Aminoglycosides and Tetracyclines

Tetracyclines Mechanism

- Broad spectrum - baceriostatic - inhibit protein synthesis by binding REVERSIBLY to R's of the 30 S subunit -> blocks binding of aminozcyl tRNA and prevents addition of new AA -> protein synth inhibited

Miscellaneous Drugs

- Chloramphenicol

Tetracycline Side effects

- GI upset -> take with food - photosensitivity - brown discoloration of teeth - slow growth of child bones

Aminoglycoside uses

- Gentamicin: topical for burns, wounds, catheter infecitons, opthalmic - Tobramycin: similar to gentamicin, ophthalmic available - Amikacin (generic): nosocomial infections resistant to gentamicin and tobramycin -x-streptomycin (generic) - x-kanamycin

Non-antibiotic effects

- Immunomodulatory and antiinflammatory activity -> inhibits lipoxygenase pathway - blocks synth. of NO and activaiton of microglia neuronal damage - improves stroke outcome -> neuroprotective

Other Adverse effects

- Neuromuscular block -> resp. paralysis - mechanism: block Ca uptake into nerve terminal -> DEC ACh release *block postsynaptic ACh R - Tx side effects with: 1) IV Ca 2) Neostigmine 3) AChEI 4) Avoid with myasthenia gravis

Mupirocin

- Ointment and cream - inhibits bacterial isoleucyl t-RNA synthetase -Used for impetigo from group A Strep or S. aureus (high resistance)

Aminoglycoside structural similarities

- all contain a unique aminocyclitol ring structure

Quinupristin/Dalfopristin (Synercid): Side effects

- arthralgias/myalgias (30-40%) - risk of superinfection and colitis - hyperbilirubinemia (25%) - severe venous irritation

Fanconi syndrome

- expired Tetracyclines form a nephrotoxin - disorder of kidney tubes -> substances are released to urine when they shouldnt be

Tigecycline

- for pt's over 18 yo - structurally similar to Tetracyclines, similar side effects, similar MOA - Tetracycline- sensitive G+/G- microbes and MRSA - INC risk of mortality if pt has hospital acquired pneumonia - Reduce dose with severe hepatic impairment

Aminoglycoside Absorption

- good or fair for all routes except ORAL - accumulate in EC space and KIDNEY - freely excreted in the kidney, unchanged

Clarithromycin and Azithromycin immunomodulatory activity

- inhibit mRNA transcription for proinflammatory cytokines - resp. infeciton + inflammation there is significant benefit with these drugs - effects similar to corticosteroids with regard to extent of inflammatory response

Erythromycin Adverse efffects

- inhibits CYP3A4 -> creating heme metabolite complexes - prolongs repolarization extending Q-T interval (torsades de pointes) effects on K+ channel

Chloramphenicol mechanism

- inhibits binding of aminoacyl-tRNA to acceptor side (tetracycline mechanism)

Rifaximin (Xifaxan)

- no significant systemic absorption Mechanism: binds DNA-dependent RNA polymerase Uses: travelers diarrhea

Colistimethate

- polypeptide suitable for intramuscular or IV -> G- rods - cidal cationic detergent - Nephrotoxic & possibly neurotoxic

Resistance

- produced primarily by enzymes from plasmid genes - act inside bacteria to modify Aminoglycoside -> prevent ribosome binding - Reduce efficacy of Aminoglycoside: * some strains less permeable - chromosomal resistance is minimal and develops slowly *EXCEPTION: streptomycin -> resistance can occur in a singe-step mutation

Aminoglycoside Mechanism

- uptake is through porin channel and down electrochemical gradient - once bound: 1) inhibit initiation 2) cause misreading of mRNA -> faulty proteins 3)premature termination - post antibiotic effect

Aminoglycoside Mode of action

-Bind to 30S subunit of 70S ribosome - bind to rRNA enabling the binding of incorrect tRNAs to the mRNA

LINEZOLID (Zyvox)

-Drug Class: oxazolidinones -Uses: Vancomycin-resistant E. faecium, MSSA & MRSA skin infections - static or cidal - Oral and IV - Risk of colitis and thrombocytopenia

Rifampin: Adverse effects

-Hepatotoxicity -> pt's recieve LFTs -Rifampicin is an inducer of hepatic cytochrome P450 enzymes (such as CYP2D6 and CYP3A4) and will increase the metabolism of a many drugs that are cleared by the liver through this enzyme system. This results in numerous drug interactions such as reduced efficacy of the oral contraceptive pill

Quinupristin/Dalfopristin (Synercid)

-IV for MRSA and voncomycin resistant infections

NITROFURANTOIN

-Mechanism: reduced by urinary bacteria to reactive intermediates that damage DNA, ribosomes and cell wall -Treatment & prevention of G+/G- UTIs -Poor systemic levels - local action in tubules

Oral Aminoglycoside

-Neomycin: prep for bowel surgery -Paromomycin: kills cysts of E. histolytica - BOTH poorly absorbed by oral admin.

Adverse effects

-Ototoxicity (auditory and vestibular) *Auditory: Tinnitus *Vestibular: vertigo, ataxia, loss of balance * accumulate in fetus -Nephrotoxicity

Rifampin

-Penetrates tissues and biofilm - most G+ & many G-; staph & MRSA; intracellular & extracellular organisms - Mechanism: inhibits DNA-dependent RNA polymerase -Excreted through bile - enterohepatic recirculation

Erythromycin Non-antibiotic effect

-Prokinetic: motilin R agonist * investigated for use to INC GI motility - used post-op to stimulate peristalisis

Quinupristin/Dalfopristin (Synercid): Mechanisms

-Quinupristin releases peptidyl-tRNA from donor site -Dalfopristin inhibits binding of aminoacyl-tRNA to acceptor site & of peptidyl-tRNA to donor site - caution: : Inhibits CYP3A so drug interactions are possible

Rifampin considerations

-Rifampin should always be used in combination with another antibiotic because when rifampin is used alone, the bacteria are rapidly able to develop resistance. - can be cidal or static - causes body fluids to turn red

NITROFURANTOIN: Side effects

-Side effects: Acute & chronic pulmonary reactions - treatment must be discontinued immediately -Acute side effects include fever, chills, cough, infiltrates, malaise, DOE, altered PFTs, pneumonitis, fibrosis -Chronic side effects include brown urine

Azithromycin

-concentrates intracellularly - community acquired pneumonia, legionnaires -MAC - T 1/2 = 70 hrs - does not inhibit P450 singe dose -shows similar efficacy as amoxicillin for Tx of AOM

Rifampin: Mechanism

-inhibits DNA-dependent RNA polymerase in bacterial cells by binding its β-subunit, thus preventing transcription of messenger RNA (mRNA) and subsequent translation to proteins. - Rifampin appears to penetrate the outer membrane of gram-positive bacteria more easily than that of gram-negative bacteria

Chloramphenicol toxicity

-inhibtes human mito. peptidyl-transferase - Erythropoietic cells most sensitive -> inhibition of G6PD predisposes to hemolytic anemia - inhibits cytochrome P450 -GRAY BABY SYNDROME *cant conjugate, underdevelopled renal function -> cant eliminate

Macrolide Resistance

-post transcriptional methylation of 23S ribosomal RNA -> alters the ribosome R site - RF can be either plasmid mediated or chromosomal - can result in cross resistance to macrolides, lincosamides, and streptogramins (MLS) - MLS phenotype appears in all strep. species isolated from man

Mechanism of Action

-sterically block translation by ribosme, WITHOUT blocking the 50S subunit. - ribosome can still produce a short peptide chain before tranlation is terminated - good activity against G+ - some actibity against G - and MSSA

Bug primarily treated by Aminoglycoside

-utilized primarily in the Tx of aerobic gram - organisms - NOT ACTIVE against anaerobic -> less uptake - can be effective against some gram + organisms - MOSTLY USED FOR G - - used with B-lactams for synergism -> INC penetration of Aminoglycoside * B-lactams inhibit cell wall synth. and INC permeability for Aminoglycoside

Mechanisms of Resistance

1) Aminoglycoside midifying enzyems (AME) render Aminoglycoside incapable of binding to the Ribosomal subunit 2) DEC cell memb. permeability limiting Aminoglycoside uptake into the cell 3) Structural alteration in the ribosomal target, hindering the attachment of the drug to site of action 4) Extrusion of drug by efflux pumps

Explain the bactericidal activity of thses drugs.

1) Disruption of the decoding function of 30S ribosomal subunit 2) Davis model for conc. depedent effects

Aminoglycoside Antibiotics

Bactericidal -enter susceptible bacteria by oxygen-dependent active transport and by passive diffusion - most anaerobes are impervious

Aminoglycoside Dosing

COCKCROFT-GAULT method - dose adjustments made for renal function based on serum creatinine levels

Lincosamides

Clindamycin Mechanism: inhibit protein synthesis -> binding to 50S ribosomal subunits -> preventing peptide bond formation. - bacteriostatic -> bactericidal

Clarithromycin

Community aquired pneumonia - MAC - Can lower blood sugar - inhibits CYP3A

Polymyxin B

Gram - microbes - Nephrotoxic & neurotoxic (neuromuscular block) - Mechanism: cidal cationic detergent disrupts cell membrane through binding to LPS -> blebbing with Tx - Resistance: from changes in LPS structure

Chloramphenicol

IV for aerobic/anaerobic G+/G- microbes -serious and fatal blood dyscrasias -> limit to serious resistant infections - Chloramphenicol eye drops effective against MRSA

Clindamycin

Inhibites translocation -Oral / IV / topical for acne / suppository for bacterial vaginosis -Penetrates tissues well (except CNS) -Risk of pseudomembranous colitis -Immunomodulatory activity -Used with high dose penicillin for group A strep

ophthalmic ointment

Polymyxin B + bacitracin

LINEZOLID (Zyvox): Side effects

Seritonin Syndrome 1) not an idiopathic D rxn. Consequence of excess serotonergic agonism 2) spectrum of clinical findings, nothing to lethal

Ketolide

Telithromycin: - INC G+ activity with activity against macrolide resistant strains due to additional ribosomal binding sites - concentrates in pulmonary tissues and WBC's - community acquired resp. infections - Active vs. B-lactam and macrolide resistant microbes - Inhibits CYP3A4, prolongs QT -hepatotoxic

Retapamulin

Topical ointment -A pleuromutilin for impetigo -blocks acceptor & donor sites of peptidyl transferase

Erythromycin pharmacology

high absorption with wide distribution with hepatic clearance and enerohepatic cycling

LINEZOLID (Zyvox): Mechanism

inhibits formation of initiation complex

Daptomycin (Cubicin)

parenteral mechanism: creates pores in membrane resulting in loss of potassium/depolarization/inhibits DNA,RNA and protein synthesis -Not for pneumonia - inactivated by surfactant

Neosporin

polymyxin B + gramicidin + neomycin

Erythromycin

similar in spectrum to the PCNs. - better activity against atypical organisms than the PNCs i.e mycoplasma and legionella

Macrolide Antibiotics

specific attack on the 50S ribosome of bacteria with mammalian ribosomes left unaffected

Intermediate acting Tetracyclines

t 1/2 12 hrs - Demeclocycline: pneumonia and resp. tract infecitons, acne, skin, genetial and urinary systems

Long acting Tetracyclines

t 1/2 16-18 hrs - Doxycycline - minocycline

Short Acting Tetracyclines

t 1/2 6-8 hrs - Tetracycline (sumycin): alternate oral or topical for acne and skin infections - Oxytetracycline: ophthalmic