1 antibiotic introduction handout

8/12/2019 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

valproic acid

May precipitate seizuresSouthwest College of Naturopathic Medicine 42


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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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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



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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

1 antibiotic introduction handout

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