Antibiotics - General Concepts & Classifications Flashcards
Mechanisms of antibiotic selective toxicity
Inhibition of a metabolic pathway found in bacteria but not humans - i.e. folate metabolism
Same pathway but differences in enzyme structure - i.e. bacterial vs. eukaryotic ribosome, bacterial gyrase vs. eukaryotic topoisomerase
Macromolecule that does not exist in humans - i.e. cell wall synthesis
Macromolecule differs between microbes and humans - i.e. fungal cell membrane
Natural (intrinsic) resistance
Microbes lack a susceptible target for drug action and thus are resistant to one or more class of antibiotics
Ex.
E. coli is resistant to penicillin because penicillin does not fit through the pores in the OM of E. coli; E. coli is susceptible to amoxicillin because its more hydrophilic
Mycoplasm is resistant to B-lactams because it has no cell wall
Antibiotic tolerance / escape resistance
Microbes are sensitive to antibiotics and the drug is able to reach its target BUT the organisms can resist killing by other adaptive mechanisms, including
Growth in biofilms
Metabolic bypass
Anaerobic growth
Stationary phase
Mechanisms of bacterial resistance to antibiotics (5)
- Altered target to which antibiotic cannot bind
Ex: DNA gyrase mutations causing fluoroquinolone resistance, PBP mutations causing B-lactam resistance - Enzymatic degradation of antibiotic
Ex: B-lactamase degradation of penicillins and cephalosporins - Increased antibiotic efflux
- Decreased antibiotic influx
Porin channel mutations - Alternative resistant metabolic pathway
Bactericidal Mechanisms of antibacterial action
Organisms are killed by the antibiotic:
Inhibition of cell wall synthesis
Disruption of cell membrane function
Interference with DNA function or synthesis
Bacteriostatic Mechanisms of antibacterial action
Organisms are prevented from growing:
Inhibition of protein synthesis
Inhibition of intermediary metabolic pathways
Which antibiotics readily enter the CSF?
Chloramphenicol
Sulfonamides
Cephalosporins (3rd/4th)
Rifampin
Which antibiotics enter the CSF with inflammation?
Penicillins
Vancomycin
Ciprofloxacin
Tetracycline
Which antibiotics enter the CSF poorly?
Aminoglycosides
Cephalosporins (1st/2nd)
Erythromycin
Clindamycin
Examples of beneficial selective distribution of antibiotics (4)
Clindamycin - into bone (osteomyelitis)
Macrolides - into pulmonary cells (URIs)
Tetracyclines - into gingival fluid (periodontitis) and sebum (acne)
Nitrofurantoin - rapidly excreted into urine (UTIs)
Examples of toxic selective accumulation of antibiotics
Aminoglycides - into the inner ear (ototoxicity) and renal brush border (nephrotoxicity)
Tetracyclines - into Ca2+ in developing bone (abnormal bone growth) and teeth (tooth discoloration)
Mechanisms of antibiotic toxicity
- Direct Toxicity, due to lack of selective toxocity - usually GI irritation, hepatotoxicity, nephrotoxicity, neurotoxicity
- Indirect toxicity - hypersensitivity, DDIs via alterations in CYP450 metabolic activity
- Disturbances of host microflora - superinfection, ex: pseudomembranous colitis due to C. dif overgrowth
- Host factors - very old, very young, pregnant/nursing mothers, drug allergies
Penicillins - 6 Classes + Representative Drugs
MOA: Cell wall synthesis inhibition, stage 3 - inhibits cross-linking of peptidoglycan polymers at the cell wall; bactericidal
Prototype: Penicillin G
Acid Stable: Penicillin V
Penicillinase-resistant: Dicloxacillin
Extended Spectrum: Amoxicillin, ampicillin
Anti-Pseudomonal: Piperacillin-Tazobactam
Penicillin plus Beta-lactamase inhibitor: Clavulanic Acid
Cephalosporins
MOA: Cell wall synthesis inhibition, stage 3 - inhibits cross-linking of peptidoglycan polymers at the cell wall; bactericidal
1st: Cephalexin, Cefazolin
2nd: Cefuroxime
3rd: Ceftriaxone
4th & 5th
Vancomycin
MOA: Cell wall synthesis inhibitor, stage 2 (inhibits linear polymerization of cell wall sub units); bactericidal
Macrolides
MOA: Reversibly binds bacterial ribosome, inhibiting protein synthesis; bacteriostatic
Azithromycin
Tetracyclines
MOA: Reversibly binds bacterial ribosome, inhibiting protein synthesis; bacteriostatic
Doxycycline
Minocycline
Lincomycins
MOA: Reversibly binds bacterial ribosome, inhibiting protein synthesis; bacteriostatic
Clindamycin
Aminoglycosides
MOA: Irreversibly binds bacterial ribosome, inhibiting protein synthesis; bacteriocidal
Chloramphenicol
MOA: Reversibly binds bacterial ribosome, inhibiting protein synthesis; bacteriostatic
Fluoroquinolones
Inhibition of DNA gyrase; bactericidal
Ciprofloxacin
Levofloxacin
Moxifloxacin
Nitrofurantoin
Interference with bacterial DNA; bactericidal
Metronidazole
Interference with bacterial DNA; bactericidal
Drug classes eliminated by renal excretion
Requires dose adjustments in patients with renal impairment; renal function monitored by serum creatine (SCr) and creatinine clearance (CrCl)
Penicillins Cephalosporins Vancomycin Aminoglycosides Fluoroquinolones
Drug classes eliminated by non-renal mechanisms
Generally metabolised in the liver; must consider DDIs and interpatient differences based on genetic polymorphisms
Doxycycline - non renally eliminated tetracycline
Quinolones - Ciprofloxacin is renally eliminated but is a non-substrate inhibitor of P450
Clindamycin - non renally eliminated
Rifampin - inducer of CYP450, potential for hepatotoxicity
Isoniazid - metabolism effected by genetic polymorphism of NAT; potential hepatotoxicity
Metronidazole - DDI with alcohol due to inhibition of aldehyde metabolism (Antabuse reaction)
Erythromycin - DDI due to inhibition of P450
Cell wall synthesis inhibition - 3 stages
- Synthesis and assembly of cell wall subunits in the cytoplasm
- Linear polymerization of subunits at the cell membrane
- Cross-linking of peptidoglycan polymers at the cell wall
Concentration-dependent killing
Kill bacteria faster in higher doses that result in high initial Cp levels - can be dosed less frequently
Aminoglycosides
Fluoroquinolones
Time-dependent killing
Kill bacteria best when Cp is above MIC for longer durations
Beta-lactams
Vancomycin
Macrolides
Post antibiotic effect
Antibiotics that continue action after Cp < MIC - allows less frequent dosing than predicted by their half lives
Aminoglycosides
Fluoroquinolones
Macrolides
Beta Lactams
What is an antibiogram?
A locally published, yearly summary susceptibility report for common pathogens and the percent of strains susceptible to different antimicrobials
Tube Dilution Susceptibility Testing
A standardized number of organisms are added to serial dilutions of antibiotic in liquid medium and incubated; the tube with the lowest concentration of antibiotic that has no visible bacterial growth is the MIC
Disk Diffusion (Kirby-Bauer)
A suspension of the test pathogen is spread onto an agar plate; disks impregnated with defined concentrations of different antibiotics are placed onto the surface of the agar; after incubation, the diameter of the zone of inhibition around each disk is proportional to the sensitivity of the organism to that antibiotic and can be referenced by various charts and related to the MIC
E test
A variation of the Kirby-Bauser (Disk Diffusion) approach; a strip is impregnated along its length with a gradient of concentrations of an antibiotic and placed onto an agar plate spread with a suspension of the test pathogen; after incubation, an ellipse-shaped area of no growth occurs and the point at which the ellipse contacts the strip is the MIC, read directly off of the strip
Minimum Inhibitory Concentration
MIC is the lowest concentration of an antimicrobial agent that will inhibit the visible growth of a standardized number of micro-organisms after overnight incubation
Minimum Bacteriocidal Concentration
MBC is the lowest concentration of an antimicrobial agent that will kill 99.9% of a standardized number of micro-organisms in a given amount of time
After overnight incubation and determination of MIC, a sample from each tube is plated on growth medium; the concentration of antibiotic that killed 99.9% of organisms (10 colonies or fewer) is the MBC
How do MBC and MIC relate to the designation of an anti-microbial as bacteriostatic or bacteriocidal?
If MBC / MIC > 4 the agent is bacteriostatic
If MBC / MIC < 4 the agent is bacteriocidal
Porins
Form hydrophilic channels in the outer membrane of gram negative bacteria only, allowing selective uptake of essential nutrients and other compounds, including some hydrophilic antibiotics
Efflux pumps
Located in the bacterial cell membranes of gram positive and gram negative organisms; pumps may be specific for one drug or may work on many drugs
