1 antibiotic introduction handout
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Southwest College of Naturopathic Medicine 1
Introduction to antibioticsDebra Wollner, PhD
Southwest College of
Naturopathic MedicineTempe, AZ
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Antibiotics Classifications and mechanisms
A little microbiology Clinical applications
Respiratory infections
Urinary tract infections
GI infections Viral infections
STDs
Fungal infections
Parasites Vaccinations
Medications affecting the immune system
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Course objectives At the conc lus ion of th is cou rse students w i l l be able to
Correctly identify the mechanisms of action of a variety ofmedications used to treat microbial diseases.
Correctly identify, using current treatment guidelines, when theuse of anti-microbial medications is NOT indicated.
Correctly prescribe the proper medications to treat conditionspresented by theoretical patients.
Recognize contraindications of given medications and applythem to theoretical patients.
Recognize known and suspected interactions of given
medications and apply them to theoretical patients. Recognize likely adverse effects of given medications and apply
them to analysis of theoretical patient case studies.
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Lecture objectives
Identify by classification antimicrobial medications
based upon the mechanism of action.
Explain the mechanisms of action of commonly usedantibiotics.
Recall basic microbiology as it relates specifically tothe use of antibiotics.
Identify and use basic terminology, including
antibiotic, selective toxicity, bacteriostatic andbacteriocidal.
Define bacterial resistance and apply to the use ofantibiotics.
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Interactions in general
Gut microbes are critical to many body processes
Gut microbes are important for the uptake and
efficacy of several medications
Bacteria make and secrete much of our vitamin K
Bacteria metabolize medications prior to absorption
This may increase or reduce drug uptake
Numerous interactions are expected when usingantibiotics in addition to other medications
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ANTIBIOTICCLASSIFICATION
Mechanisms of action
Spectrum of activity (not very reliable)
Choice of antibiotic
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Classifications
Based on mechanisms
Cell wall synthesis inhibitors
Penicillins, cephalosporins, imidazole antifungal Cell membrane disruptors
Detergents and polyene antifungals
Protein synthesis inhibitors
Tetracyclines, aminoglycosides DNA synthesis inhibitors
Rifamycins, TMP, acyclovir
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How Resistance develops
Drug fails to reach target
Drug is inactivated
Target is changed
Mutation, transformation, conjugation Antibiotics exert selective pressure
Selecting for the resistant strains More than 50% of persons carry multiply resistant
coliform bacilli, also found in sewage
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New antibiotics
Uncontrolled use (abuse) has led to the
development of multiple resistances
Requires the constant influx of new drugs Increases costs dramatically
Drug resistant epidemics MRSA, MDRTB, XDRTB
Require more responsible use of antibiotics May see a return to the pre-antibiotic era (60 years ago)
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Limit resistance
Usually, no antibiotic is necessary Follow specific published guidelines for
recognizing when an antibiotic is needed
Dont prescribe antibiotics when not needed
When clearly indicted Do not select the most broad spectrum medication
Choose antibiotic most likely to be effective giventhe specific infection
Be aware of the spread of resistant strains
Dont use the newest antibiotics unless clearlynecessary
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Selection of appropriate antibiotic
If an antibiotic is required
Empirical
Determine most likely infectious agent May try to identify organism
Definitive - tailored to the organism Institute as soon as the infectious agent is
identified Use narrow spectrum, low toxicity to complete
therapy
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-cidal vs -static Bactericidal kills microbes
Bacteriostatic prevents microbial growth Does not kill the existing microbes
Must use -cidal for Immune suppressed
Endocarditis
Meningitis
Pseudomonas in CF
Watch for toxin producers May release more toxin when using cidal drugs
May add corticosteroids to reduce inflammation
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Sensitivity testing
Disk diffusion and agar or broth dilution
Clear zone show sensitivity to a given drug
Minimal inhibitory concentration (MIC) Lowest concentration that prevents growth
Minimal bactericidal concentration
(MBC) Lowest dose that kills 99.9% of the
infectious organisms
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Other considerations
Access of antibiotic to site of infections
Transport across membranes
Transport out of fluids Decrease in integrity of membranes during
inflammation
Plasma binding of drug and other kineticconsiderations
Dosing schedules Pulse-intermittent or continuous
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Patient status
Renal functions
Use nomograms to change dosage
Liver functions Age of patient, genetics, allergy, seizures
Route of administration
Host defense mechanisms Location of infection-abscess, prosthetic
device
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Combination therapy
Consider interactions
May potentiate activity, toxicity
Different mechanisms
Additive or synergistic effects
Necessary for mixed infections
Unknown organism
Prevention of resistance
Always in H.pylori, HIV, TB
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Superinfections
New infections appearing during treatment
Due to death of normal protective flora
Competition for nutrients Broader spectrum more likely to produce
Resistant bacteria Fungal infections
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Major problems of usage
Untreatable infections
Viruses, measles, mumps
Fever of undetermined origin Short or long term
Cause may not be bacterial
Improper dosage
May need adjunctive therapy
Abscess drainage
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Herb-drug interactions
Typically, ginseng potentiates antibiotic
effects
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CI pregnancy
Aminoglycosides
Tetracyclines
Chloramphenicol Quinolones
Caution sulfamethoxazole (cleft palate in rats)
Caution trimethoprim (folate antagonist)
Caution clarithromycin- animal studies showharm yet category C
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MECHANISMS OF
ACTIONANTI-BACTERIALS
Cell wall synthesis inhibitorsProtein synthesis inhibitors
Anti-metabolites
DNA inhibitors
Membrane disrupters
Others
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Examples
Amoxicillin
Amoxicillin/clavulin (clavamox)
Cephalexin
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History
Cell wall synthesis inhibitors Fleming
Penicillin has been available since the
40s
Beta lactam ring
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Penicillin
International Units
Activity in 0.6 mg of Na-penicillin G
1 mg pen G-Na = 1667 units
1 mg pen G-K = 1595 units
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Mechanism: blactam
antibiotics Penicillin binding protein (PBP) is the
target
PBP is a transpeptidase Links a dipeptide (d-Ala-d-Ala) into
peptidoglycan chain
Forms the cell wall
Inhibited by the blactam antibiotics
These are generally bactericidal
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Serious side effects
Usually cross sensitization among b
lactams
Rash is common
Anaphylaxis possible and most
serious
Dysbiosis common
Including pseudo membranous colitis
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Classification by spectrum
Penicllin G and V
Useful against sensitive gram positive microbes
G is more active against some anaerobes
Methicillin (iv), nafcillin, oxacillin, cloxacillin, dicloxacillin
Penicillinase resistant antibiotics
Ampicillin, amoxicillin
Gram positive and negative
Others available
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Excretion
Mostly through kidney
Rapid
Probenecid impairs tubular secretion
Penicillinase resistant
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Penicillinase resistantantibiotics
Oxacillin, cloxacillin, dicloxacillin Oral
Nafcillin
Not as active as Pen G Usually injected
Binds plasma proteins
May be used in CSF for meningitis
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Ampicillin, amoxicillin
Broader spectrum
Lactamase sensitive
Not useful for most staphyloccal infections
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b-lactamase inhibitors
Clavulanic acid
Streptomyces clavuligerus
Suicide inhibitor of b-lactamase
Found in Augmentin (oral) and Timentin
(inj)
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CEPHALOSPORINS
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Cephalosporins
Fungal culture
blactam
Classified by generations
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Generations First generation
cephalexin (keflex), cefadroxil (Duricef) Gram positive, some negative, some anaerobes
Second generation cefaclor (Ceclor), cefuroxime (Ceftin), cefprozil
(Cefzil) More active against gram negative, less than 3rd
Third generation cefpodoxime (Vantin), cefixime (Suprax)
Less active than first against gram positive More active against entrobacteriaceae and pseudomonas
Fourth generation cefepime
Increased activity, stability
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Ceftriaxone
When administered with calcium to
neonates
May precipitate in kidney
May cause a lethal interaction
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CARBAPENEMS
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Carbapenems
blactam antibiotic
Aztreonam (Azactam)
Monobactam Given iv, limited cross sensitivity
Imipenem
Broader spectrumAdministered with cilastatin
Inhibits dipeptidase in renal tubule
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Carbapenem
Meropenem (iv)/ Merrem
Used for multi-drug resistant infections
Including staphs and streps
Interaction with valproic acid
IV only
Pregnancy B
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Carbapenem
Doripenem /Doribax iv
complicated intra-abdominal infections
caused by E.coli, Klebsiella,Pseudomonas, Bacteroides, Strep,
peptostreptococcus
Complicated pyelonephritis
Decreases serum concentration of
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VANCOMYCIN
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Vancomycin
Usually given iv
Oral for GI infections
C. dificile
S. aureus
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Vancomycin side effects
Major
Ototoxicity
Anaphylaxis red man syndrome
Phlebitis at site of injection
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TELAVANCIN/VIBATIV
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Televancin/Vibativ
Developed for complicated skin
infections
MRSA, Strep pyogenes, Strep agalactiae,Strep anginosus, Enterococcus faecalis
IV only
Nephrotoxic, c.dif, may prolong QTinterval
Black box warning pregnancySouthwest College of Naturopathic Medicine 49
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Protein synthesis inhibitors
Aminoglycoside
Tetracycline
Chloramphenical
Erythromycin
Clindamycin
Ketolides
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Examples
Azithromycin
Erythromycin
Tetracycline
Doxycycline
Tobramycin
Mupirocin
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Resistance
Mutations in bacterial ribosomes
Metabolizing enzymes
Impaired transport of drug into bacteria
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AMINOGLYCOSIDES
Streptomycin
Neomycin
Kanamycin
Gentamicin
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Aminoglycosides
Streptomycin aerobic gram positive and negative
Neomycin Not used orally, severe renal toxicity
Kanamycin (rarely used)
Gentamicin (broader spectrum)
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Aminoglycosides
Pharmacokinetics Polar, not widely distributed
Little plasma binding
High concentrations in renal tubule andendo-and perilymph of the ear
Relatively high renal and ototoxicity
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CHLORAMPHENICOL
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Chloramphenicol
Protein synthesis inhibitor, binds 50S
Inhibits mitochondria
Causes many side effects Wide spectrum
Resistance
Acetyltransferase inactivates drug Some decreased permeability to drug
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Chloramphenicol kinetics
Oral or parenteral
Well distributed
Found in CSF, milk, bile, placenta
Excreted by kidney
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Chloramphenicol Toxicity
(severe) Mitochondrial
Hypersensitivity
Bone marrow effects
Potentially fatal aplastic anemia
More likely with genetic predisposition
Nausea, dysgeusia, vomiting
Fatal toxicity in neonates, gray baby syndrome (due
to liver problem)
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Chloramphenicol
Drug interactions Irreversibly inhibits cP450
Enzyme inducers shorten t1/2
Rifampin, phenobarbital
Prolong t 1/2 of
Dicoumeral, phenytoin
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MACROLIDES
Erythromycin
Azithromycin
Clarithromycin
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Macrolides
Erythromycin
Clarithromycin
Azithromycin
Protein synthesis inhibitors
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Macrolides
Bacteriostatic
Often used in pen allergic patients
Aerobic gram positive Resistance is developing
Lack of uptake
Decreased affinity of ribosome Enzymatic degradation
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Macrolide Drug interactions
Erythromycin
Potentiates the effects of
Carbamazepine, corticosteroids,cyclosporine, digoxin, ergots, theophylline,
valproate, warfarin
Inhibits cP450 metabolism
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Macrolide Toxicities
Allergy
Hepatitis and jaundice
GI distress
Ototoxicity
Cardiac arrythmias- erythromycin
prolong QT interval
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CLINDAMYCIN
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Clindamycin
A protein synthesis inhibitor
Broad spectrum, aerobes and
anaerobes Oral, topical
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Clindamycin Toxicity
Diarrhea
Black box warning
Pseudomembranous colitis May give with vancomycin
Skin rashes
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TETRACYCLINES
Tetracycline
Doxycycline
Minocycline
Tigecycline
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Tetracyclines
Aerobic and anaerobic gram positive
and negative
Bacteriostatic
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Tetracyclines Mechanisms
Inhibit protein synthesis
Bind 30 S ribosomal subunit
Also effect eukaryotic cells at highconcentration
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Tetracyclines Resistance
Decreased uptake, increased efflux
Development of ribosomal protection
proteins Enzymatic cleavage of tetracyclines
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Tetracyclines
Pharmacokinetics Orally available
Widely distributed
Found in most secretions Milk, tears, saliva
Excreted through kidneys
Some hepatobiliary recycling
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Novel use for minocycline
Anti-apoptotic and anti-inflammatoryeffects in vitro
Has been used in ALS Gorden et al. suggests not effective
412 patients, those on minocycline 9 mos.declined more rapidly than placebo
Lancet Neurol. 2007 Dec;6(12):1045-53. Is still used to treat stroke and multiple
sclerosis
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Tigecycline/Tygacil
Used IV for MRSA and other multi-drug
resistant microbial infections
Not for pregnant women Discolors teeth, not for children unless
necessary
Associated with pseudomembranouscolitis
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KETOLIDES
Telithromycin
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MUPIROCIN
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Antimetabolites
Folate antagonists
sulfonamides
trimethoprim
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Examples
Sulfamethoxazole
Trimethoprim
S lf id t i th i
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Sulfonamides, trimethoprim +
sulfamethoxazole(TMP-SMX) UTIs, otitis, bronchitis, sinusitis,
pneumonia
Broad spectrum Gram negative bacilli and cocci,
staphylococci
Orally available
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Sulfonamides
Bacteriostatic
Gram positive and negative
Often used in combination therapy
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Anti-metabolite Resistance
Change in dihydropteroate synthase
Inactivation of drug
Alternative pathway for the productionof folic acid
Production of excess PABA
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Anti-metabolite Toxicity
Crystallization in the urine Hydration therapy
Acute hemolytic anemia
Hypersensitivity Drug interactions
Oral anticoagulants
Sulfonylurea hypoglycemics
Hydantoin anticonvulsants Are potentiated by sulfa drugs
A ti t b lit U i
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Anti-metabolite Use in
newborns Depends on status
Must be conjugated in liver
In immature liver, conjugation reactionis compromised
This may cause increased sensitivity in the
newborn to the sulfonamides antibiotic
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Nucleic acid synthesis
inhibitorsQuinolones
Rifampin
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Quinolones
DNA gyrase inhibitors
Ciprofloxacin (Cipro), ofloxacin (Floxin),
levofloxacin (Levaquin) Norfloxacin, moxifloxacin, gemifloxacin,
ofloxacin
Nalidixic acid
Broad spectrum, oral, some resistance
developing
Bactericidal
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Quinolones Mechanisms
Inhibitor of DNA gyrase
Superwinds the DNA, causing breaks
Resistance from mutation in gyrase
Can crossreact with eukaryotic
topoisomerase, but only at high
concentration
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Examples
Levofloxacin
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Quinolones Toxicity
Nausea
Hallucinations and seizures
Rashes and photosensitivity
Arthropathy in young animals
Tendonitis
Not recommended for pregnant women
and prepubertal children
CI with NSAIDs
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RIFAMPIN
RNA Polymerase inhibitor
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Membrane disruptors
Polymixins
Cyclic lipoproteins
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Polymixin B
Used topically, otc
Gram negative
Amphipathic Detergent action
Cell wall and membrane disruption
Cyclic lipoproteins
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y p p
Daptomycin/Cubicin
Inserts into bacterial membrane, allowing K efflux and
cell death but not cell lysis
Active against aerobic gram positive
Useful in vancomycin resistant MRSA Depolarizes bacterial membrane-bactericidal
Associated with pseudomembranous colitis
Associated with myopathy, caution with statins
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Quinpristin/dalfopristin (Synercid)
Approved for life threatening infections associated withvancomycin-resistant Enterococcus faecium (VREF)
Accelerated approval regulations that allow marketing ofproducts for use in life-threatening conditions when othertherapies are not available.
Approval of drugs for marketing under these regulations isbased upon a demonstrated effect on a surrogate endpoint thatis likely to predict clinical benefit.
Enterococcus faecium (Vancomycin-resistant and multi-drugresistant strains only)
Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pyogenes
NOT enterococcus faecalis
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Lantibiotic
Nisin Made in lactococcus lactus
Effective against many gram positive microbes Inclu. Food borne pathogens
bactieriCidal Disrupts cell wall biosyntheses
Binds lipid II Essential intermediate in peptidoglycan biogenesis
Forms pores in the cell membrane
GRAS Food additive
Not currently listed as drug
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Urinary antiseptic
Methenamine and nitrofurantoin
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Urinary antiseptics
Inhibit many species of bacteria growth
High concentration in renal tubules
Not useful systemically
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Methenamine
Decomposes to formaldehyde at pH 5-6
Enteric coating
Nearly all bacteria are sensitive No resistance
Side effects
GI distress, painful micturition
May be okay in renal insufficiency
CI with sulfamethizole (antagonistic)
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Nitrofurantoin (Furadantin)
Damage DNA when reduced
Reduced well by bacteria
Some resistance Nausea and vomiting, chills, fever, liver
toxic
Blackbox warning Lung toxicity
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Phenazopyridine (Pyridium)
Not an antiseptic
Analgesic
Alleviates symptoms of UTI
Azo dye, can cause GI upset
Azo Gantrisin is phenazopyridine plussulfisoxazole
On the blueprints
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Lecture recap
Introduction to antibiotics and their
mechanisms of action
Basic information regarding side effectsand contraindications
Next, basic microbiology recall
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Infections
URI, LRI
ABECB
CAP
UTI
STDAcute diarrhea and ulcer
Skin
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Microbial classifications
Gram
Cocci v bacilli
Aerobic v anaerobic
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Common pathogenic aerobes
GPB (gram positive bacilli) Bacillus anthracis
Few other human pathogens
GNB Enterobacteriaceae
E.coli, Proteus mirabilis, Klebsiella pneumonia, Provstuartii, M. morganii, Citrobacter sp., Salmonella sp.,Shigella sp.
Non-enterobacteriaceae Hemophilus influenzae, Helicobacter pylori,
Pseudomonas aeruginosa,Acinetobacter sp., others.
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Culturing
Shows many microbes
Not all are causes of infection
Dont need to treat all organisms
Can guess which organism is mostly
likely to be responsible, treat thatorganism
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ORGANISMS BY INFECTIONS
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Strep infections- GPC
Pneumonia
Pyrogenes(A)
Agalactial(B)
Viridans
Otitis
Sinusitis
Pneumonia
Strep throat Cellulitis
Neonatal sepsis
Chronic adult skin
Diabetic foot UTI
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Staph-GPC
Aureus
MSSA, MRSA
Meth sensitive
Meth resistant
Skin
Boils
Abcesses
Impetigo
Cellulitis
E GNB
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Enterococcus-GNB
Fecalis
Faecium
Nosocomial
Chronic adult UTI
Skin Diabetic foot
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B ill GPB
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Bacillus-GPB
Anthracis Anthrax
Inhalational
Skin
Enterobacteriaceae-GNB;
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Enterobacteriaceae GNB;
coliforms E.Coli Most common UTI
Proteus mirabilis- Express urease, alkaline urine
2ndmost common UTI
Klebsiella pneumonia 3rdmost common UTI
Prov stuartii andM. morganii
UTI in nursing homes Relatively uncommon
Citrobacter sp.
Found in normal stool
N t b t i GNB
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Non-enterobacteriaceae-GNB
Hemophilus influenzae 2ndmost common RTI
Helicobacter pylori Ulcer
Psuedomonas aeruginsa Pulmonary, usually found only in chronic illness
Actinetobacter sp. Some pneumonia
Others less common These are not usually found in the gut
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Pathogens in stool
Salmonella sp.
Shigella sp.
Diarrhea
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R i t T t I f ti
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Respiratory Tract Infections
Strep pneumonia
Neissaria moracella
Hemophilusinfluenza
Otitis
Simusitis
Bronchitis Pneumonia
UTI
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UTI
E.Coli
Proteus mirabilis
Klebsiella pneumonia
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Oth i
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Other organisms
Bacteria
Fungi/yeast
Virus Protozoa
Worms
Lice and scabies
Oth i t t B t i
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Other important Bacteria
Legionella(pneumonia)
Chlamydia pneumoniae(atypical pneumonia)
Chlamydia trachomatis(STP, urethritis)
Mycoplasma sp.(pneumonia) M.hominis(genital urethritis)
M.genitalium (genital urethritis)
Ureaplasma urealyticum(urethritis)
Mycobacterium tuberculosis
MAC (avium complex, seen in HIV)
Treponema pallidum(syphillis spirochete)
Lect re recap
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Lecture recap
Overview of anti-bacterial antibiotics
Overview of basic microbiology
Now put them together
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