides
Preventative
Use of
Antibiotics
Sometimes—dental procedures,
surgeries require use of antibiotics for the
prevention of an infection
Unnecessary use of antibiotics can cause
bacterial resistance and superinfection— preventative use is restricted to clinical
situations where benefits outweigh the
risks
Complications of Antibiotic Therapy
Hypersensitivity
-Immune reactions
-Penicillins can cause urticaria, anaphylactic shock
-Some reactions related to rate of infusion—”Red Man Syndrome” from rapid infusion of Vancomycin
-Patients with history of Stevens-Johnson syndrome or Toxic Epidermal Necrosis from an antibiotic should NEVER be rechallenged, not even for antibiotic desensitization
Direct Toxicity
-High serum drug levels can cause toxicity by directly affecting cellular processes in the patient
-Aminoglycosides can cause ototoxicity by interfering with membrane function in the auditory hair cells
-Chloramphenicol can be toxic to mitochondria leading to bone marrow suppression
-Fluoroquinolones can have effects on cartilage and tendons
-Tetracyclines can directly affect bones
-Many antibiotics can cause photosensitivity
Superinfections
-Antimicrobials—especially those with broad spectrums or combinations can cause altered normal bacterial flora in respiratory tract, mouth, GI and GU tracts— thus allowing overgrowth of opportunistic agents,
fungi or resistant bacteria
-These infections will then require secondary therapy
Sites of
Antimicrobial
Action
Antimicrobials are classified by:
-Chemical structure
-Mechanism of action
-Activity against particular types of pathogens
