Antimicrobial Therapies Flashcards
Explain aminoglycosides
Gentamicin, streptomycin
Bactecidal. Target protein synthesis 30s ribosomal subunit
So causes lack of proofreading so poor protein production, damage to membrane when inserted
High toxicity so limited use- so increasing use, can cause hearing loss
Describe rifampicin
Bactericidal
Targets RpoB subunit of RNA polymerase so stops transcription
Great activity inside host cells such as neutrophils and macrophages
Spontaneous resistance is frequent
Makes secretions go orange or red
Describe vancomycin
Targets II lipid component of cell wall biosynthesis as well as cross- linking via D- ala residues
Toxicity limited use so increasing use to MRSA
Give it to the methicillin resistant staphylococcus aureus bacteria
Describe Linezolid
Bacteriostatic
Inhibits the initiation of protein synthesis by binding to 50s rRNA subunit
Gram positive spectrum of activity
New
Not affect gram negative as it hasnLPS on the membrane
Describe Draptomycin
Bactericidal
Targets bacteria cell membrane
Only Gram positive because it can’t target the LPS in the membrane
Toxic so limits dose and needs to be given IV to patients only
Describe Beta lactams
Interfere with synthesis of the peptidoglycan component of the bacterial cell wall
Penicillin Methicillin
Binds to penicillin binding proteins
Inhibits wall biosynthesis and leads to bacterial killing
What are some things that the antimicrobials can affect
- inhibition of cell wall synthesis penicillin, cephalosporins, bacltracin, vancomycin
- inhibition of protein synthesis chloramphenicol, erythromycin, tetracyclines, streptomycin
- inhibition of nucleic acid and replication and transcription quinolones, rifampin
- injury to plasma membrane, polymycin B
- inhibition of synthesis of essential metabolites sulfanilamide, trimethoprim
Selective toxicity
Protein synthesis tends to be a bit different so peptidoglycan production and LPS layer of gram negative bacteria
Explain macrolides
Erythromycin azithromycin
Gram positive and some gram negative infections targeted by azithomycin
Targets 50s ribosomal subunits preventing amino acrylic transfer and thus truncation of polypeptides
Describe quinolones
Synthetic broad spectrum
Target DNA grease in gram negative and topoisomerase IV in gram positive
DNA damage and death of the organism
Gonocococal infections and lung and bloodstream
What do we mean by resistance
Above the breakpoint ( clinically- achievable concentration)
The scale goes sensitive intermediate resistant
Minimal inhibitory concentration MIC
Lowest concentration of AB required to inhibit growth
MIC links to the break point
Explain antibiotic resistance
Population contains cells with AB resistance due to mutation and acquired. DNA probably with a fitness cost
Presence of selection pressure -resistant mutants out complete
( in absence of selection pressure the resistance strains have no advantage)
4 ways antibiotic resistance
Altered target site
Inactivation of antibiotic
Altered metabolism
Decreased drug accumulation
What is altered target site?
Alternative gene or a gene that encodes a target modifying enzyme
MRSA - encodes an alternative PBP (PBP2a) with low affinity for beta lactams
Streptococcus pneumoniae -resistance accur via acquisition of erm gene which encodes an enzyme that methylates the AB target site in the 50s ribosomal subunit
Explain inactivation of antibiotic
Enzymatic degradation or alteration, rendering antibiotic ineffective
Beta- lactamase( breaks bond in the beta lactam ring of penicillin to disable the molecule, bacteria with this enzyme can resist the effects of penicillin and other beta lactam antibiotics) chloramphenicol acetyl - transferase cat
ESBL and NDML-1 examples of broad spectrum beta - lactamases
Explain altered metabolism
Increased production of enzyme substrate can outcompete antibiotic inhibitor
(Increased production of PABA confers resistance to sulfonamides)
Alternatively bacteria switch to other metabolic pathways, reducing the requirement of PAB
Explain decreased drug accumulation
Reduce penetration of antibiotic increased influx of antibiotic out of the cell drug does not reach concentration to be affective
What are the sources of antibiotic resistance
Plasmids - extra chromosomal circular DNA - often multiple copy
Transposons - integrate into chromosomal DNA, allow transfer from genes to plasmid and to chromosome and vice versa
Naked DNA - dna from dead bacteria released to environment
How can DNA be shared
Transformation - uptake of extra cellular DNA
Conjugation - pilus mediated DNA transfer
Transduction- phage mediated DNA transfer
What are some none genetic mechanism of resistance
Biofilm - matrix in cased communities of bacteria that are highly drug tolerant
Intracellular location - stay within cells so hard to access
Slow growth - not many processes to replicate so antibiotic can’t inhibit them eg tuberculosis
Spores - resistant to antibiotics, antiseptics and heat
Persister - dormant organisms, not using processes so not inhibited or killed
Other reasons for treatment failure
Innaproptpriate choice of organism
Poor penetration of AB into target site
Innapropriate half life
Inappropriate administration (oral vs IV)
Presence of AB resistance within comensal flora eg secretion of beta lactamase
Why do hospitals provide a strong selective pressure for antibiotic resistance
Large number of infected people receiving high doses of antibiotics
Strong selective pressure for emergence/ maintenance of AB resistance
State 8 HAIs
MRSA VISA - vancomycin insensitive S. aureus C. Difíciles Vancomycin resistant enterococci VRE E. Coli - ESBL, NDM-1 P. Aeruginosa Afineterbacter baumannii Stenotrophomonas maltophilia
Risk factors for HAIs
Immunosuppression
Crowded wards
Presence of pathogens
Broken skin
In dwelling devices - intubation
AB therapy supress normal flora - gut health
Transmission by staff - contact with multiple patients
Ways to prevent emergence of drug resistant bacteria and nosocomial infections
Prescribing strategies
Reduce use of broad spectrum antibiotics
Quicker ID of infections caused by resistant strains
Combo therapy - 2 or more
Knowledge of local strains/ resistance patterns
How to overcome resistance? 2
Modificati of existing medication - prevent cleavage of beta lactams and enhance efficacy
Combination of antibiotic and inhibitor - beta lactamase
