34 Attacking the enemy: antibiotics Flashcards
Interaction between host, microbial pathogen, and antimicrobial agent can be considered as a triangle, with one side inevitably affecting the other sides.
Antimicrobial agents have selective toxicity, what is this?
Antimicrobial agent should act on target site of infection organism, which is absent on host cells.
Easier in prokaryotes, as they are very different. But eukaryotes are more similar to host.
Antiviral agents need to be able to enter host cells without damaging, then attack virus
What are desired antimicrobial properties of ideal drug?
Selective toxicity for microbes, not host
Cidal activity - kills pathogen
Slow emergence of resistance
Narrow spectrum of activity - usually preferred as less resistance/ microbiota disturbance. However sometimes broad spectrum required for polymicrobial infections e.g meningitis
What are desired pharmacological properties of antimicrobial agent
Selective toxicity
Long plasma half life - e.g for once daily dosing
Good tissue distribution e.g CSF
Low plasma protein binding
Oral and parenteral dosing forms
No interaction with other drugs
Antibiotics strictly means natural metabolic product of fungi/ bacteria which kill other microbes.
Many antibiotics are synthetic, or semi-synthetic, so term anti-microbial preferred.
How were antimicrobials discovered in the past, and how has this been modernised?
Previously through random screening of soil microbes to assess for antimicrobials.
Now computer modelling and genomics informs of potential drugs by identifying target sites
What are three ways of classifying antibacterial agents?
Bactericidal or bacteriostatic
By target site
By chemical structure - does not have any practical use alone, but when combined with target site allows us to group antibacterials into specific families
Antibacterial agents can be classified by target site, what are the five main targets
Cell wall synthesis
Cell membrane function
Nucleic acid synthesis
Protein synthesis
Metabolic pathways
Define antibacterial resistance
Organism will not be inhibited or killed by antibacterial agent at concentrations of drug achievable in body after normal dosage.
Some are naturally resistant, as they may not actually have target site for antibacterial to work, or naturally produce an enzyme which inactivates antibiotic
What are three ways in which drug resistance can evolve?
Chromosomal-mediated resistance - mutant selection
Plasmid-mediated resistance - spread of resistant plasmid
Plasmid-mediated resistance on transposon - spread of resistance gene
How does chromosomal mutation result in resistance?
Single chromosomal mutation can result in altered protein e.g ribosome, cell wall which changes target site
Multiple mutations can completely change proteins such as penicillin binding proteins (PBPs) in penicillin resistant pneumococci
These selective advantages allow bacteria to survive and outgrow competition. Can cross-infect other patients
How does plasmid transfer confer resistance?
Plasmid can contain genes which can provide resistance. This is very efficient, and does not rely on chance such as mutation. Multiple genes can be transferred.
Resistance can spread through population quickly
How do transposons confer resistance?
Transposons are “jumping genes”, and in replicative process can be integrated into other areas of DNA or a plasmid
If in plasmid, can be rapidly spread throughout population
Resistance genes can be transferred on chromosome, plasmids, or transposons found in both locations.
In some cases, multiple resistance genes may come together in structure known as integron casette. This can move into variety of DNA molecules, or act indepdendently as mobile genetic element
What do integron cassettes contain?
Excision/ recombination enzyme such as integrase, which allows excision and integration of cassette
Resistance genes
A promoter which directs transcription of cassette-encoded genes
What is name of staphylococcal methicillin resistance cassette
Staphylococcal genes for methicillin resitance are organised into unique cassette termed SCCmec
What are three broad mechanisms of antimicrobial resistance
Altered target site - lowers affinity for drug
Altered uptake -
- altering entry of drug (reduce cell wall permeability)
- pump drug out of cell (efflux)
Drug inactivation - enzymes which modify or destroy antibacterial agent
- e.g beta lactamases, aminoglycoside-modifying enzymes, chloramphenicol acetly transferases
Peptidoglycan component of cell wall is specific to bacteria, so can provide selective toxicity.
Peptidoglycan syntehsis begins in cell cytoplasm, moves to cytoplasmic membrane, then subunits attach to growing peptidoglycan chain.
Which antibiotics are cell wall inhibitors?
Beta-lactams - penicillin, carbopenems, cephalosporins, monobactams
Glycopeptides
Bacitracin - savilon
Fosfomycin
Beta-lactams is a large family of different antimicrobial compounds, all containing beta lactam ring.
What is beta-lactam mechanism of action?
Which organisms do beta lactams-not work on?
Bind to penicillin binding proteins (PBPs) prevent cross-linking of bacterial cell wall
Those without cell wall e.g mcoplasma
Impermeable wall e.g TB
Intracellular pathogen e.g brucella, chlamydia, legionella
What drugs are part of beta-lactam family?
Penicillin
Cephalosporins - cefalexin, cefuroxime, ceftazidime
Carbapenems - meropenem
Monobactam - aztreonam
Cephamycins - cefoxitin
Resistance to beta-lactams can occur in three ways - altered target site, resistance in access to target site, production of beta lactamases (drug inactivation)
How does MRSA become resistant?
Synthesise additional Penicillin-binding protein (PBP2a) which has lower affinty for beta lactams, and co can continue cell wall synthesis when other PBPs are inhibited
mecA gene
Other bacteria such as strep pneumoniea, neisseria gonorrhoea, hameophilus an also utilise PBP changes to resist beta-lactams
MRSA also produces beta-lactamase
How do gram negative cells resist beta-lactams?
Beta-lactams normally diffuse through porins in outer membrane. Mutation in porin gene results in decreased permeability of outer membrane, generating resistance.
Also gains cross-resistance to unrelated antibiotics that use same porins
How to beta-lactamases provide resistance
Hydrolyse beta-lactam ring, to yield inactive compound
Hundreds of beta-lactamses exist, some are more specific to certain beta-lactams. Some drugs are hydrolysed by very few enzymes (carbapenems), whereas others (ampicillin) are much more easily inactivated
What is ESBL and why is it bad?
Extended-spectrum beta-lactamases
Can broadly inactivate most beta-lactam compounds, so difficult to treat
Gene can be carries in plasmids
How does co-amoxiclav inactivate beta-lactamases?
Clavulanic acid contains beta-lactam rings, and act as suicide inhibitors, binding to beta-lactamses and prevent them from destroying beta-lactams
Little bactericidal activity on its own
Other drugs like tazocin have piperacillin + tazobactam. Tazobactam inhibits beta lactamases
What are toxic effects of beta-lactams
Type 1 hypersensitivity reaction occurs in 0.5% - 4% of patients, although anaphylaxis occurs up to only 0.04% occasions
Rash is common
If allergic to penicillin, often allergic to cephalosporins as well
Neurotoxicity and seizures can occur if beta-lactams improperly doses for body weight/ kidney function - unconsciousness, mycolonic spasms, hallucinations
What is general spectrum of action of these beta-lactams
Penicillins
Cephalosporins
Carbapenems
Monobactams
Penicillins - mostly gram positive, some gram negative cover. Tazocin has good gram neg cover
Cephalosporins - gram positive. But 4th/5th generation have activity against gram negatives
Carbapenems - gram positive and negative
Monobactams - gram negative
Give examples of different generations cephalosporins
First - cephalexin
Second - cefuroxime
Third - cefotaxime, ceftazidime, ceftriaxone
Fourth - cefepime
Fifth - ceftolozane, ceftaroline
Glycopeptides include vancomycin and teicoplanin. Very large molecules, so cannot penetrate gram negative cell walls. Not absorbed by GI tract or cross BBB as large molecules. Can be used for meningitis as increased permeability of BBB. Excretion via kidney
What is their mechanism of action?
Bactericidal
Inhibit cell wall synthesis by binding to terminal
D-alanine-D-alanine at end of pentapeptide chain in growing bacterial cell wall, preventing further subunits joining to cell wall
Glycopeptides act at earlier stage on cell wall production that beta-lactams, so not useful to combine these.
When are glycopeptides indicated?
Treatments of gram positive bacteria, especially those resistant to beta-lactams e.g MRSA
Allergy beta-lactams
C. Difficile - although risk of promoting emergence of glyocopeptide-resistant enterococci in gut flora
What are side effects of glycopeptides?
Red man syndrome - histamine release if administered too quickly. Can cause lip swelling and hypotension - anaphylactoid reaction
Nephrotoxicity
Ototoxicity
What are mechanisms whereby organisms can be resistant to glycopeptides
Gram negative naturally resistant to glycopeptides as too large to move through outer membrane
Acquire resistance genes -
- vanA - transmissible
- vanB - transmissible
- vanD - non-transmissible (chromosomal change)
VRE associated with plasmid uptake of resistance genes
Has also been seen in staphylococci
Which antibiotic classes are inhibitors of protein synthesis
30S inhibitors 2
50S inhibitors 6
Inhibit RNA synthesis from DNA 2
30S inhibitors
Aminoglycosides
Tetracyclines
50S inhibitors Chloramphenicol Fusidic acid Lincosamides Macrolides Oxazolidinones (linezolid) Streptogramins
Inhibit RNA synthesis from DNA
Rifampicin
Fidaxomycin
Which protein inhibitors prevent mRNA formation from DNA?
Fidaxomycin
Rifampicin
Both do not act on ribosome.
They inhibits DNA-dependent RNA polymerase
Which protein inhibitors prevents binding of new tRNA to acceptor site?
Tetracyclines
Act early on protein production pathway - inhibit 30S subunit
Which protein inhibitors prevents formation of peptide bonds/ chain elongation?
50S inhibitors
Chloramphenicol Fusidic acid Lincosamides Macrolides Oxazolidinones Streptogramins
Act later on protein production pathway - inhibit 50S subunit
Aminoglycosides interfere with ribosome 30S subunit, preventing binding of fmet-tRNA.
What are examples of these three classes of aminoglycosides
- Streptidine-containing
- 4,6-distrubted 2-deoxystreptamines
- 4,5- dissubstitued 2-deoxystreptamines
- Streptidine-containing -
- streptomycin. Oldest one, now just used for TB treatment
- 4,6-distributed 2-deoxystreptamines -
- gentamicin - broad spectrum
- tobramycin - similar gent, better against pseudomonas
- amikacin - useful if resistant to gentamicin
- 4,5- disubstitued 2-deoxystreptamines
- neomycin - too toxic for parenteral use, useful topically for decontamination e.g burns/ ulcers
How are aminoglycosides administered?
Do they penetrate bone/ tissue/ BBB?
How are they excreted?
IV/ IM
Occasionally streptomycin intrathecal for TB meningitis
Not absorbed well from gut
Do not penetrate tissue and bone
Do not cross BBB
Renally excreted
What are side effects of aminoglycosides?
Nephrotoxic
Ototoxic
What are uses for aminoglycosides
Only use in severe infection
Gram neg septicaemia including:
- pseudomonas
- HAI - e.g HAP/ VAP
- IE
- device infections - catheter, cannula
- pyelonephritis
- intra-abdominal infection
What do aminoglycosides not work on?
Streptococci
Anaerobes
What are mechanisms by which organisms develop resistance to aminoglycosides?
Aminoglycoside-modifying enzymes inactivate antibiotic. Carried on plasmids. Most common mechanism
Can alter ribosome protein so cannot bind
Can alter cell wall permeability, so cannot cross cell membrane
Tetracyclines are bacteriostatic.
What are examples of these?
Which ones give less side effetcs?
Tetracycline Doxycycline Demclocycline Minocycline Tigecycline
Doxycycline/ minecycline are more completely absorbed in GI tract, so give less side effects.
What are tetracyclines mechanism of action?
Inhibit protein synthesis by binding to small ribosomal subunit preventing tRNA binding
Can work on eukaryotic and prokaryotic cells, but uptake much greater in prokaryotes, so tetracyclines have more selective action
How are tetracyclines excreted?
Bile
Urine
What is activity of tetracyclines?
Can penetrate host cells, so useful against intracellular bacteria e.g chlamydia, mycoplasma, rickettsiae
What is mechanism by which organisms become resistant to tetracyclines?
Why is tetracycline resistance widespread
Resistance gene carried on transposon
Allows bacteria to efflux drug out of cell
Resistance widespread, as drugs used commonly, and also used in cattle as growth promoters in animal feed
When should tetracyclines be avoided?
What are side effects
Pregnancy/ Children under 8 - brown staining teeth in fetus/ children
GI upset
Photosensitivity
What is mechanism of action of chloramphenicol?
Prevents peptide bond synthesis by binding to 50S subunit, inhibiting peptidyl transferase
Bacteriostatic
How is chloramphenicol administered?
Topically
Orally
IV
Well dsitrbuted in body, and penetrates host cells
What are indications for chloramphenicol use?
Broad spectrum - gram pos/ negative, aerobes, anaerboes, intracellular orgnaisms
What are serious side effects of chloramphenicol
Inhbitory effects on human mitochondrial 70S ribosomes causes bone marrow suppression. Reversible when treatment stopped
Aplastic anaemia can occur on rare occasions, and can occur after treatment stopped.
Toxic to neonates with underdeveloped liver - levels need to be monitored
What is mechanism whereby resistance to chloramphenicol arises?
Plasmid-mediated chloramphenicol acetyl-transferases convert drug into inactive form, which cannot bind ribosomes.
Macrolides are bacteriostatic.
Clarithromycin has improved peak serum concentration compared to erythromycin, with less side effects.
What is there mechanism of action?
Bind to 23S ribosomal RNA in 50S subunit of ribosome
Blocks translocation step of protein synthesis, preventing release of tRNA after peptide bond formation
How are macrolides metabolised?
Concentrated in liver, and excreted in bile
What are indication for macrolide use?
Gram positive cocci
Atypical/ intracellular - legionella, chlamydia, mycoplasma
How does resistance to macrolides occur
Macrolides, lincosamides and streptogramins share overlapping binding sites on ribosomes, so resistance to one group confers resistance to the others (MLS resistance).
Plasmid encoded mef or erm genes cause either:
efflux of drug
alteration of 23S ribosomal subunit prevents binding
Fidaxomicin, used for clostridium difficile. Beneficial as does not upset gut microbiota
What is mechanism of action
Inhibits bacterial RNA polymerase preventing mRNA transcription
Clindamicin is most common lincosamide.
What is mechanism of action?
Binds to 50S ribosomal subunit, inhibiting protein synthesis.
Similar to MLS
What is clindamicin penetration?
How is it metabolised?
Bone/ tissue, but does not penetrate CSF even if meninges inflamed
Liver
What is clindamicin spectrum of action?
Similar to macrolides
More active against anaerobes (gram pos and neg)
Tissue penetration means suitable for osteomyelitis
Increased risk of C. diff
Streptogrammin drugs available are a mixture of streptogrammin A + B
What is the name?
Dalfopristin/Quinupristin
What is streptogrammin mechanism of action?
Bind to 23S RNA in 50S ribosomal subunit, preventing elongation of peptide chains.
Bacteriostatic
How are streptogrammins administered?
How are streptogrammins metabolised?
IV
Liver
What are examples of an oxazolidinone?
What is mechanism of action?
Linezolid
Inhibits protein synthesis by targeting 23S ribosomal RNA in 50S subunit, which prevents formation of 70S subunit. Slightly different mechanism from MLS
What is linezolid spectrum of action?
Gram positives
What is mechanism of action of fusidic acid?
What is the distribution of fusidic acid?
Inhibits protein synthesis
Tissue/ bone, but not CSF
How is fusidic acid administered?
Why is it not often used?
Oral/ IV
Useful for staphylococcal infection.
Rapid emergence of resistance. Should be used in conjunction with other agents.
Nucelic acid synthesis inhibitors, what are three mechanisms of action?
Antimetabolites inhibiting precursor synthesis - sulphonamides, trimethoprim
Inhibitors of RNA polymerase - rifampicin
Inhibitors of DNA replication - quinolones
What is specific mechanism of action of quinolones?
Inhibit topoisomerase IV and DNA gyrase to prevent nucleic acid synthesis
How does quinolone resistance occur?
Usually chromosomal mediated -
- mutation preventing quinolone binding
- change in cell membrane - reduced uptake, efflux
Plasmid-encoded quinolone resistance exists, involves production of a protein that protects DNA from quinolone binding
How are quinolones administered?
What are indications for quinolone use?
Orally - as good GI absorption, and high bioavailability
Gram negative organisms - including pseudomonas
What are side effects of quinolones?
GI upset
Tendon rupture. Not recommended for children/ pregnant women as affects cartilage development
Rifamycins include rifampicin and rifabutin.
Bacteriostatic
What is mechanism of action?
Binds to DNA-dependent RNA polymerase and blocks synthesis of mRNA
What is distribution of rifampicin?
Cross BBB
Appears to have affinity for plastics, so useful for prostheses infection
How is rifampicin metabolised?
Metabolised in liver, excreted in bile/ urine
Rifabutin excreted more slowly than rifampicin, so allows less frequent administration e.g TB therapy
Compound is red, so urine, sweat, saliva all turn orange
What are uses for rifampicin?
TB
Prophylaxis of closs contact of meningococcal/ haemophilus meningitis
Usually used in combination with other drugs, as resistance develops quickly
Which drugs are anti-metabolites affecting nucleic acid synthesis?
Sulphonamides
Trimethoprim
Both bacteriostatic
What is normal folate metabolism?
Normal folate metabolism:
1. para-aminobenzoic acid (PABA) converted to dihydrofolic acid
- Dihydrofolic acid converted to (by dihydrofolic reductase)
- tetrahydrofolic acid (THFA), which is used to make purines and pyrimidines
Bacteria need to synthesis THFA, whereas humans lack ability to synthesis this, and rely on exogenous supply of folic acid. This gives selective toxicity
Sulphonamides are usually adminsitered orally in combination with trimethoprim (co-trimxazole)
What is there mechanism of action?
Step 1 - Inhibits conversion of para-aminobenzoic acid (PABA) to dihydrofolic acid
What are uses for sulphonamides?
Gram neg organisms except pseudomonas
Resistance widespread, as plasmid containing genes for altered metabolism of folate
What are examples of sulphonamides?
Sulfamethoxazole
Dapsone
What is trimethoprim mechanism of action?
Step 2 - inhibits dihydrofolate reductase. Enzyme present in humans, bacteria, protozoa, but has greater affinity for bacterial enzymes
Similar mechanism of action to antimalarial pyrimethamine and methotrexate
Why are trimethoprim and sulphonamides combined together with co-trimoxazole?
Mutant bacteria are unlikely to be resistant to both
Drugs work synergistically, and can have bactericidal effect, that is greater than either agent alone
What is trimethoprim spectrum of action?
Gram negative rods (except pseudomonas) - UTI
What is co-trimoxazole spectrum of action?
What are side effects?
Wide range - UTI/ HAP/ PCP/ salmonella typhi/ nocardia
Nausea/ vomiting
Neutropenia
How does trimethoprim resistance occur?
Plasmid encoded dihydrofolate reducase has reduced affinity for trimethoprim, so can continue to metabolise folate
What are examples of nitroimidazoles?
What is their mechanism of action
Metronidazole
Has antibacterial and antiparasitic activity.
Once enters cells, metronidzaole is reduced to another compound which causes breakage DNA. Only works on protozoa/ anaerobes, as aerobes cannot reduce it
What are uses for metronidazole?
Bacteria -
Anaerobes
Bacterial vaginosis
C. Difficile
Protozoa -
Entamoeba histolytica
Giardiasis
Trichomonas vaginalis
What are examples of drug classes which inhibit cytoplasmic membrane function?
Can be selectively toxic as mammal cell membrane different to bacteria
Lipopeptides - daptomycin, useful for gram positive including VRE
Polymyxins - polymyxin B/ polymyxin E (colistin) - very toxic so not often used. But active against gram negative
Nitrofurantoin is class by itself. Absorbed orally, and excreted in urine to inhibit urinary pathogen. Accumulated within cells, where it is reduced by bacteria to produce reactive species which damage DNA
Why is proteus naturally resistant to this?
Requires acidic pH urine to work, proteus naturally alkalises urine
Why are mycobacterium so difficult to treat?
Have outer waxy layer - impermeable to antibiotics
Intracellular pathogen
Grow/ multiply slowly - takes long time for drug to work. Long term antibiotics allows resistance to develop
What is first line regimen for TB?
Rifampicin
Isoniazid
Pyyrazinamide
Ethambutol
4 drugs for 2 months
Then rifampicin/ isoniazid for 4 months
What is mechanism of action of isoniazid?
Bacteriocidal
Inhibits mycolic acid synthesis - so selective toxicity
What is mechanism of action of ethambutol?
What are side effects?
Bacteriostatic
Inhibits polymerisation of arabinoglycan a critical constituent of mycobacterium cell wall
Resistance appears quickly if used alone
Check visual acuity as optic neuritis can occur
What is mechanism of action of pyrazinamide?
What are side effects?
Inhibits mycolic acid synthesis
Resistance appears quickly if used alone
Hepatotoxicity
What is treatment of leprosy?
Used to be dapsone (sulphonamide) monotherapy - now resistance
Dasone, rifampicin, clofazimine multidrug therapy
Antibiotic susceptibility can be tests by disk diffusion tests, and dilution tests.
What is process of disk diffusion test?
Add isolate to agar plate
Add filter disks containing antibiotic - disks should provide concentration similar to plasma levels reached during treatment
Antibiotics differ in ability to diffuse in agar, so do not just use inhibition zone size as gauge of susceptibility. Instead measure zone size, and compare with resistance name. Either susceptible, intermediate, resistant
Intermediate resistant could mean that it is susceptible if higher doses are used, or if used in different site e.g urine if antibiotic excreted in urine
Antibiotic susceptibility can be tests by disk diffusion tests, and dilution tests.
What is process of dilution test?
- Serial dilutions of test antibiotic combined with suspension of test organism. Incubated overnight. MIC recorded highest dilution in which no macroscopic growth
- E-test - filter paper impregnanted with gradient of antibiotic. Concentration on strip at which growth is inhibited is MIC
What are benefits of dilution test?
Provides more quantitative estimate of susceptibility to an antibiotic, by providing result of MIC (minimal inhibitory concentration).
Test to find lowest concentration that will inhibit visible growth of bacterial isolate
How can dilution test/ MIC be used to calculate MBC
MIC can be extended to calculate MBC (minimal bacterial concentration), which is lowest concentration of an antibiotic required to kill an organism. To establish whether an anitbiotic has killed, rather than merely inhibited a pathogen
Test dilutions are subcultured onto drug-free medium, incubated overnight to see if they grow. Considered bactericidal is MBC is equal to or not greater than fourfold higher than the MIC
What are killing curves, and what are their benefits?
Downside of MIC/ MBC is that result read at only one point in time. More dynamic estimate of bacterial susceptibility can be gained by measuring decrease in viability of population over time
What is antibiotic synergy and antagonism?
Synergy - activity of combined antimicrobies is greater than sum of individual parts e.g penicillin and gentamicin has more effect for IE than either used alone
Antagonism - activity of drug compromised by presence of another
What are indications for combining antibiotics?
Obtain synergistic effect - co-trimoxazole
Reduce resistance emerging - e.g RIPE for TB
Treat polymicrobial infection - intrabdominal infection
To treat life threatening infection before organism identified
Why is it important to use antibiotic assays to measure drug levels?
When antibiotic has narrow therapeutic index - therapeutic level is close to toxic level e.g aminoglycosides
When normal route of excretion impaired e.g renal excreted drugs in renal failure
When absorption unclear e.g after oral administration
To check concentration of drug in certain sites e.g CSF
If receiving prolonged therapy e.g IE
In neonates
If patient fails to respond to treatment
To check patient compliance
What are ways in which we can control and prevent infectious disease?
Sanitation - water, sewage, housing (less crowding/ mosquitoes)
Food - pasteurisation, cold storage, food inspection, adequate cooking
Control vectors - mosquitoes/ ticks/ lice
Control animal reservoir - rabies
Specific treatment - chemotherapy
Specific prevention - vaccines, condoms, IVDU, screen blood transfusion
Patient on warfarin, has CAP, looking for oral therapy.
Resistant to tetracycline
What is best option
Clarithromycin Doxycycline Linezolid Temocillin Vancomycin
Clarithromycin - interacts with warfarin
Doxycycline - resistant
Linezolid - best choice
Temocillin - only works gram neg, and only IV
Vancomycin - not absorbed form GI tract
Patient with fever, and aortic root collection. Blood cultures grow Enterococcus faecium
Has history of depression on phenelzine
Which antibiotic should be used?
Amoxicillin Ceftriaxone Daptomycin Linezolid Metronidazole
Amoxicillin - intrinsically resistant to this
Ceftriaxone - intrinsically resistant
Daptomycin - best choice. Normally vancomycin would be first line
Linezolid - acceptable choice, but will interact with monoamine oxidase inhibitors such as phenelzine
Metronidazole
Haematology patient with neutropenia. Develops ground glass CT lung changes, with halo appearance - suspect fungal infection. Suspect candidaemia, as has history of this. History of rash to capsofungin
What is best treatment?
Fluconazole Flucytosine Micafungin Terbinafine Voriconazole
Fluconazole - does not treat aspergillus
Flucytosine - would not be used as sole agent
Micafungin - had reaction to capsofungin which is in same class
Terbinafine - does not treat aspergillus
Voriconazole - best answer
Which antibiotics are classified as broad spectrum?
Beta-lactam plus beta lactamase e.g co-amoxiclav/ tazocin
Cephalosporins
Carbapenems
Chloramphenicol
Tetracyclines
Which antibiotics have activity mainly against gram-positive bacteria?
penicillin fusidic acid macrolides clindamycin glycopeptides oxazolidinones streptogramins
Which antibiotics have activity mainly against gram negative bacteria?
Polymyxin Trimethoprim Temocillin Aminoglycosides Monobactams
Which agents are bactericidal?
beta-lactams
glycopeptides
fluoroquinolones
aminoglycoside
Which agents are bacteriostatic?
macrolides clindamycin tetracyclines trimethoprim sulphonamides
What should people avoid if taking metronidazole?
Alcohol
When a person consumes alcohol, the body breaks it down in two steps. First, it breaks alcohol into a compound called acetaldehyde. Then converted to acetate using an enzyme called aldehyde dehydrogenase. Metronidazole blocks this enzyme
As a result, alcohol cannot be fully digest and toxic acetaldehyde builds up in the bloodstream.
Symptoms: nausea vomiting a rapid heartbeat low blood pressure headaches flushing of the face
What is the benefit of using an antibiotic with high therapeutic index?
Cheaper Easier to monitor Lower dose More effective Safer
Safer
High therapeutic index means that there is a wide margin between therapeutic level, and toxic level. Means less side effects, and patient does not need monitored
What is best way to test for ESBL?
broth microtitre dilution disc diffusion gradient strip plating on ESBL selective agar real-time PCR
PCR
Other methods can be used, but need second step for confirmation
Elderly patient with MRSA, sensitive to vancomycin. Patient continues to deterirorate. Repeat diffusion test is reported as susceptibile.
What is nex lab test?
Repeat vancomycin disc diffusion test to confirm zone size
PCR mecA and mecC genes
PCr for vanA and vanB genes
Teicoplanin Etest
Vancomycin Etest
Vancomycin Etest allow us to see MIC
Vancomycin disc diffusion no longer recommended.
mecA and mecC genes likely to be present, as this confers resistance to methicillin - hence why we have MRSA here
vanA and vanB confer resistance to vancomcyin, but rare cause of resistance in S aureus
Patient suitable for OPAT. No history of MRSA.
What is antibiotic of choice?
If MRSA?
If penicillin allergic?
Ceftriaxone MSSA
Teicoplanin/ daptomycin if MRSA
Teicoplanin/ daptomycin if penicillin allergic
Patient suitable for OPAT. Blood culture grew E. coli ESBL
Which antibiotic is best treatment for OPAT?
Amikacin Ceftriaxone Ertapenem Gentamicin Meropenem
Ertapenem as once a day id drug of choice
Amikacin is option, avoid if renal impairment.
50% ESBL can be resistant to gentamicin
ESBL intrinsically resistant to cephalosporins
Patient with vertebral discitis commenced on ceftriaxone and rifampicin.
What is likely relapse rate/ need for readmission?
Approx 20% in OPAT cohorts
