- Synthesis of aminoglycoside modifying enzymes - Altered aminoglycoside uptake (loss of porin channel, efflux pump) - Change in binding site at ribosome/target modification

Pharm Unit 3 Flashcards by Emil Bielecki

Aminoglycoside Mechanism of Action

Irreversibly bind and inhibit 30S subunit - block bacterial protein synthesis

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Aminoglycoside MOR

Synthesis of aminoglycoside modifying enzymes
Altered aminoglycoside uptake (loss of porin channel, efflux pump)
Change in binding site at ribosome/target modification

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Gentamicin

Aminoglycoside
Good gram negative activity (enterobacteriaceae) and gram positive activity (synergistic with cell wall agent for S. aureus, S. pyogenes, Veridans strep, Enterococcus)

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Tobramycin

Similar to gentamycin but more active against pseudomonas

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Amikacin

More active against nosocomial gram negative organisms (tobra still more active against pseudomonas)
Has activity against mycobacteria and nocardia

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Streptomycin

Mainly used to treat gram positive infections in combination with cell wall agent
Has activity against mycobacteria

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AGs used to treat gram negatives

Gentamycin, Tobramycin, Amikacin

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AGs used to treat gram positives

Gentamycin, Streptomycin

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AGs used to treat mycobacteria

Amikacin, Streptomcyin

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Aminoglycoside Pharmacokinetics

Administered primarily IV - poor oral absorption
Poor penetration of CNS - high concentration in urine
Concentration-dependent killing - PAE ranges from 0.5 to 7.5 hours
Most are renally eliminated
Extended dosing interval can help reduce ototoxicity (irreversible) and nephrotoxicity (reversible)

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Cephalosporin MOA

Binds PBPs - interfere with bacterial cell wall synthesis (prevent transamination step)
Bactericidal

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Cephalosporin MOR

1) Production of beta lactamase enzymes
2) Alterations in PBPs leading to decreased affinity
3) Alteration of outer membrane leading to decreased penetration to PBPs

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First generation cephalosporins

Best activity against gram positives, good activity against gram negatives (PEK)

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Second generation cephalosporins

More active against gram negative aerobes (HENPEK)

Cephamycins - only cephalosporins to have activity against anaerobes (B. fragilis)

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Third generation cephalosporins

More active against gram negative aerobes (HENPECKSSS)
Ceftriaxone, cefotaxime - best activity against gram positive aerobes, including pen-resistant S. pneumonia
Ceftazidime has pseudomonas activity

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Fourth generation cephalosporins

Even more activity against gram negatives
Includes activity against pseudomonas and beta lactamase producing enterobacter species
Only cefepime currently available

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Fifth generation cephalosporins

Activity against respiratory pathogens (H flu, strep pneumo, Moraxella, staph aureus, MRSA)
Only ceftaroline available

Cephalosporin Pharmacokinetics

Oral forms well absorbed but food decreases absorption
*CSF concentrations only achieved with IV cefuroxime, 3rd and 4th generation cephalosporins
Eliminated by kidneys - adjust dose in RI
Short half life except ceftriaxone (8 hours; all others 2 hours)

Cephalosporin Adverse Effects

Hypersensitivity - cross reactivity with penicillins
Hypoprothrombinemia in agents that have MTT side chain
Ethanol intolerance
Leukopenia and thrombocytopenia
Precipitation of ceftriaxone if given with IV calcium

Carbapenem MOA

Inhibit cell wall synthesis - binds to and inhibits PBP-2; time-dependent killing
*Most broad spectrum of all agents available - has activity against gram positive, gram negative aerobes and anaerobes.

Carbapenem MOR

1) Beta lactamase production
2) Decreased permeability
3) Alterations in PBPs

Carbapenem Spectrum of Activity

Most broad spectrum of activity of all agents available
Imipenem and doripenem - gram positive activity
Doripenem and meropenem - gram negative activity
Ertapenem does not have activity against pseudomonas aeruginosa

Carbapenem Pharmacokinetics

Meropenem has best CSF penetration
All eliminated by kidney - dose adjustment with RI
Imipenem has to be given with cilastatin - DHP inibitor, prevents metabolism

Carbapenem Clinical Uses

Empiric therapy for hospital acquired infections
Polymicrobial infections
Do not use ertapenem when suspecting pseudomonas infection

Carbapenem Adverse Effects

Hypersensitivity - 5-15% cross reactivity with penicillins GI effects Increased risk for seizures

Aztreonam MOA

Inhibits cell wall synthesis by binding and inhibiting PBP3 - only has activity against gram negative aerobes

Aztreonam Pharmacokinetics

Only available IV Penetrates CSF in presence of inflamed meninges Eliminated by kidneys - dose adjustment in RI Used for typical gram negative infections - UTIs, RTIs, meningitis, bacteremia, SSTIs

Aztreonam Adverse Effects

GI Hypersensitivity No cross reactivity with penicillins - can be used in penicillin-allergic patients

Vancomycin MOA

Inhibits bacterial cell wall synthesis by inhibiting D-ala-D-ala; prevents elongation and crosslinking Exhibits time-dependent bactericidal activity

Vancomycin MOR

1) Modification of D-ala-D-ala binding site of PPG | 2) VISA - thickened cell wall

Vancomycin Spectrum of Activity

Effective against intrinsically resistant gram positive organisms - MRSA - MSSA - Strep pneumo, PRSP - C. difficile if given orally

Vancomycin Pharmacokinetics

Time-dependent bactericidal activity IV for systemic infection - orally for C. diff infection Poorly absorbed in GI tract Draw peak 1 hour after infusion, draw trough 30 minutes before infusion Eliminated by kidney - can lead to long half life if RI present; not removed by dialysis

Vancomycin Adverse Effects

Red Man Syndrome - due to histamine release caused by very rapid infusion rates Nephrotoxicity/Ototoxicity - uncommon with vancomycin monotherapy - more common in used in combination Can also lead to rash, neutropenia, thrombocytopenia, interstitial nephritis

Linezolid MOA

Binds 50S subunit - inhibits bacterial protein synthesis (bacteriostatic)

Linezolid Spectrum of Activity

Resistant gram positive organisms | - MRSA, VISA, PRSP, VRE

Linezolid Pharmacokinetics

100% bioavailable, 30% CSF penetration | Eliminated renally and nonrenally - dose adjustment not necessary; removed by dialysis

Linezolid side effects

Serotonin syndrome when used with SSRIs/MAOIs Enhanced pressor effect with adrenergic/serotonergic agents Lactic acidosis Peripheral neuropathy Thrombocytopenia/anemia

Daptomycin MOA

Depolarizes bacterial membrane - leads to decreased protein, DNA, RNA synthesis Exhibits concentration dependent killing

Daptomycin Pharmacokinetics

Only administered IV 90% protein bound Primarily eliminated renally - dose adjustment necessary in RI *Should not be used for treatment of pneumonia*

Daptomycin Adverse Effects

GI Headache Myopathy and CPK elevation