Antimicrobial AgentsAntimicrobial Agents(Aminoglycosides, tetracyclines, (Aminoglycosides, tetracyclines, macrolides and other assorted macrolides and other assorted

drugs) drugs) Dr. Jeff HobdenDr. Jeff Hobden

MIPMIP

The AminoglycosidesThe Aminoglycosides• Two or more amino Two or more amino

sugars attached to a sugars attached to a hexose nucleushexose nucleus

• Narrow spectrum of Narrow spectrum of coverage (G- coverage (G- aerobes)aerobes)

• Bactericidal protein Bactericidal protein synthesis inhibitorsynthesis inhibitor

• ResistanceResistance• Enzymatic modification Enzymatic modification • Impaired uptakeImpaired uptake• Mutation in ribosomeMutation in ribosome

The AminoglycosidesThe Aminoglycosides• Given parenterally Given parenterally

onlyonly• Poor penetrationPoor penetration

• Inside cells (no Inside cells (no effect on effect on intracellular bugs)intracellular bugs)

• CSFCSF• EyeEye

• Accumulates in Accumulates in perilymph and perilymph and endolymph of the endolymph of the inner earinner ear

• Excreted mostly Excreted mostly through kidneys, a through kidneys, a little through the liverlittle through the liver

StreptomycinStreptomycin

• An anti-TB drugAn anti-TB drug• Also useful for:Also useful for:

• Bacterial Bacterial endocarditis endocarditis when combined when combined with a beta-with a beta-lactamlactam

• TularemiaTularemia• PlaguePlague

TuberculosTuberculosisis

PlaguePlague

Gentamicin, Tobramycin, Gentamicin, Tobramycin, Amikacin, NetilmicinAmikacin, Netilmicin

• Gentamicin and Gentamicin and tobramycin are tobramycin are good against good against P. P. aeruginosaaeruginosa

• amikacin and amikacin and netilmicin are netilmicin are effective against effective against gentamicin-gentamicin-resistant bugsresistant bugs

Therapeutic UsesTherapeutic Uses(+ a beta-lactam)(+ a beta-lactam)

• UTIUTI• Community Community

acquired acquired pneumoniapneumonia

• MeningitisMeningitis• Dialysis associated Dialysis associated

peritonitisperitonitis• Bacterial Bacterial

endocarditisendocarditis• SepsisSepsis• Topical infections Topical infections

(keratitis)(keratitis)

Toxicity/Contraindications Toxicity/Contraindications of the Aminoglycosidesof the Aminoglycosides

• Ototoxic (Ototoxic (commoncommon))• Auditory Auditory

dysfunctiondysfunction• Vestibular Vestibular

dysfunctiondysfunction• Nephrotoxic Nephrotoxic

((commoncommon))• Rare side effectsRare side effects

• Neuromuscular Neuromuscular blockadeblockade

• hypersensitivityhypersensitivity

The TetracyclinesThe Tetracyclines

• Natural products of Natural products of StreptomycesStreptomyces or semi- or semi-synthetic derivativessynthetic derivatives

• Broad spectrum but work Broad spectrum but work better against G+ than G-better against G+ than G-

• Work against anaerobes, Work against anaerobes, intracellular bacteria, intracellular bacteria, and atypical bacteriaand atypical bacteria

• BacteristaticBacteristatic• Resistance due to Resistance due to

decreased influx or decreased influx or active efflux, production active efflux, production of protection protein, of protection protein, enzymatic inactivationenzymatic inactivation

Pharmacology of Pharmacology of the Tetracyclinesthe Tetracyclines

• Absorbance is Absorbance is incompleteincomplete

• Oral or parenteralOral or parenteral• Dairy products, Dairy products,

antacids, etc antacids, etc interfere with interfere with absorptionabsorption

• Wide distribution in Wide distribution in tissues and fluids tissues and fluids (including CSF)(including CSF)

Pharmacology of Pharmacology of the Tetracyclinesthe Tetracyclines

• Crosses placenta Crosses placenta and enters fetal and enters fetal circulationcirculation

• Found in breast Found in breast milkmilk

• Most are excreted Most are excreted by kidneys, by kidneys, others are others are concentrated into concentrated into bile and pooped bile and pooped outout

Tetracyclines are secreted Tetracyclines are secreted here…here…

……and excreted here!and excreted here!

Pharmacology of Pharmacology of Select TetracyclinesSelect Tetracyclines

• Tetracycline, oxytetracycline, Tetracycline, oxytetracycline, democyclinedemocycline• Incompletely absorbed from stomach Incompletely absorbed from stomach

(60-80%)(60-80%)• Primarily excreted through the kidneysPrimarily excreted through the kidneys

• Minocycline, doxycyclineMinocycline, doxycycline• Completely absorbed from stomach Completely absorbed from stomach

(95-100%)(95-100%)• Excreted through liverExcreted through liver

TigecyclineTigecycline• A glycylcycline A glycylcycline

antibiotic, a antibiotic, a derivative of derivative of minocyclineminocycline

• Truly broad Truly broad spectrumspectrum

• Complicated intra-Complicated intra-abdominal abdominal infections, soft infections, soft tissue infectionstissue infections

• Toxicities and side Toxicities and side effects similar to the effects similar to the tetracyclinestetracyclines

Therapeutic UsesTherapeutic Uses of Tetracyclines of Tetracyclines

• Rickettsial infectionsRickettsial infections• RMSFRMSF• All forms of typhusAll forms of typhus• Q feverQ fever

• MycoplasmaMycoplasma infectionsinfections

• Chlamydia infectionsChlamydia infections• Lymphogranuloma Lymphogranuloma

venereumvenereum• TrachomaTrachoma• Non-specific urethritisNon-specific urethritis

RMSFRMSF

LGVLGV

Therapeutic UsesTherapeutic Uses of Tetracyclines of Tetracyclines

• SyphilisSyphilis• AnthraxAnthrax• Bacillary infectionsBacillary infections

• BrucellosisBrucellosis• TularemiaTularemia• CholeraCholera

• Infections with Infections with spirochetesspirochetes• YawsYaws• Lyme diseaseLyme disease• Relapsing feverRelapsing fever

Vibrio Vibrio choleraecholerae

Lyme Lyme DiseaseDisease

Toxicity/Contraindications Toxicity/Contraindications

of Tetracyclinesof Tetracyclines• Gastrointestinal Gastrointestinal

• Nausea, vomiting, etc.Nausea, vomiting, etc.• Food helps (not dairy)Food helps (not dairy)

• PhotosensitivityPhotosensitivity• Hepatic toxicityHepatic toxicity

• Large dosesLarge doses• Worse when pregnantWorse when pregnant

• Renal toxicityRenal toxicity• Fanconi syndrome Fanconi syndrome

• Degraded drugDegraded drug• Nausea, vomiting, Nausea, vomiting,

etc.etc.

Toxicity/Contraindications Toxicity/Contraindications

of Tetracyclinesof Tetracyclines• Because drug is Because drug is

deposited in tooth deposited in tooth dentine and enamel, dentine and enamel, brown bands form brown bands form

• Do not give to children or Do not give to children or pregnant/nursing womenpregnant/nursing women

• Misc. side effectsMisc. side effects• ThrombophlebitisThrombophlebitis• Various WBC dystrophiesVarious WBC dystrophies• Increased intracranial Increased intracranial

pressure in neonatespressure in neonates• Hypersensitivity Hypersensitivity

reactionsreactions

ChloramphenicolChloramphenicol

• A natural product A natural product (contains a (contains a nitrobenzene nitrobenzene moiety)moiety)

• Broad spectrumBroad spectrum• BacteristaticBacteristatic• Resistance Resistance

• AcetylationAcetylation• EffluxEfflux• Mutations in Mutations in

ribosomeribosome

ChloramphenicolChloramphenicol

• Given orally or parenterallyGiven orally or parenterally• Wide distribution, including CSFWide distribution, including CSF• Present in bile, milk, and Present in bile, milk, and

placental fluidplacental fluid• Rapidly excreted by kidneysRapidly excreted by kidneys• Used to treat typhoid fever, Used to treat typhoid fever,

bacterial meningitis, anaerobic bacterial meningitis, anaerobic infections, rickettsial disease infections, rickettsial disease (second choice drug)(second choice drug)

Toxicity/Contraindications Toxicity/Contraindications

of Chloramphenicolof Chloramphenicol• Hypersensitivity Hypersensitivity • Hematological toxicity – anemiaHematological toxicity – anemia• Gastrointestinal – nausea, vomiting, nasty taste, Gastrointestinal – nausea, vomiting, nasty taste,

diarrheadiarrhea• Gray baby syndrome (2-9 days after dose)Gray baby syndrome (2-9 days after dose)

• Within 24 hours, baby starts to vomit, stops eating, Within 24 hours, baby starts to vomit, stops eating, rapid and irregular respiration, abdominal rapid and irregular respiration, abdominal distension, periods of cyanosis, and pooping loose distension, periods of cyanosis, and pooping loose green stoolgreen stool

• Baby then turns ashen gray and becomes flaccid and Baby then turns ashen gray and becomes flaccid and hypothermichypothermic

• Also can occur in adults who ODAlso can occur in adults who OD• Death in 40% of casesDeath in 40% of cases

• Prolongs half lives of warfarin, dicumerol, and Prolongs half lives of warfarin, dicumerol, and anti-retroviral protease inhibitorsanti-retroviral protease inhibitors

The MacrolidesThe Macrolides• Erythromycin is natural Erythromycin is natural

product, clarithromycin product, clarithromycin and azithromycin are and azithromycin are semi-synthetic semi-synthetic derivativesderivatives

• 14 to 15 member 14 to 15 member lactone ring attached to lactone ring attached to one or more deoxy one or more deoxy sugarssugars

• Effective against G+ Effective against G+ • Effective against Effective against

atypical mycobacteria atypical mycobacteria and some intracellular and some intracellular bugsbugs

• Bacteristatic, binds Bacteristatic, binds ribosomes much like ribosomes much like chloramphenicolchloramphenicol

• Resistance – efflux, Resistance – efflux, ribosomal protection, ribosomal protection, esterases, mutate esterases, mutate ribosomeribosome

Pharmacology of Pharmacology of the Macrolidesthe Macrolides

• Administered orallyAdministered orally• Adsorbed in upper small intestineAdsorbed in upper small intestine• Gastric acid inactivates drug so pills are coated Gastric acid inactivates drug so pills are coated • Food delays adsorption of erythromycin and Food delays adsorption of erythromycin and

azithromycinazithromycin

• Readilly diffuses in all intracellular fluids Readilly diffuses in all intracellular fluids except CSF and brainexcept CSF and brain

• Crosses placenta and enters fetal Crosses placenta and enters fetal circulationcirculation

• Secreted in breast milkSecreted in breast milk• Excreted by kidney and liver (through bile)Excreted by kidney and liver (through bile)

Pharmacology of Pharmacology of Select MacrolidesSelect Macrolides

• ClarithromycinClarithromycin• More effective against More effective against

staph and strep than staph and strep than erythromycinerythromycin

• Can be given with Can be given with foodfood

• AzithromycinAzithromycin• Slightly less effective Slightly less effective

against G+ but works against G+ but works better than other 2 better than other 2 against against Haemophilus Haemophilus influenzaeinfluenzae

• good against atypical good against atypical mycobacteriamycobacteria AzithromycAzithromyc

inin

Therapeutic UsesTherapeutic Uses of Macrolides of Macrolides

• Mycoplasma Mycoplasma infectionsinfections

• Legionairre’s Legionairre’s DiseaseDisease

• Chlamydia infectionsChlamydia infections• Diphtheria/pertussisDiphtheria/pertussis• Staph/strepStaph/strep• GI infectionsGI infections• TetanusTetanus• AIDs related AIDs related

infectionsinfections

pseudomembranpseudomembrane e

of diphtheriaof diphtheria

H. pyloriH. pylori

Toxicity/Contraindications Toxicity/Contraindications

of the Macrolidesof the Macrolides• Epigastric distress with large dosesEpigastric distress with large doses• Cholestatic hepatitis (rare)Cholestatic hepatitis (rare)• Potentiate the effects ofPotentiate the effects of

• CarbamazepineCarbamazepine• CorticosteroidsCorticosteroids• CyclosporineCyclosporine• DigoxinDigoxin• Ergot alkaloidsErgot alkaloids• TheophyllineTheophylline• TriazolamTriazolam• ValproateValproate• warfarinwarfarin

The StreptograminsThe Streptogramins

• Two agents combined Two agents combined (Synercid)(Synercid)

• Derived from Derived from pristinamycinpristinamycin

• Covers G+ cocciCovers G+ cocci• Effect on bugs similar Effect on bugs similar

to macrolidesto macrolides• Only given IV in 5% Only given IV in 5%

dextrose in waterdextrose in water• Wide distributionWide distribution• Mostly hepatic Mostly hepatic

excretionexcretion

The StreptograminsThe Streptogramins

• Treatment of vancomycin-Treatment of vancomycin-resistant enterococci, MSSA, resistant enterococci, MSSA, and strep infectionsand strep infections

• ToxicityToxicity• Infusion related pain and Infusion related pain and

phlebitisphlebitis• Potentiates same drugs as Potentiates same drugs as

macrolidesmacrolides

ClindamycinClindamycin

• similar to macrolides in many wayssimilar to macrolides in many ways• Good against anaeobesGood against anaeobes• Given orally, parenterally, or topicallyGiven orally, parenterally, or topically• Food does not interfere with Food does not interfere with

absorptionabsorption• Wide distribution excluding CSFWide distribution excluding CSF• Crosses placentaCrosses placenta• Accumulates in PMN, alveolar Accumulates in PMN, alveolar

macrophages, and pusmacrophages, and pus• Excreted by liver and kidneysExcreted by liver and kidneys

ClindamycinClindamycin

• Good for anaerobic Good for anaerobic infections (except infections (except brain abscesses)brain abscesses)

• Staph infections Staph infections (including MRSA)(including MRSA)

• Diarrhea is common Diarrhea is common side effectside effect

• Pseudomembranous Pseudomembranous colitis to toxic colitis to toxic megacolonmegacolon

• Skin rashSkin rash• Rare side effects – SJS, Rare side effects – SJS,

anaphylaxisanaphylaxistoxic toxic megacolonmegacolon

LinezolidLinezolid• Synthetic agent (an Synthetic agent (an

oxazolidinone)oxazolidinone)• G+ coverage only, no G+ coverage only, no

anaerobesanaerobes• Prevents assembly of Prevents assembly of

ribosomeribosome• Oral or IV = 100% Oral or IV = 100%

absorptionabsorption• Food does not Food does not

interfere with interfere with absorbtionabsorbtion

• Distributed widely to Distributed widely to well perfused tissueswell perfused tissues

• Excreted mostly by Excreted mostly by kidneykidney

• Treat VR enterococci, Treat VR enterococci, MSSA, MRSAMSSA, MRSA

• Well tolerated, minor Well tolerated, minor gastrointestional gastrointestional complaintscomplaints

VancomycinVancomycin• Tricyclic GlycopeptideTricyclic Glycopeptide• G+ coverage onlyG+ coverage only• Inhibits polymerization Inhibits polymerization

of peptidoglycan of peptidoglycan subunitssubunits

• given IV over an hour given IV over an hour or orally for or orally for pseudomembranous pseudomembranous colitiscolitis

• Wide distributionWide distribution• Secreted by kidneysSecreted by kidneys• Treatment of MRSATreatment of MRSA• Red-man syndrome: a Red-man syndrome: a

complication of too complication of too rapid an infusionrapid an infusion

MRSAMRSA

The The End?End?

AlmostAlmost……