Aminoglycoside Mechanism of Action
Irreversibly bind and inhibit 30S subunit - block bacterial protein synthesis
Aminoglycoside MOR
- Synthesis of aminoglycoside modifying enzymes
- Altered aminoglycoside uptake (loss of porin channel, efflux pump)
- Change in binding site at ribosome/target modification
Gentamicin
Aminoglycoside
Good gram negative activity (enterobacteriaceae) and gram positive activity (synergistic with cell wall agent for S. aureus, S. pyogenes, Veridans strep, Enterococcus)
Tobramycin
Similar to gentamycin but more active against pseudomonas
Amikacin
More active against nosocomial gram negative organisms (tobra still more active against pseudomonas)
Has activity against mycobacteria and nocardia
Streptomycin
Mainly used to treat gram positive infections in combination with cell wall agent
Has activity against mycobacteria
AGs used to treat gram negatives
Gentamycin, Tobramycin, Amikacin
AGs used to treat gram positives
Gentamycin, Streptomycin
AGs used to treat mycobacteria
Amikacin, Streptomcyin
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)
Cephalosporin MOA
Binds PBPs - interfere with bacterial cell wall synthesis (prevent transamination step)
Bactericidal
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
First generation cephalosporins
Best activity against gram positives, good activity against gram negatives (PEK)
Second generation cephalosporins
More active against gram negative aerobes (HENPEK)
Cephamycins - only cephalosporins to have activity against anaerobes (B. fragilis)
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
Fourth generation cephalosporins
Even more activity against gram negatives
Includes activity against pseudomonas and beta lactamase producing enterobacter species
Only cefepime currently available
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