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Brunton LL, Lazo JS, Parker KL, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th
Edition (2005)
Drusano GL, Antimicrobial Pharmacodynamics: Critical Interactions of ‘Bug and Drug’ (2004)
Nature Reviews Microbiology 2:289-300
Wright GD, The Antibiotic Resistome: The Nexus of Chemical and Genetic Diversity (2007)
Nature Reviews Microbiology 5:175-186
Armstrong GL et al., (1999) JAMA 281:61-66
Infectious disease mortality rate 1900-1996
๏ A combination of improved sanitation, access to clean water, hygiene, vaccination, and antibiotics led to a decrease in mortality starting around the industrial revolution (late 19th century)
Armstrong GL et al., (1999) JAMA 281:61-66
Infectious disease mortality rate 1900-1996
๏ A combination of improved sanitation, access to clean water, hygiene, vaccination, and antibiotics led to a decrease in mortality starting around the industrial revolution (late 19th century)
1918 influenza pandemic~50-100 million deaths (~3% of world population)~30% of world population infected
Taylor JB and Triggle DJ (eds), Comprehensive Medicinal Chemistry II, vol7Walsh CT, Antibiotics: Actions, origins, resistance, (2003) ASM Press, Washington DC, USA
Coates A, et al., Nature Rev. Drug Discovery (2002) 1:895-910
Impact on health care๏ Antibiotics make up a substantial fraction of prescriptions:๏ ~42% of patients admitted to hospitals receive antibiotics๏ ~50% of drug prescription costs go to antibiotics, where prescription costs amount to
10-15% of total health care costs
๏ Most likely place for an individual to acquire an antibiotic-resistant infection is the ICU
๏ U. Michigan Health System study: In 2002, 41 million antibiotic prescriptions for people suffering from colds (viral), more than one-third of patients who saw a doc about a cold (Feb 24, 2003 edition of Archives of Internal Medicine)
Selective Toxicity
Antimicrobial: Microbial secondary metabolites or synthetic compounds that in
small doses inhibit the growth and survival of microorganisms without serious
toxicity to the host (us)
Antibiotic: Natural product subset of antimicrobials
We are >90% bacterial
For our 10 trillion cells, ~100 trillion bacterial cells make their home in and on us.
Introduction of antimicrobials impacts the pathogens as well as our flora.
Implications for side effects and the emergence/harboring of resistance.
Ways commensal bacteria impact our health
๏ In many cases the flora-host interaction is mutualistic. Commensal bacteria provide for us:๏ Aid in digestion of food and production of vitamins๏ Processing of nutrients and drugs in our gut๏ Prevent establishment of pathogenic competitors๏ Immunity๏ Imbalance can impact asthma
Organs and internal tissues are normally sterile. Commensal bacteria do
colonize “exterior” including skin, gut, respiratory tract, mouth, eyes,
urogenital tract, etc.
Normal flora
Something to keep in mind for the future:Native flora is specific to an individual, impact of treatment may differ significantly
๏ Appears human microbiome of the gut may be categorizable into 3 main “enterotypes”, each dominated by a main genus
๏ Not related to nation, ethnicity, gender, or age๏ There may be a link between the enterotype found in an individual and
susceptibility to disorders/diseases “Enterotypes of the human gut microbiome”Arumugam et al., Nature (2011)
472:7343
Impact on our microbial flora
๏ The antimicrobials are not so specifically targeted that they knock out only the primary pathogen, they can act potently against other species of the flora.
๏ Can compromise the balanced bacterial ecology, especially of the gut๏ e.g. leading to diarrhea, Clostridium difficile overgrowth
๏ The flora can also be reservoirs for transferable resistance factors (R-factors).๏ After antibiotic treatment, R-factors can be detected even during the course of
the therapy, and persist for years
Sources of pathogenic bacterial infections
๏ Some of the commensal bacteria may become pathogens if they gain access to normally sterile internal sites through wounds, medical device insertion, etc. OPPORTUNISTIC PATHOGENS.
๏ Compromised immune systems also can create opportunities for pathogenesis.
๏ Some pathogens are extrinsic and not related to our commensal flora.
Organs and internal tissues are normally sterile. Commensal bacteria do
colonize “exterior” including skin, gut, respiratory tract, mouth, eyes,
Production of pigmented secondary metabolites by Streptomyces colonies. (a) Typical colonial morphologies of Streptomyces isolated from the soil. Colonies often excrete colored pigments, providing a visual recording of secondary metabolite biosynthesis. The chemically diverse compounds represent a vast array of bioactive compounds that often have pharmaceutical applications. (b) A panoramic view of Streptomyces coelicolor colonial morphology. Both
Minimum Inhibitory Concentration: lowest concentration of drug that gives no visible growth after 24h incubation
Minimum Bactericidal Concentration: concentration of drug that gives no visible growth even in the absence of drug
Concentration-time curve
conc
entr
atio
n
MIC
CMAX
time post-administration
AUC (Area Under the Curve)
๏ MIC: minimum inhibitory concentration
๏ AUC: a measure of the total exposure to the drug
๏ Cmax: maximum concentration attained
Time-dependent killing
๏ Beta-lactams
๏ Length of time where concentration>MIC is most important
๏ So long as concentration>MIC, absolute concentration does not matter too much
๏ Related to number of target enzymes for the drug and their saturation
๏ Frequent, lower doses
conc
entr
atio
n
MIC
t>MIC
CMAX
time post-administration
Concentration-dependent killing
๏ Aminoglycosides and fluoroquinolones
๏ AUC/MIC is the critical index for effective control
๏ Concentration-dependent mechanism of killing
๏ Relates to barriers in drug getting to target site.
๏ Less frequent, higher doses
conc
entr
atio
n
MIC
CMAX
time post-administration
Time versus concentration-dependent activity
Craig WA, “Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men,” (1998) Clin. Infect. Dis. 26:1-12
beta-lactamaminoglycoside fluoroquinolone
Post-antibiotic effect (PAE)
๏ Post-antibiotic effect: after initial dosing, even when concentration in the
blood drops below the MIC, microbial growth may be inhibited
๏ Believed to be due to either drugs that remain bound or are
concentrated in/near infection or due to damage to the bacteria that
they must repair before they can recommence their growth
AUC/MIC but not concentration-dependent killing
๏ Example: Vancomycin, macrolides (e.g. azithromycin)๏ AUC/MIC is the critical index for effective control, but higher concentrations not
necessarily more effective above a certain point๏ Strong post-antibiotic effect (PAE), likely reflects antibiotic-induced cell damage๏ The duration of the PAE is increased by increasing the AUC/MIC๏ When MIC is relatively high and AUC/MIC is low, these drugs may act similarly to
time-dependent agents
conc
entr
atio
n
MIC
CMAX
time post-administration
Time versus concentration-dependent activity
Antimicrobialclass Goal of therapy index
type Iconc-dependent
killing long PAE
aminoglycosidesdaptomycin
fluoroquinolonesketolides (telithromycin)
maximize concentrationAUC/MICCmax/MIC
type IItime-dependent
killing minimal PAE
beta-lactamslinezolid
erythromycin, clarithromycinmaximize duration of
exposure
type IIItime-dependent
killingmoderate to
long PAE
tetracyclinesglycopeptide (vancomycin)
clindamycinmaximize total exposure AUC/MIC
t>MIC
Example AUC/MIC, T>MIC values
๏ Fluoroquinolones vs gm+ bacteria AUC/MIC>40
๏ Fluoroquinolones vs gm- bacteria AUC/MIC>125
๏ Aminoglycosides, Cmax/MIC~8-10
๏ Beta-lactams, T>MIC comparable to dosing interval
๏ Vancomycin, AUC/MIC >125-400
Varability in bioavailability across populations
๏ The same dosage to a population of patients will result in a broad range of effective drug concentrations (exposures) in those patients.