Microbiology JC088: Antimicrobial Resistance Flashcards
***Beta-lactams
- Penicillin
- Penicillin G (Strept)
- Cloxacillin (Staph)
- Piperacillin (Pseudomonas) - Cephalosporin
- 1st gen: Cephalexin
- 2nd gen: Cefuroxime (+ Gram -ve)
- 3rd gen: Ceftriaxone (++ Gram -ve), Ceftazidime (+ Non-fermenters), Cefoxitin, Cefotaxime
- 4th gen: Cefepime (+ Gram +ve)
- Anti-MRSA: Ceftaroline - BLBLI (Beta-lactam/Beta-lactamase inhibitor)
- Augmentin
- Tazocin
- Timentin - Carbapenems
- Imipenem
- Meropenem (broadest Gram +ve/-ve spectrum)
Antibiotic resistance
Intrinsic
- a **trait of the bacterial Genus / Species
- all members in the Genus / Species are resistant
- some intrinsic resistance can be difficult to detect (and may require special laboratory techniques)
- will not bother to testing susceptibility ∵ already known
- reason:
—> **no target for antibiotics
—> possess resistance mechanism as part of chromosomes (i.e. ***born with resistance mechanism)
- example: Proteus mirabilis: intrinsic resistance to Nitrofurantoin, Colistin
Acquired
- wild type are susceptible but turn resistant because of various mechanisms
—> **Mutational
—> **Horizontal gene transfer
Antibiotic / Organism combination where mutational resistance readily develop
Example:
- Staphylococci: Fusidic acid, Rifampicin, Fluoroquinolone
- Erythromycin-resistant staphylococci: Clindamycin
- Strept. pneumoniae: Ciprofloxacin
- Pseudomonas aeruginosa: All anti-pseudomonal antibiotics, except colistin and possibly meropenem
- Burkholderia cepacia: ***All relevant antibiotics
Implications:
- Use alternative agents to treat infections caused by these organisms
- Never use these agents as Monotherapy for these organisms
Acquired resistance by Horizontal gene transfer
Acquisition of ***exogenous genes from other bacterial species / genus
Vehicles that facilitate horizontal gene transfer:
- ***Integron
- ***Transposon
- integrated into chromosome / carried by plasmid from one bacterial cell to another
- Transposable elements are “jumping genes” with an ability to change their genomic / plasmid positions
Implication:
- Antibiotic resistance does NOT evolve in a ***step-wise manner!
- even if treated with only 1 antibiotic —> bacteria will select for acquisition of plasmid encoding multi-resistant genes —> resistance to multiple antibiotics
Resistance phenotype where special laboratory technique needed
∵ Expression of resistance trait is inducible
Example:
Erythromycin: induce expression of resistance gene in bacteria —> resistant to Clindamycin —> Positive D-test
(Erythromycin令到bacteria都resistant to Clindamycin)
***Big gun antibiotics
It depends on:
1. Reliable coverage against ***“most” of
- usual / unusual CAI
- usual / unusual HAI
—> affected by antimicrobial resistance (different for different areas, patient population, other factors)
- Prescribed ***infrequently (require senior endorsement)
- ***Reserved when other antibiotics doesn’t work
- Initial therapy for ***deadly infections
- ***Expensive (administrators)
Big gun = Exit doors when clinicians are faced with uncertainties
No single big gun is good for all:
- Need to localise infections (e.g. in GI / lung / UTI / heart) (i.e. Syndromic diagnosis)
—> Allow educated guess of “likely” organisms + historical susceptibility
—> Look up susceptibility table (Antibiogram) from local data (Susceptible / Intermediate / Resistant)
(Non-susceptible = Intermediate / Resistant)
Drug of choice for serious infections (e.g. bacteraemia)
- MRSA: **Vancomycin, **Linezolid, Daptomycin
- VRE: ***Linezolid, Daptomycin
- ESBL: ***Carbapenem
- CRE: no drugs
- CRAB: no drugs
Limited Population Antibacterial Drug (LPAD): fast track FDA approval pathway
- only for products to treat **serious / life-threatening infections with **few / no treatment options
—> not intended for products that would treat non-serious infections / that already have a satisfactory set of treatment options - LPAD drugs can be approved based upon ***smaller clinical trials
- ***no change in standard of evidence
- drug label would be specified as such
Antimicrobial resistance ecosystem
3 connected ecosystems:
- Clinical ecosystem: High selection pressure
- Non-clinical ecosystem: Medium selection pressure
- Environmental ecosystem: Low resistance gene selection
One health approach: collaborative efforts of multiple disciplines
- e.g. reduce reservoirs in food-producing animals to limit transmission of drug-resistant bacteria from food-producing animals to human
***Multidrug-resistant organism (MDRO)
Definition:
- Resistance to “one” critically important ***class
Example:
- MRSA: total β-lactam failure —> need Vancomycin, Linezolid
- VRE: vancomycin failure —> need Linezolid
- ESBL: cephalosporin failure —> need Carbapenem
- CRE: total β-lactam failure —> No drugs
Metrics for superbugs must be interpreted with care
- ***Percentage (can be misleading ∵ no absolute value)
- MRSA 46%
- ESBL-EC 27%
- CRAB 43%
- VRE <0.1% - ***Incidence rate (standardised but difficult concepts)
- per 1000 admission
- per bed day occupied
- per 100,000 populations
—> for trend analysis by epidemiologists - Numbers (easy to understand)
- no. of patients with a bacteria
- no. of patients with blood culture positive for a bacteria
***Antibiogram % susceptible / non-susceptible can be calculated in different ways
- All isolates
- using duplicate isolates from multiple specimens from the ***same patient may cause bias - First isolate per patient
- result of only ***first isolate of a given species recovered from each patient during the investigated time interval, regardless of body source / specimen type - ***Episode-based (denominator: 入院次數)
- commonly used (∵ doctor see patient on an episode basis) - ***Most resistant interpretation per patient
- “what percent of patients was found to have >=1 MRSA isolate?”
- gives the worst case scenario
Therefore percent must be interpreted in context (i.e. the method used to calculate the %)
Sample size is important as well!!!
—> In general, % should not be calculated if the size is <30 / use 95% confidence interval
ESBL (Extended Spectrum Beta Lactamase)
A group of enzymes produced by some Enterobacteriaceae
- ***E. coli
- Klebsiella pneumoniae
- Proteus
- Enterobacter
- Shigella
- Salmonella
Resistant to ***extended spectrum Cephalosporin:
- Ceftazidime
- Rocephin (Ceftriaxone)
Often ***multi-drug resistant:
- Cotrimoxazole
- Fluoroquinolone
- Aminoglycoside
Epidemiology:
- 50% of in-patient ESBL burden in >=75 yo
- 3 fold increase from 2003
- Seasonal surge (esp. flu season ∵ overcrowding in wards)
MRSA
MSSA (virulent) acquiring resistance gene ***SCCmec (mecA) —> MRSA (virulent + resistant)
MRSA:
- resistant to **ALL β-lactam antibiotics (with exception of anti-MRSA β-lactam e.g. **Ceftaroline)
Methicillin:
- not clinically used to treat patients
- previously used for detection of this resistance mechanism in SA
Epidemiology (annually):
- 10000+ colonisations
- 3000+ infections
- 600 bacteraemia
- 200 deaths
Acinetobacter baumannii
- less virulent
- infections are usually hospital-acquired
- causes a wide range of infections esp. pneumonia
- ***intrinsic resistance to wide range of drugs —> very limited treatment options
- ***acquired resistance occurs readily during treatment
- Carbapenem was previously treatment of choice —> widespread emergence of resistance
- some isolates are resistant to all available antibiotics including ***Colistin
2 definitions commonly used for surveillance:
- CRAB
- MRAB
- **MDR: non-susceptible to >=1 agents in >=3 classes
- **XDR: non-susceptible to >=1 agents in all but >=2 classes
- **PDR (pandrug): non-susceptible to all agents listed
Traditional approach (Culture):
- 3 cultures needed stepwisely
- Turn Around Time (TAT, time to identify organism): 4 days
- **MALDI-TOF approach:
- only 1 culture needed —> then send for MALDI-TOF
- TAT: 2 days
Antibiotic algorithm - Inpatient infections
Factors:
- age, underlying disease, infection source, severity, VIP, antibiotic history, recent culture results
Low risk infection (majority): ***Escalation strategy
- Start with narrow spectrum (Cefuroxime, Augmentin, Levofloxacin, Ciprofloxacin)
—> Tazocin
—> Carbapenem
- Excessive antibiotic therapy is harmful
—> antibiotic budget
—> ecological consequence - hospital flora
—> small gain off-set by increase in: yeast, C. difficile, more problematic superbugs (e.g. S. maltophilia, KPC, CRAB) - Minimise vicious cycle —> some patients will receive discordant treatment initially
High risk infection: ***De-escalation strategy
- Start with big gun antibiotic (Carbapenem) —> reduce down to Cefuroxime, Augmentin, Levofloxacin, Ciprofloxacin
- The later the worse: each hour of delay in antimicrobial administration over 6 hours was associated with decrease in 8% survival
