Antibacterials Flashcards
Sterilise
To kill all microbes
Sanitise
To kill most microbes
Aseptic
Absence of microbes
Disinfectant
o Non-selective chemical for killing microbes
o Unsuitable for use on living tissue
o High concentrations required
o E.g. sodium hypochlorite
Antiseptic
o Non-selective chemical for killing microbes
o Appropriate for use on living tissue, usually skin
o High concentrations required
o E.g. betadine
Antibiotics
o Target particular pathways
o Pathways are unique to bacteria or group of bacteria
o Very small concentrations required
o For use on or in living tissues
Broad spectrum antibiotics
Effective against many bacterial groups
Narrow spectrum antibiotics
Effective against only a few bacterial groups
Bactericidal antibiotics
Kill bacteria
Bacteriostatic antibiotics
Inhibit growth of microbes, immune system kills.
Complication in the definition of bactericidal and bacteriostatic.
Decreasing concentration: bactericidal becomes bacteriostatic.
Increasing concentration: bacteriostatic becomes bacteriocidal.
Prophylactic therapy
- Before the infection risk occurs e.g. surgery
- Antimicrobial choice based on known or likely pathogen
- Use only if: there is evidence for effectiveness or an infection is disasterous
Empirical therapy
• Best guess
• Use only when:
o Bacterial infections are very likely
o Treatment has substantial benefit
o ID, sensitivity unknown
• Use narrowest spectrum antibiotic for most likely pathogen
• First obtain specimens for MC&S testing
• Change to directed therapy when laboratory results are available.
Directed therapy
• Antimicrobial therapy with evidence from laboratory testing
o Microbial pathogen has been identified
o Antimicrobial sensitivity has been determined
• Then choose the antimicrobial that is:
o Most effective
o Least toxic
o Narrowest spectrum
• Directed therapy is the most desirable antimicrobial therapy
The antimicrobial creed
Microbiology guides therapy wherever possible
Indications should be evidence-based
Narrowest spectrum required
Dosage appropriate to the site and type of infection
Minimise duration of therapy
Ensure monotherapy in most situations
Oral antimicrobial administration
- Preferred
- Less serious adverse effects
- Cheaper products
- Lower costs to administer
- Just as ‘powerful’ as injections
- Drugs must have good oral bioavailability
Parenteral antimicrobial administration
• When oral administration is ineffective
o Poor oral bioavailability
o Swallowing difficulties
o Absorption problems (e.g. vomiting, diarrhoea)
o Higher concentrations are required than possible oral route
o Time critical (rare)
• Reassess daily and convert to oral ASAP
Topical antimicrobial administration
- Use only when effectiveness is proven
* Antimicrobial different from oral and parenteral types, for avoidance of resistance
Adverse effects
• All microbials can cause adverse effects
• Adverse effects are usually mild, self-limiting
• Adverse effects more likely in:
o Elderly
o Patients with renal or hepatic impairment
Antimicrobial hypersensitivity (allergy)
- Very commonly reported, esp. to penicillin
- 5 to 10% of patients
- But often vague details, inaccurate
- Usually from parenteral administration
- True anaphylaxis in 0.01% to 0.04% of courses of penicillin
- 10% of anaphylaxis fatal
When can a patient be given allergy causing antibiotics?
- The antibiotics is clearly the most effective
- Patient is carefully observed
- Patient undergoes desensitisation therapy
Multi-drug resistant bacteria
o Myobacterium tuberculosis o Staphylococcus aureus o Enterococcus o Enterics (E. coli, Klebsiella, Enterobacter) o Pseudomonas aeruginosa
Antibiotic resistant mechanisms
- Enzymes that degrade antibiotics e.g. beta-lactamases
- Decreased inner cell membrane permeability
- Decreased outer membrane permeability
- Efflux pumps removing antibiotic from inside cells
- Alteration of the binding site e.g. MRSA
How to bacteria gain resistance genes?
• Inherent (natural) e.g. many Gram-negs to penicillin
• Vertical gene transfer
o Mutations after selection pressure of antibiotics
o Then transferred ‘vertically’ to progeny
• Horizontal gene transfer
o Genes transferred to related bacteria
o Mechanisms
Horizontal gene transfer mechanisms
• Conjugation
o Related bacteria in direct contact
o Plasmid (ring of DNA) containing the gene transferred
o Main mechanisms of antibiotic resistance transfer
• Transformation
o DNA from external environment (dead bacteria) taken up
• Transduction
o Bacteriophages transfer DNA between closely related bacteria
Research into new antibiotics
• To overcome problems with resistance? • Previously much research. • Now very limited. • Only one new antibiotic (Lipopeptides) with a novel mechanism of activity discovered in past 50 years. • Not a good business: o Resistance develops too quickly o We expect antibiotics to be cheap
Overcoming antimicrobial resistance
• Change how we prescribe antibiotics o Prescribe only when absolutely necessary o Narrowest spectrum o Directed therapy when possible o Monotherapy o Correct dose o Only as long as necessary o Discuss antibiotic resistance with patients o Antimicrobial stewardship
Antimicrobial sterwardship
- Co-ordinated interventions designed to improve the appropriate use of antimicrobial therapy
- All healthcare facilities in Australia now require to demonstrate they have an effective Antimicrobial Stewardship program.
RHH Antimicrobial stewardship
o Antimicrobials must be prescribed in accordance with the current version of Therapeutic Guidelines Antibiotic or local guidelines, where appropriate.
o Patient’s medication chart shows for all prescriptions:
Dose, frequency and route
Indication
Proposed duration with a review date or stop date documented
o Classification of antimicrobials
Class A: unrestricted
Class B: approval required
Class C: higher level approval required
Antibiotic sensitivity testing
• Patient specimens sent to the laboratory
o Blood
o Urine
o Swabs
o Aspirates
• Microscopy, culture and sensitivity (MC&S) requested
• If pathogen is isolated:
o Tested for sensitivity to a variety of antibiotics
o Tested for appropriate antibiotic concentration if required
Antibiotic sensitivity testing methods
Agar disc diffusion, Broth dilution assay, Epsilometer (E) test
Agar disc diffusion
o Make a ‘lawn’ of bacteria on agar plate
o Stamp with antibiotic impregnated discs
o Incubate then measure zones of inhibition (MM)
o Compare zones of inhibition with predetermined ‘break points’
o Inhibition zone > breakpoint: sensitive (S)
o Inhibition zone < breakpoint: resistant (R)
o Qualitative only: result shows sensitive or resistant only
Broth dilution assay
o For when treatment concentration is required
Appropriate antibiotic already known
Make antibiotic dilution series
Add test bacteria and growth medium
Incubate. Cloudiness shows growth.
MIC = lowest antibiotic concentration with no growth
o For minimum bactericidal concentrations (MBC):
Plate out concentration with no growth, incubate
MBC = lowest concentration with no growth
Epsilometer (E) Test
o For when a treatment concentration is required
o E test strips: antibiotic concentration gradient on plastic strip
o Make a ‘lawn’ of bacteria on again plate
o Place E test strips for different antibiotics on bacterial lawn
o Incubate
o Intersection of clearing zone with scale shows minimum inhibitory concentrations (MIC)
o Ensure antibiotic concentration in the blood is at least the MIC
Beta-lactams
• Most widely used group
• Cabapenams, cephalosporins, monobactams, penicillins
• All have beta-lactam ring structure
• Well tolerated (unless hypersensitive)
• Interfere with cell wall synthesis
• Mechnisms of activity
o Target Penicillin Binding Proteins (PBPs)
o PBPs are enzymes that catalyse the cross-linking of peptidoglycan in bacterial cell walls
o Beta-lactam antibiotics bind to and inactivate PBPs
o Cross0linking of peptidoglycans is inhibited
o Peptidoglycan precursors accumulate in cell
o Autolysis signal
o Cells die
Aminoglycosides
- Very effective against gram-negatives
- Aerobes and facultative anaerobes only
- Potential serious side effects
- Binds to bacterial ribosomes
- Bacteria fail to make proteins – death
- E.g. gentamcin, tobramycin, amikacin streptomycin, paromycin, neomycin, framycetin
Chloramphenicol
- Very effective, broad spectrum
- Binds to ribosomes – inhibit protein synthesis
- Potential serious side effects
- Systemic use only if no alternative
- Mainly topical use: eye and ear infections
- Chloramphenicol only
Daptomycin
- Effective against gram-positives only
- Attaches to and disrupts bacterial cell membrane
- Alternative t glycopeptides
- Skin and soft tissue infections
- S. aureus bacteraemia
- Daptomycin only
Glycopeptides
- Effective against gram-positives only
- Inhibit cell wall synthesis, like beta-lactams
- Bind to precursor peptidoglycan units inside cells
- Prevents formation of peptidoglycan chains and prevents peptidoglycan chains cross linking
- No cell wall formed, new cells die
- E.g. vancomycin, teicoplanin
Lincosamides
- Effective on gram-positive aerobes and anaerobes
- Bind to ribosomes, inhibit protein synthesis
- Significant adverse effects
- Only use if non others appropriate
- Clindamycin and lincomyin only
Macrolides
- Wide spectrum activity, except gram-negative rods
- Binds to ribosomes, inhibiting protein synthesis
- Binding is reversible: bacteriostatic only
- Erythromycin, azithromycin, clarithromycin
Nitroimidazoles
- Bacteria and protozoa: anaerobes only
- Damage to microbial DNA
- Metronidazole, tinidazole only
Oxazolidonones
- Excellent against antibiotic resistant gram-positives
- Reserved for antibiotic resistant staphylococcal, streptococcal and enterococcal infections
- Binds to ribosomes, inhibiting protein synthesis
- Some potential for adverse reactions
- Linezolid only
Polymyxins
- Gram-negative rods
- Insert into bacterial outer membrane
- Increase cell permeability – death
- Potential serious side effects
- Mainly used externally
- Polymixin B, polymyxin E (colistin)
Quinolones
- Very widely used
- Excellent activity against aerobic gram-negatives
- Extended spectrum types are effective against gram-positives, intracellular bacteria and anaerobes
- Inhibit DNA replication and repair
- Ciprofloxacin, moxifloxacin, norfloxacin, ofloxacin
Rifamycins
- Gram-positives only, especially staph., strep.
- Effective against Myobacterium tuberculosis
- Inhibits RNA synthesis – no proteins made
- Combination use only – resistance develops rapidly
- Rifampin and rifabutin only
Streptogramins
- Gram-positives only: reserved for vancomycin resistant Staphylococcus, Enterococcus infections
- Bind to ribosomes – inhibit protein synthesis
- Synergistic combination: quinupristin-dalfopristin
- Pristinamycin is effective against Gram-negatives as well as Gram-positives
Sulfonamides and Trimethoprim
- Broad spectrum
- Potential serious side effects
- Only for serious infections: MRSA, L. monocytogenes
- Inhibit folate synthesis
- Sulfamethoxazole-trimethoprim
- Very effective synergistic combination
Tetracyclines
- Broad spectrum. Also Plasmodium
- Reasonably safe
- Bind to ribosomes – protein synthesis inhibited
- Binding is reversible – bacteriostatic only
- Doxycycline, minocycline, tigecycline
