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ID exam one > bacterial resistance > Flashcards

bacterial resistance Flashcards

1
Q

risk factors for bacterial resistance - technologic and societal changes

A

introduction of broad spectrum antibiotics
elderly, debilitated, immunocompromised hosts
day care attendance

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2
Q

risk factors for bacterial resistance - economics

A

homelessness
poor nutrition
inadequate medical care
reduction in public health services

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3
Q

risk factors for bacterial resistance - microbial characteristics

A

propensity to exchange genetic material
intrinsic resistance
survive varying environmental conditions

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4
Q

risk factors for bacterial resistance - reservoir

A

ecologic niche where organisms persist

opportunity to exchange genetic material

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5
Q

risk factors for bacterial resistance - antimicrobial use (overuse and abuse)

A

correlation between usage and resistance

selective pressure by antibiotics on bacteria favoring organisms capable of resistant effect of antibiotic

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6
Q

factors influencing development and proliferation of bacterial resistance

A

overall consumption of antibiotics
-inappropriate dose, interval, duration of therapy
-effect of antibiotic on “innocent bystanders”
eradication of bacteria from site of infection
-failure to eradicate pathogen - resistance - transmission
proliferation of multiply resistant clones
inability to detect emerging pathogens
presence of invasive devices (catheters, ET tubes, etc)
more severely ill/immunocompromised patients
resistance in the community
ineffective infection control and compliance
lack of or delay in knowledge of microbial etiology of infection

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7
Q

impact of bacterial resistance

A

impact factor in patient outcomes and overall use of hospital resources
increased morbidity and mortality - delay in effective treatment, may only have a few drugs to treat resistant organisms
increase in incidence of disease - continued risk of transmission/spread of resistant isolates
increased cost of medical care - prolonged hospitalization, increase in number of procedures, use of combination and/or expensive antibiotics

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8
Q

intrinsic vs acquired resistance

A

intrinsic resistance:
-organisms always resistant to a given antibiotic
-mechanisms: absence of target site; bacterial cell impermeability
-examples: B-lactams vs mycoplasma, vancomycin vs gram-negatives, cephalosporins vs enterococci, aminoglycosides vs anaerobes
acquired resistance:
-organisms initially susceptible to drug become resistant
-occurs when there is a change in bacterial DNA (mutation) or acquisition of new DNA (chromosomal or extrachromosomal)

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9
Q

acquisition of new DNA

A

plasmids: self-replicating, extrachromosal DNA, genes encoding for resistance to many antibiotics can exist on a single plasmid, transferred from organism to organism
transposons: capable of moving from a plasmid to a chromosome and vice versa, single transposon may encode for resistance to multiple antibiotics

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10
Q

antimicrobial resistance threat report - CDC 2013 - urgent threats

A

carbapenem-resistant enterobacteriaceae
drug-resistant Neisseria gonorrhoeae
Clostridium difficile

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11
Q

antimicrobial resistance threat report - CDC 2013 - high-consequence antibiotic-resistant threats

A

significant risks identified across several
may not be currently wide spread but have the potential to become widespread, requiring urgent public health attention to identify infections and to limit transmission

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12
Q

antimicrobial resistance threat report - CDC 2013 - serious threats

A

significant antibiotic-resistant threats
not considered urgent for various reasons - low or declining domestic incidence, reasonable availability of therapeutic agents
threats will likely worsen and become urgent without ongoing public health monitoring and prevention activities
multidrug-resistant Acinetobacter baumannii
fluconazole-resistant Candida
Extended-spectrum B-lactamase producing Enterobacteriaceae (ESBL’s)
Multidrug-resistant Pseudomonas aeruginosa
Vancomycin-resistant enterococci
Methicillin-resistant Staphylococcus aureus
Drug-resistant Streptococcus pneumoniae
Drug-resistant tuberculosis

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13
Q

antimicrobial resistance threat report - CDC 2013 - concerning threats

A

threat of antibiotic resistance is low and/or multiple therapeutic options are available
these bacterial pathogens cause severe illness
threats require monitoring and rapid incident or outbreak response
vancmoycin-resistant Staphylococcus aureus
erythromycin-resistant Group A streptococcus
Clindamycin-resistant Group B streptococcus

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14
Q

specific mechanisms of resistance **

A

enzymatic inactiviation: B-lactamases, aminoglycoside-modifying enzymes
alteration of target site: PBPs, cell wall precursors, ribosomes, DNA gyrase/topoisomerase
altered permeability of bacterial cell: efflux pumps, porin changes

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15
Q

narrow-spectrum B-lactamases

A

Class: A

characteristics: hydrolyze penicillin, produced by enterobacteriaceae
examples: staphylococcal penicillinase, TEM-1, TEM-2, SHV-1

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16
Q

ESBL B-lactamases

A

Class: A

characteristics: Hydrolyze narrow and extended-spectrum B-lactams
examples: SHV-2, CTX-M-15, PER-1, VEB-1

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17
Q

serine carbapenemases B-lactamases

A

Class: A

characteristics: hydrolyze carbapenems
examples: KPC-1, IMI-1, SME-1

18
Q

Metallo-B-lactamases

A

Class: B

characteristics: hydrolyze carbapenems
examples: VIM-1, IMP-1, NDM-1

19
Q

Cephalosporinases B-lactamases

A

Class: C

characteristics: Hydrolyze cephamycins and oxyimino B-lactams
examples: AmpC, P-99, ACT-1, CMY-2, FOX, MIR-1

20
Q

OXA-type enzymes B-lactamases

A

Class: D

characteristics: hydrolyze oxacillin, oxyimino B-lactams, carbapenems
examples: OXA enzymes

21
Q

Group I (AmpC) B-lactamases *

A

cephalosporinases (substrate - cephalosporins) - greater hydrolysis of cephalosporins than penicillins
Primarily seen in Serratia, Pseudomonas, Indole-positive Proteus, Citrobacter, Enterobacter (SPICE)
-Indole + : P. vulgaris, Providencia, Morganella
-SPACE if replace Indole-positive Proteus with Acinetobacter
Referred to as Amp-C or inducible organisms
Primarily chromosomalmediated, but plasmid-mediated resistance reported
Not inhibited by previous B-lactamases inhibitors** (clavulanic acid, tazobactam, sulbactam)
inhibited by avibactam (combined with ceftazidime)
induction of B-lactamase production (inducible)
-transient elevation in enzyme production in the presence of certain B-lactam agents
-initially, gene for B-lactamase production is repressed* - inducer - gene derepressed* - increased B-lactamase production
-remove inducer - gene repressed - B-lactamase production back to low level
different B-lactams induce AmpC B-lactamases to varying degrees

22
Q

strong inducers vs weak inducers **

A

Strong inducer (B-lactamase producing) and labile: Pen G, ampicillin, 1st gen cephalosporins, cefoxitin
strong inducers and stable: imipenem and meropenem
weak inducer and labile: 2nd and 3rd generation cephalosporins, ureidopenicillins, monobactams
weak inducer and stable: carbenicillin

23
Q

Group I (AmpC) B-lactamases - selection of stably derepressed mutants

A

may develop in AmpC B-lactamse producing organisms during therapy with 3rd generation cephalosporins
evolved by genetic mutation from native B-lactamases (TEM-1, TEM-2, SHV-1)
over 200 genetic variants of TEM- and SHV-type enzymes
most frequently reported in Klebsiella species and E coli
Confer resistance to ceftazidime, cefotaxime, ceftriaxone, and azatreonam; cefepime activity variable
inhibited by avibactam; may be inhibited by tazobactam (CTX-M enzymes)***

24
Q

risk factors for infection/colonization with ESBL-producing pathogens

A 
prolonged hospital stay
prolonged ICU stay
residency in long-term care facility
exposure to 3rd generation cephalosporins
exposure to ciprofloxacin
exposure to aminoglycosides
total antibiotic use
delayed appropriate therapy
indwelling catheter
severity of illness
decubitus ulcer
endotracheal or NG tube
ventilator days, ARDS
25
Q

ESBLs - treatment

A

carbapenems - treatment of choice***
-imipenem, meropenem, doripenem, ertapenem
ceftazidime-avibactam (very expensive)
Tigecycline
high dose pip/tazo - less effective than carbapenems; may be acceptable for CTX-M enzymes
fluoroquinolong - high prevalence of cross resistance
aminoglycoside - not usually used as monotherapy
TMP/SMX
colistin - only if multidrug-resistant

26
Q

Class A carbapenemases

A

5 major grous: KPC, GES, SME, IMI, NMC-A
KPC* - Klebsiella pneumoniae carbapenemase
-plasmid mediated
-found in K. pneumoniae, E. coli, E. cloacae, C. freundii, K. oxytoca, others
-confers resistance to all B-lactams
-identified in hospitals and long-term care facilities
-inhibited by avibactam

27
Q

Class B carbapenemases

A

metallo-B-lactamases
IMP, VIM, NDM (New-Delhi metallo-B-lactamase)**
widespread in P. aeruginosa, Acinetobacter species and Enterobacteriaceae
Significant increase in rates of occurance
genes located on chromosome of plasmid
not inhibited by any B-lactamase inhibitor
Aztreonam is stable and active (but get hydrolyzed by other enzymes - aztreonam/avibactam - investigational)

28
Q

Class D OXA carbapenemases

A

primarily found in acinetobacter species
weak hydrolytic activity (need additional resistance mechanism(s))
genes located on chromosome or plasmids

29
Q

Duration of carriage of CRE after hospital discharge

A

patient with CRE-positive culture were followed up by rectal swab cultures
mean time to CRE negativity - 387 days
percent of patients with positive cultures:
-78% at 3 months
-65% at 6 months
-39% at 12 months
duration of carriage associated with: repeat hospitalization and clinical culture

30
Q

Treatment of carbapenemase-producing gram-negatives

A

If a serine carbapenemase:
-ceftazidime-avibactam (+/- another agent?)
-colistin + meropenem
-colistin + meropenem + tigecycline
If a metallo-B-lactamase
-Azteonam + ceftazidime-avibactam
-therapy determined by susceptibility testing

31
Q

Ceftazidime/avibactam outcomes in CRE infections

A

Retrospective study of 37 patients with CRE infections treated with CAZ/AVI
-K. pneumoniae (31), E coli (3), enterobacter sp. (3)
-KPC in 29 isolates; no metallo-B-lactamases
-all initial isolates were susceptible to CAZ/AVI; monotherapy in 26 patients
clinical success 59%; 30-day survival 76%

32
Q

aminoglycoside-modifying enzymes

A

3 mechanisms: acetylation, nucleotidylation, phosphorylation
modify aminoglycoside structure by tranferring chemical group to a specific side chain - impairs uptake and/or binding to bacterial ribosome
nomenclature - based on chemical group transferred and site of transfer
-AAC 6’ - transfers an acetyl group to 6’ position
-bifunctional enzyme - AAC 6’-APH 2”

33
Q

Altered target site - penicillin binding proteins (PBPs)

A

altered PBP - decreased binding affinity for target
depends on degree of alteration - organism may exhibit increased MIC but remain susceptible or organism may be resistant
Methicillin resistance in S. aureus (production of new PBP 2a or 2’ encoded by mecA gene)
penicillin and cephalosporin resistance in S. pneumoniae

34
Q

altered target site - altered cell wall precursors

A

mechanism of vancomycin resistance in enterococci
vancomycin inhibits cell wall synthesis by binding to the D-alanine-D-alanine terminus of the pentapeptide (peptidoglycan precursors)
Alteration of D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser

35
Q

altered target site - ribosomes

A

macrolide/azalide resistance in S. pneumoniae
-ermB gene; cross resistance with clindamycin
aminoglycoside resistance in gram-negatives
clindamycin resistance

36
Q

altered target site - DNA gyrase/topoisomerase IV

A

fluoroquinolone resistance in gram-negatives and S. pneumoniae
high-level fluoroquinolone resistance associated with mutations in both targets

37
Q

efflux-mediated resistance

A

tetracyclines - gram-negatives, many others
Chloramphenicol
Fluoroquinolones - P. aeruginosa, S. pneumoniae, staphylococci
Macrolides, azalides - S. pneumoniae - mefA gene - susceptible to clindamycin
carbapenems - P. aeruginosa - meropenem more than imipenem

38
Q

reduced outer membrane permeability

A

porins - facilitate passage of antibiotics through outer membrane of gram-negative organisms
rate of antibiotic diffusion is dependent on number/properties of porin and physiochemical characteristics of the antibiotic
mutations result in loss (or change) in specific porins - resistance
most commonly seen with enterobacteriaceae and P. aeruginosa
-common in carbapenem-resistant P. aeruginosa (imipenem more than meropenem or doripenem)
-fluoroquinolones

39
Q

Plasmid-mediated quinolone resistance in K. pneumoniae

A

PMQR arise from expression of proteins encoded by qnrA, qnrB and qnrS genes that protect DNA gyrase
85 non-duplicate clinical isolates of K. pneumoniae with reduced carbapenem susceptibility studied
42 isolates contained blaKPC genes
2/42 isolates encodes a PMQR determinant

40
Q

Emergence of colistin resistance and heteroresistance

A

described in A. baumannii, P. aeruginosa, and K. pneumoniae
most common mechanism - modification of lipopolysaccharide
recently report describing colistin resistance in A. baumannii due to complete loss of lipopolysaccharide production
risk factors: age, duration of ICU stay, duration of mechanical ventilation, surgical procedures, use of colistin monobactams, duration of 3rd generation cephalosporin use
multivariate analysis - use of colistin

41
Q

colistin resistance - MCR-1

A

first identified in November 2015 in China and May 2016 in USA
mcr-1 gene encodes for resistance to colistin
located on a plasmid, transferrable to other bacteria
identified in 5 patients and 2 pigs in USA
real possibility of gram-negative bacteria becoming resistance to every available antibiotic

42
Q

seven steps to preserve the miracle of antibiotics

A

establish a US database for antibiotic use and resistance comparable to the EU
restrict use of antibiotics in agriculture
prevent selected nosocomial infections
aggresively promote antimicrobial stewardship
promote use of new diagnostics with emphasis on point-of-care molecular methods
reduce FDA antibiotic barrier
facilitate public-private partnerships for antibiotic development

ID exam one (11 decks)

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