Unit 06: antibacterial drug therapy and beta lactams Flashcards
explain the gram reaction
gram positive stain purple
gram negative counterstained red
- fix cells, add crystal violet, idoine treatment which bidns to crystal violet and traps in cells, add alcohol then counterstain with safranin
describe the gram negative bacteria
have an outer membrane, asymmetirc bilayer in which the outer leadlet is comprised of lipopolysaccharide
- structurally unusual membrane forms a permeability barrier that excludes wide bariety of mol and limits penetraiton of gram stain
- the murein layer is thinner and is surrounded by a second, outer lipid bilayer membrane.
Hydrophilic molecules cross this outer membrane through channels, which are formed by a cylindrical arrangement of pore proteins (porins).
have lipopolysaccharide (LPS) in the outer membrane- major antigen for the immune response to Gram-negative organisms.
describe gram positive bacteria
- have a thick peptidoglycan (murein) layer whereas gram negative only have a thin layer
- thick later allows nutrients, waste producst and antibiotics to difuse
- lipoteichoic acids in outer leaflet of membrane intercalate through the cell wall to the outer surface - inolved in cell adherance, feeding and envasion of host immune system
- peptidoglycan consists of sugars (polysaccharides) and amino acids (polypeptide) that are cross linked to form the outside of the PM
- since gram stain binds to peptidoglycan- thck layer makes it stain purple
what are the steps in anybacterial drug susceptibility testing
- determine the MIC - lowest conc of drug that inhibits vidible growth
- determine the MBC- minimum bactericidal conc, lowest conc reuqired to kill a particular bacterium
*determine by taking dilutions of the MIC and sub-culturing onto ati-bacterial free media, then test tubes for growth.
*even though may not be growth bacteria may still be alive
MIC/MBC testing is $$$ what is usually done instead
- Kirby-Bauer disk diffusion test
- paper disks are impregnated with drug and palced on a plate with uniform “lawn” of bacteria
- drug idffuses into the agar and the zone of inhibition around each disk is measured after a specific time
- zone diameter is copmared to a standard regression curve that correlates this with MIC (Ug/mL) - bacterial isolate is reported as sensitive, intermediate or resistant to drug
is bacterial resistant all or none?
- resistance to any drug is not an all or none charcateristic
- each infection contains a mix of bacteria of different sensitivities and therapy may leave the most resistant strains to grow
- different strains of the same abcterium from different patients may also difer in sensitivity even in same geographic area
what are the 5 steps to selecting and administering antimicrobial drugs?
- if possible identify the organism
- initiate treatment immediately
. select a drug
- determine dosage
- assess drug safety
describe step 1 of selecting/administering antimicrobial drugs - identiy the organism
- accomplished through Gram or other stains, using the literature or previous experience with a similar organism.
- Culture and sensitivity testing should also be performed for most life threatening infections or when a non-critical infection is resistant to empirical therapy.
describe step 2 of selecting/administering antimicrobial drugs - initiate treatment
- want to do immediately
- delay may lead to other infections like meningitis or septic arthritis (v dangerous)
- treatment can begin while you are wating on results of the culture and sensitivity teating
*at this point treatment is essentially an educated guess
describe step 3 of selecting/administering antimicrobial drugs - select a drug
- based on bacterial sensitivity and preferable you should use narrow spectrum drugs to avoid killing comensal bacteria
- need to determine if ebst to prescribe a bacteriostatic (stops bacteria from reproducing) or bactericidal (kills the bacteria)
- bactericidal drugs are often used if the immune system is compromised or infection is life threatening
- also consider safety, adverse effects, drug dsitribution (CNS and prostate are difficult tissues for drug to enter) and the cost to patient
describe step 4 of selecting/administering antimicrobial drugs - determine dosage
- usualy done by commerical government labs
- label recommendations or consultation with a reference text is advised
- dose can be adjusted according to patients needs
describe step 5 of selecting/administering antimicrobial drugs - safety
imp to consider when need for drug is not critical
what disease processes require special consideration and basic principles cannot be applied
osteomyelitis, foreign bodies, abcesses, intracellular pathogens and immunodeficiency
why does osteomyelitis reuqire special consideraition before antibiotic prescription
- type of infection and inflammation of the bone or bone marrow
- in chronic osteomyelitis patients, antibitic therapy is unually prolonged compared to toher infections -lasting 6-12 weeks
despite this recurrence of infection is common
why do foreign bodies reuqire special consideraition before antibiotic prescription
- foreign bodies like quils, slivers, nails or plant awns always come with risk of subsequent bacterial infection
- the foreign material must first be removed and then prophylactic antimicrobials are administered (generally broad spectrum) before any signs of infection appear
why do abscesses reuqire special consideraition before antibiotic prescription
- abcess is a collection of pus (neutrophils) that has accumulated in tissue as a response to ifnection agent
- before treatment can be administered, abscess needs to be drained
- in some cases dont need antimicrobial after
why do intracellular pathogen reuqire special consideraition before antibiotic prescription
- mycobacteria, salmonella and legionells surive inside cells therefore it is necessary to use a drug that enter cells readily
why do immunodeficiencies reuqire special consideraition before antibiotic prescription
- deficient host defences sucha s those that are the result of infectious disease, stres,autoimmune or inherited diseases and idopathic immunodeficiency may reuqire drug conc that are much higher than normal
describe prophylactic treatment usign antimicrobials
- refers to use of pharmacologic agents fr prevention rather than treatment
- used in situations where there is high risk of serious infection following trauma like meningitis and/or when a patients condition predisposes them to more serious infection like UTI
- risk period must be known and covered in order for this treatment to be successful
- ex prophylactic therapy could be used following radiation therapy in some cases where the individuals immune system may be compromised as the benefits during period outweigh risks adn ride effects
prophylactic treatment during surgical situations
- microbes could enter body during procedure
- includes the opening of any portion of GI tract or major abdominal or thoracic organ (gut resection, hysterectomy, C-section, cardiac surgery), opening a joint, major proedures of head/neck or placement of prosthesis
appropriate antimicrobal drug selection for prophylactic sue requires knowledge on
General spectrum of activity
Major adverse effects
Distribution/elimination
First line, second line, or emergency classification
Cost
Possible routes of administration
what are the 6 main categories of antimicobial drugs
beta-lactams, aminoglycosides, tetracyclines, sulfonamides, fluoroquinolones, and macrolides.
what are the 5 main sites of action for antimicrobial drugs
Inhibition of cell wall assembly
Damage to cell membrane
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Damage to DNA
what are the 3 general groups of antibacterial drugs
those that inhibit eznymes in DNA synthesis and integrity
- those targeting transcription and translation to inhibit bacterial processes that meidate RNA and protien synthesis
- those that inhibit steps in bacterial cell wall synthesis
what is a beta lactam
- common systemic antimicrobial agent that is very safe and effective
- only works for actively growing bacteria
- contain a four membered lactam (cyclic amide) which confers antibacterial activivty but sensitive to destruction by bacteria expressing beta-lactamases
what are commonly prescribed beta lactams
- penicillins and cephalosporins
how are bacteria resistant to B lactams
- able to cleave the B lactam bond reuqired for antibiotic action
- B lactamase inhibiots like clavulanic acid and sulbactam act as decoys by binding to (inhibiting) B-lactamase enzymes
*structural similarity between B lactamase inhibitos and the B lactam antibioitcs
what is clavulanic acid
act as decoys by binding to (and thereby inhibiting) β-lactamase enzymes.
what is sulbactam
act as decoys by binding to (and thereby inhibiting) β-lactamase enzymes.
what is the mechanism of action for beta lactams
- inhibition of cell wall synthesis
- bacterial cell wall is made up of cross linked peptidogylcans
- enzyme bacterial transpeptidase catalyzes the cross linking of sugars with the amino acids to form the outer layer of the cell wall
*beta lactams inhibit cell wall synthesis by inactivating bacterial transpeptidase which results in a defective cell wall and ultimately cell lysis
how do penicillins work
- bind covalently to bacterial transpeptidase and result in the destruction of enzyme
- inhibits cell call synthesis
what is penicillin G
- narrow spectrum of activity but highly effective
- penicillin G is used to treat serious infections with Gram positive bacteria (rod and cocci) as well as some anaeobes
- not very stable in acidic conditions so reuqired to injection rather than oral admin
what is penicillin V
Gastric acid stable counterpart
Can be taken oraly but less effective
what penicillians are resistant to penicillinase
- dicloxacilin, oxacilin and cloxacilin
- have little activity against baceria other than gram positive bacteria
- stable in acidic environments
what is dicloxacilin used to treat
stubborn S. aureus infections which are resistant to most penicillins
what is amoxicillin
penicillin with borad spectrum of action
- target gram positive aerobes, anerobes and several important gram neg pathogens
- high bioavailability comparied to other penicillins (~80%)
- much more effective in combination with penicillinase inhibitors like clavulanic acid
pharmacokinetics of beta lactams
- distribution involes most tissues except for the CNS and prostate (unless they are inflammed)
- elimination of agent occurs via urine excretion
- 10% filtered while other 90% is actively secreted into the tubules
- half life of penicillines might increase as much as 20 fold in cases of renal failed
resistnace to beta lactams
- poor to no penetration of beta lactam complex in gram negatie cell walls, making most penicillins ineffective against gram neg bacteria
- bacteria can acquire bacterial penicillinases during growth- plasmid encoded and can be transferred to other bacteria
- altered penicillin binding protein (such as those in staph infections) can reduce the binding affinity of penicillin for transpeptidase
adverse effects of penicillins
- hypersensitivity reactions - mild allergy to anaphylactic rxn (rare)
- various subgroups of penicillins thet are all corss sensitixing - approx 5% of all humans have reported haivng a penicillin allergy at some point
- non allergic skin rashed have been reported with amoxicillin
- seizures may occur following admin of b lactams bc they lower seizure threshhold
- avoid high doses in patients with renal disease or epileptic episodes
- certain animals can experience colitis which can cause diarrhea and be life threatening
what are cephalosporins?
- v similar to penicillins in terms of mechanisms, distribution, elimination and fact they cause hypersensitivity reactions
**cephalosporinsa re not susceptible to penicillinases
- 5-10% of humans with a penicillin allergy are also allergic to cephalosporins, and should thus these should also be avoided to be safe.
describe spectrum of actiivty of cephalosporins
classified by “generations”, indicating changes and/or improvements to their structure and activity since the first cephalosporin was discovered in 1945.
- first genertion v similar to amoxicillin
- used to treat gram postive aerobes, anerobes and some medically ipmortnat gram neg aerobes like E.coli
cephalexin is common ex of first gen
Cefuroxime
Second gen
Also used against anerobes
Most second gen drugs are more effective against gram neg bacteria than first gen
cefotaxime
- example of third gen
- greater affinity for gram negative aerobes
- can cross BBB in CNS readily so use to treat meningitis (specific to cefotaxime)
fourth generation cephalosporins
reserved for life threatening infections
- rapidly penetrate through the outer memrbane of gram negatie bacteria enhancing their activity
- aslo active against B lactamase producing bacteria which amy inactivate third gen cephalosporins
