Antimicrobial Agents (Aminoglycosides, tetracyclines, macrolides and other assorted drugs) Dr. Jeff Hobden MIP

The Aminoglycosides Two or more amino sugars attached to a hexose nucleus Narrow spectrum of coverage (G- aerobes) Bactericidal protein synthesis inhibitor Resistance Enzymatic modification Impaired uptake Mutation in ribosome

The Aminoglycosides Given parenterally only Poor penetration Inside cells (no effect on intracellular bugs) CSF Eye Accumulates in perilymph and endolymph of the inner ear Excreted mostly through kidneys, a little through the liver

Streptomycin An anti-TB drug Also useful for: Bacterial endocarditis when combined with a beta-lactam Tularemia Plague Tuberculosis Plague

Gentamicin, Tobramycin, Amikacin, Netilmicin Gentamicin and tobramycin are good against P. aeruginosa amikacin and netilmicin are effective against gentamicin-resistant bugs

Therapeutic Uses (+ a beta-lactam) Community acquired pneumonia Meningitis Dialysis associated peritonitis Bacterial endocarditis Sepsis Topical infections (keratitis)

Toxicity/Contraindications of the Aminoglycosides Ototoxic (common) Auditory dysfunction Vestibular dysfunction Nephrotoxic (common) Rare side effects Neuromuscular blockade hypersensitivity

The Tetracyclines Natural products of Streptomyces or semi-synthetic derivatives Broad spectrum but work better against G+ than G- Work against anaerobes, intracellular bacteria, and atypical bacteria Bacteristatic Resistance due to decreased influx or active efflux, production of protection protein, enzymatic inactivation

Pharmacology of the Tetracyclines Absorbance is incomplete Oral or parenteral Dairy products, antacids, etc interfere with absorption Wide distribution in tissues and fluids (including CSF)

Pharmacology of the Tetracyclines Crosses placenta and enters fetal circulation Found in breast milk Most are excreted by kidneys, others are concentrated into bile and pooped out Tetracyclines are secreted here… …and excreted here!

Pharmacology of Select Tetracyclines Tetracycline, oxytetracycline, democycline Incompletely absorbed from stomach (60-80%) Primarily excreted through the kidneys Minocycline, doxycycline Completely absorbed from stomach (95-100%) Excreted through liver

Tigecycline A glycylcycline antibiotic, a derivative of minocycline Truly broad spectrum Complicated intra-abdominal infections, soft tissue infections Toxicities and side effects similar to the tetracyclines

Therapeutic Uses of Tetracyclines Rickettsial infections RMSF All forms of typhus Q fever Mycoplasma infections Chlamydia infections Lymphogranuloma venereum Trachoma Non-specific urethritis RMSF LGV

Therapeutic Uses of Tetracyclines Syphilis Anthrax Bacillary infections Brucellosis Tularemia Cholera Infections with spirochetes Yaws Lyme disease Relapsing fever Vibrio cholerae Lyme Disease

Toxicity/Contraindications of Tetracyclines Gastrointestinal Nausea, vomiting, etc. Food helps (not dairy) Photosensitivity Hepatic toxicity Large doses Worse when pregnant Renal toxicity Fanconi syndrome Degraded drug

Toxicity/Contraindications of Tetracyclines Because drug is deposited in tooth dentine and enamel, brown bands form Do not give to children or pregnant/nursing women Misc. side effects Thrombophlebitis Various WBC dystrophies Increased intracranial pressure in neonates Hypersensitivity reactions

Chloramphenicol A natural product (contains a nitrobenzene moiety) Broad spectrum Bacteristatic Resistance Acetylation Efflux Mutations in ribosome

Chloramphenicol Given orally or parenterally Wide distribution, including CSF Present in bile, milk, and placental fluid Rapidly excreted by kidneys Used to treat typhoid fever, bacterial meningitis, anaerobic infections, rickettsial disease (second choice drug)

Toxicity/Contraindications of Chloramphenicol Hypersensitivity Hematological toxicity – anemia Gastrointestinal – nausea, vomiting, nasty taste, diarrhea Gray baby syndrome (2-9 days after dose) Within 24 hours, baby starts to vomit, stops eating, rapid and irregular respiration, abdominal distension, periods of cyanosis, and pooping loose green stool Baby then turns ashen gray and becomes flaccid and hypothermic Also can occur in adults who OD Death in 40% of cases Prolongs half lives of warfarin, dicumerol, and anti-retroviral protease inhibitors

The Macrolides Erythromycin is natural product, clarithromycin and azithromycin are semi-synthetic derivatives 14 to 15 member lactone ring attached to one or more deoxy sugars Effective against G+ Effective against atypical mycobacteria and some intracellular bugs Bacteristatic, binds ribosomes much like chloramphenicol Resistance – efflux, ribosomal protection, esterases, mutate ribosome

Pharmacology of the Macrolides Administered orally Adsorbed in upper small intestine Gastric acid inactivates drug so pills are coated Food delays adsorption of erythromycin and azithromycin Readilly diffuses in all intracellular fluids except CSF and brain Crosses placenta and enters fetal circulation Secreted in breast milk Excreted by kidney and liver (through bile)

Pharmacology of Select Macrolides Clarithromycin More effective against staph and strep than erythromycin Can be given with food Azithromycin Slightly less effective against G+ but works better than other 2 against Haemophilus influenzae good against atypical mycobacteria Azithromycin

Therapeutic Uses of Macrolides Mycoplasma infections Legionairre’s Disease Chlamydia infections Diphtheria/pertussis Staph/strep GI infections Tetanus AIDs related infections pseudomembrane of diphtheria H. pylori

Toxicity/Contraindications of the Macrolides Epigastric distress with large doses Cholestatic hepatitis (rare) Potentiate the effects of Carbamazepine Corticosteroids Cyclosporine Digoxin Ergot alkaloids Theophylline Triazolam Valproate warfarin

The Streptogramins Two agents combined (Synercid) Derived from pristinamycin Covers G+ cocci Effect on bugs similar to macrolides Only given IV in 5% dextrose in water Wide distribution Mostly hepatic excretion

The Streptogramins Treatment of vancomycin-resistant enterococci, MSSA, and strep infections Toxicity Infusion related pain and phlebitis Potentiates same drugs as macrolides

Clindamycin similar to macrolides in many ways Good against anaeobes Given orally, parenterally, or topically Food does not interfere with absorption Wide distribution excluding CSF Crosses placenta Accumulates in PMN, alveolar macrophages, and pus Excreted by liver and kidneys

Clindamycin Good for anaerobic infections (except brain abscesses) Staph infections (including MRSA) Diarrhea is common side effect Pseudomembranous colitis to toxic megacolon Skin rash Rare side effects – SJS, anaphylaxis toxic megacolon

Linezolid Synthetic agent (an oxazolidinone) G+ coverage only, no anaerobes Prevents assembly of ribosome Oral or IV = 100% absorption Food does not interfere with absorbtion Distributed widely to well perfused tissues Excreted mostly by kidney Treat VR enterococci, MSSA, MRSA Well tolerated, minor gastrointestional complaints

Vancomycin Tricyclic Glycopeptide G+ coverage only Inhibits polymerization of peptidoglycan subunits given IV over an hour or orally for pseudomembranous colitis Wide distribution Secreted by kidneys Treatment of MRSA Red-man syndrome: a complication of too rapid an infusion MRSA

The End? Almost…