4.3 - Antimicrobial Therapies Flashcards
1
Q
What is an antibiotic?
A
- an antibiotic is an antimicrobial agent produced by a microorganism that kills or inhibits other microorganisms
- most antibiotics in use today are produced by soil-dwelling fungi or bacteria
- antibiotics synthesised today encompass a range of natural, semi-synthetic and synthetic chemicals with antimicrobial activity
- antimicrobial - chemical that selectively kills or inhibits microbes
- bactericidal - kills bacteria
- bacteriostatic - stops bacteria growing
- antiseptic - chemical that kills or inhibits microbes that is usually used typically to prevent infection
2
Q
What is resistance?
A
- minimal inhibitory concentration (MIC) - the lowest concentration of antibiotic required to inhibit growth
- breakpoint - clinically achievable concentration - defines whether bacteria is susceptible or resistant
- if MIC </= breakpoint, then the bacteria is considered susceptible to that antibiotic
- antibiotic resistance evolved through natural selection
- population contains cells with AB resistance due to mutations/acquired DNA
- in absence of selection pressure (e.g. ABs), AB resistant chains have no advantage = low prevalence of AB resistant chains in patient population
- in presence of selection pressure (e.g. ABs), it is advantageous = high prevalence of AB resistant strains in patient population
- natural selection has been driving antibiotic production and the development of resistance mechanisms for millions of years
- human use has provided strong selective pressure for the acquisition or development of AB resistant genes
3
Q
Misconceptions at the dawn of the antibiotic era
A
- resistance against more than one class of antibiotics at the same time would not occur
- horizontal gene transfer would not occur
- resistant organisms would be significantly less ‘fit’
4
Q
What does AB resistance lead to?
A
- increased mortality, morbidity and cost
- increased time to effective therapy
- requirement for additional approaches e.g. surgery
- use of expensive therapy e.g. drugs
- use of toxic drugs e.g. vancomycin
- use of less effective ‘second choice’ antibiotics
5
Q
Major AB resistant bacterial pathogens - gram negative
A
- Pseudomonas aeruginosa - cystic fibrosis, burn wound infections - survives on antibiotic surfaces
- E. Coli (ESBL), Klebsiella spp. - GI infection, neonatal meningitis, septicaemia, UTI
- Salmonella spp. - GI infection, typhoid fever
- Acinetobacter baumannii - opportunistic, wounds, UTI, pneumonia
- Neisseria gonorrhoeae - gonorrhoea
6
Q
Major AB resistant bacterial pathogens - gram positive
A
- Staphylococcus aureus (MRSA, VISA) - wound and skin infection, pneumonia, septicaemia, infective endocarditis
- Streptococcus pneumoniae - pneumonia, septicaemia
- Clostridium difficile - pseudomembranous colitis, antibiotic-associated diarrhoea
- Enterococcus spp. (VRE) - UTI, bacteraemia, infective endocarditis
- Mycobacterium tuberculosis - tuberculosis
7
Q
Protonsil
A
- sulphonamide antibiotic
- bacteriostatic
- synthetic
- e.g. sulphamethoxazole, sometimes used together with Trimethoprim
- uses: treat UTIs, RTIs, bacteraemia and prophylaxis for HIV+ individuals
- becoming more common due to resistance to other antimicrobials, despite some host toxicity
- only against gram positive bacteria
8
Q
Beta-lactams
A
- interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
- e.g. penicillin, methicillin
- binds to penicillin-binding proteins (PBPs)
- PBPs catalyse a number of steps in the synthesis of peptidoglycan
9
Q
Aminoglycosides
A
- e.g. gentamicin, streptomycin
- bactericidal
- targets protein synthesis (30S ribosomal subunit), RNA proofreading and causes damage to cell membranes
- toxicity has limited use, but resistance to other antibiotics has led to increasing use
10
Q
Rifampicin
A
- bactericidal
- targets RpoB subunit of RNA polymerase
- spontaneous resistance is frequent
- makes secretions go orange/red - affects compliance
11
Q
Vancomycin
A
- bactericidal
- targets lipid II component of cell wall biosynthesis, as well as wall crosslinking via D-ala residues
- toxicity has limited use, but resistance to other antibiotics has led to increasing use
12
Q
Linezolid
A
- bacteriostatic
- inhibits initiation of protein synthesis by binding to 50S rRNA subunit
- gram positive spectrum of activity
13
Q
Daptomycin
A
- bactericidal
- targets bacterial cell membrane
- gram positive spectrum of activity
- toxicity limits dose
14
Q
Macrolides
A
- e.g. erythromycin, azithromycin
- gram-positive and some gram-negative infections
- targets 50S ribosomal subunit preventing amino-acyl transfer and thus truncation/production of polypeptides
15
Q
Quinolones
A
- synthetic, broad spectrum, bactericidal
- target DNA gyrase in Gm-ve and topoisomerase in Gm+ve
16
Q
Selective toxicity
A
- large number of differences between mammals and bacteria result in multiple targets for AB therapy - selective toxicity
17
Q
Mechanisms of antibiotic resistance - altered target site
A
- can arise via acquisition of alternative gene / gene that encodes a target-modifying enzyme
- e.g. MRSA encodes an alternative PBP with low affinity for beta-lactams
- e.g. Streptococcus pneumoniae resistance to erythromycin occurs via the acquisition of the ‘erm gene’ - encodes an enzyme which methylates the AB target site in the 50S ribosomal subunit
18
Q
Mechanisms of antibiotic resistance - inactivation of antibiotic
A
- enzymatic degradation or alteration, rendering antibiotic ineffective
- e.g. beta-lactamase (bla) and chloramphenicol acetyl-transferase (cat)
- ESBL and NDM-1 are examples of broad-spectrum beta-lactamases
19
Q
Mechanisms of antibiotic resistance - altered metabolism
A
- increased production of enzyme substrate can outcompete AB by competitive inhibition (e.g. increased production of PABA confers resistance to sulfonamides)
- alternatively, bacteria switch to other metabolic pathways, reducing requirement for PABA
20
Q
Mechanisms of antibiotic resistance - decreased drug accumulation
A
- reduced penetration of AB into bacterial cell (permeability) and/or increased efflux of AB out of the cell - drug does not reach concentrations required to be effective
21
Q
Multiple resistance systems can coexist
A
antibiotic, resistance mechanism, acquired
- penicillin, penicillinases, plasmid-transformation
- penicillin, target site modification, point mutation
- tetracycline, efflux pump, plasmid-conjugation
- quinolone, target site modification, point mutation
- cefotaxime, target site modification, point mutation
- spectinomycin, target site modification, point mutation
22
Q
Sources of antibiotic resistant genes
A
- plasmids - extra chromosomal circular DNA, often multiple copy, often carry multiple AB res genes - selection for one maintains resistance to all
- transposons - integrate into chromosomal DNA - allow transfer of genes from plasmid to chromosome and vice versa
- naked DNA - DNA from dead bacteria released into environment
- genes responsible for conferring AB resistance can be shared between bacteria via several different mechanisms - transformation (uptake of extracellular DNA), conjugation (pilus-mediated DNA transfer), transduction (phage-mediated DNA transfer)
23
Q
Non-genetic mechanisms of resistance / treatment failure
A
- biofilm - matrix-encased communities of bacteria that are highly drug tolerant
- intracellular location - some bacteria persist within human cells, making it hard for AB to access
- slow growth - if bacteria aren’t using many processes to replicate, it’s hard for AB to inhibit
- spores - impermeability of the spore coat is thought to be responsible for resistance
- persisters - dormant organisms that aren’t using any processes that AB inhibit so not killed by them - do not grow in the presence of antibiotics
Other reasons for treatment failure:
- inappropriate choice for organism
- poor penetration of AB into target site
- inappropriate dose (half-life)
- inappropriate administration (oral vs IV)
- presence of AB resistance within commensal flora e.g. secretion of beta-lactamase
24
Q
Hospital acquired infections (HAIs)
A
- large numbers of infected people receiving high doses of antibiotics = strong selective pressure for AB resistance
- MRSA
- VISA (vancomycin-insensitive S. aureus)
- Clostridium difficile
- VRE (vancomycin-resistant enterococci)
- E. coli (ESBL/NDM-1)
- P. aeruginosa
- Acineterbacter baumannii
- Stenotrophomonas maltophilia
25
Q
Risk factors for HAI
A
- high number of ill people (immunosuppression)
- crowded wards
- presence of pathogens
- broken skin - surgical wound/IV catheter
- indwelling devices - intubation
- AB therapy may suppress normal flora
- transmission by staff - contact with multiple patients
26
Q
Addressing and overcoming resistance
A
- prescribing strategies - tighter controls, temporary withdrawal of certain classes, restriction of ABs for certain serious infections
- reduce use of broad-spectrum ABs
- quicker identification of infections caused by resistant strains
- combination therapy
- knowledge of local strains / resistance patterns
Overcoming resistance:
- modification of existing mechanisms to e.g. prevent cleavage (beta-lactams) or enhance efficacy (e.g. methicillin)
- combinations of AB + inhibitor of e.g. beta-lactamase e.g. augmentin
- however this is a reactive approach in response to emergency
27
Q
Measuring resistance
A
- swabs are typically streaked out onto diagnostic agar to identify the causative organism
- once identified, the pathogen streaked over a plate and then overlaid with AB-containing test strips or discs
- other approaches include broth micro-dilution and PCR detection of resistance genes
- measurements are made in vitro = may not fully reflect the situation in vivo
28
Q
What are the three classes of conditions fungi cause in humans?
A
- allergy - allergic reactions to fungal products e.g. allergic bronchopulmonary aspergillosis (ABPA)
- mycotoxicoses - ingestion of fungi and their toxic products e.g. aflatoxin
- mycoses - superficial, subcutaneous or systemic colonisation, invasion and destruction of human tissue
29
Q
What are the targets for antifungal therapy?
A
- cell membrane - fungi use principally ergosterol instead of cholesterol
- DNA synthesis - some compounds may be selectively activated by fungi, arresting DNA synthesis
- cell wall - unlike mammal cells, fungi have a cell wall
