What are general mechanisms of antibiotic resistance?
Antibiotic inactivation
Alteration of Ab target
Decreased uptake
What are genetic mechanisms of resistance in bacteria?
Spontaneous DNA mutations (SNPs)
- no cost to bacteria, permanent resistance
Acquisition of new DNA
- bacteriophages - plasmids - transposons
- energy cost - must reproduce both nuclear and plasmid DNA, can be reduced in frequency with reduced selection pressure
What is conjugation?
transfer of DNA from mobile plasmid via pilus to other bacteria (From relaxosome to transferosome)
What is transformation?
Release DNA from lysed cells incorporated back into the new bacterial chromosome
What is transduction?
Transfer of resistance genes via bacetriophages
What is NORSA?
Non-multiply resistant, oxacillin resistant S. aureus
- skin infections and necrotising pneuimonia
- necrotising Fasciitis, rapidly progressive septicaemia, osteomyeltitis
- often susceptible to clindamycin, co-trimoxazole, macrolides, gentamicin
- panton-valentine leucocidin associated with virulence
- pore forming cytotoxin
What are definitions of MRSA/VISA/VRSA?
MRSA/VSSA MIC =16ug/ml
What are features of hVISA
heterogenous MRSA with minority VISA
MIC usually 1-2
ASsoc with thickened cell wall - D-Ala-D-Ala
vancomycin failures common
treat wtih linezolid, tigecycline, rifampicin/fusidate, ceftaroline
In what patients is VISA assocaited?
mainly in dialysis patients, or those with infected foreign bodies
also associated with thickened cell wall
How is VISA detected clinically?
poor response to gylcopeptide Antibiotics despite appropriate dosing and debulking
prolonged positive cultures
dialysis patients receving prolonged courses of glycopeptide antibiotics
What are features of VRSA?
rare
assoc with VAN genes from VRE
What are features of VRE?
E. faecalis and E. faecium generally
Contain Van A, B +/- others
Vancomycin resistance gene cluster
- change D-ala-D-ala to D-ala-D-lac - no vanc binding
- eliminates any produced D-ala-D-ala
- dipeptidase to cleave D-ala-D-ala
Can transfer resistance genes to staphs in vitro
What are features of Van A?
High level resistance (>64), teicoplanin resistant, inducible
What are features of Van B?
Lower level resistance (4-32), no teicoplanin resistance, inducible
What are treatment options of VRE?
Linezolid (neutropenias post 2/52 Rx)
Tigecycline
Daptomycin
What are features of non-penicillin susceptible S. pneumoniae?
caused by altered penicillin binding proteins (not beta lactamase)
RFs - children, day care centres, recent Ab use (azithro)
PSSP MIC =8
meningitis MIC =0.12
What are features of pneumococcal resistance?
Pen-resistance often confers other resistance - macrolides, cephalosporins, quinolones
Rates of PISP/PRSP vary around the world (Spain, USA, Hungary, France, Greece)
generally only relevant for meningitis and OM
What are beta lactam enzyme classes?
A - penicillinases (TEM, SHV, CTX-M)
B - Metalloenzymes (NDM, VIM, IMP)
C - cephalosporinases (AmpC)
D - oxacillinases (OXA)
What are bacteria associated with inducible beta-lactamase?
AmpC gene
- > ESCAPPM
- Enterobacter
- Serratia marcescens
- Citrobacter freundii
- Acinetobacter
- Providencia spp.
- Proteus
- (SOME Pseudomonas)
- Morganella morganii
What are features of ESBL producing bacteria?
mutations in existing b-lactamase genes (TEM, SHV) - plasmid mediated transfer
Spread from person to person, and by antibiotic pressure
Klebsiella, E. coli, Salmonella, Proteus, Enterobacter, Citrobacter, Serratia, Pseudomonas
Treat with - carbepenems, colistin, amikacin
may appear treatable in vitro with 3rd gen cephalosporins
Linked to fluoroquinolone use
What are features of Class B - metallo-beta-lactamases?
Zn dependent
Pseudomonas, acinetobacter
plasmid mediated usually - hydrolyses all b-lactams except aztreonam
hydrolyses all carbapenems
What are features of linezolid?
good activity against G+ (plus mycobacteria and nocardia)
good tissue penetration and B/A
totally synthetic, nil pre-existing resistance
no clear advantage over vanc
SE: GIT, cytopenias, neuropathy, MAO-inhibition
Avoid SSRIs, tramadol
What are features of daptomycin?
Cyclic lipopeptide
bacterial activity against most Gram positives
similar to glycopeptides + VRE
? use in VISA, VRSA
inhibited by surfactant - not in pneumonia
Binds to cell membrane and leads to inhibition of synthesis of DNA, RNA and protein - bacteriacidal
What are features of tigecycline?
derivative of minocycline protein synthesis inhibitor bacteriostatic Low MICs for MRSA, MSSA, VISA, VRE active against many gram negatives (not pseudomonas, possesses an efflux pump) BUT - MICs similar to serum levels
What are features of ceftaroline?
Novel cephalosporin - active against MRSA
Not great for VRE
Similar to cefepime for gram negs (not for ESBLS)
mainly for pneumonia and soft tissue infections
What are features of colistin?
binds to lipopolysaccharides and phospholipids in outer cell membrane - disrupts membrane and causes leakage and cell death.
renal and neurotoxicity
resistance via change in outer membrane
active: pseudomonas, acinetobacter, e. coli, some enterobacter, klebsiella, salmoneall
non-active: burkholderia cepacia, serratia, proteus, providencia, morganella, G-C, gram +ves
What are features of fosfomycin?
inhibits MurA enzyme
bacteriacidal
inhibits cell wall biogenesis
mainly for resistant UTIs (G-, G+, not pseudomonas)
What are features of moxifloxacin?
very broad spectum MSSA, NORSA, Streps, many gram -ves, anaerobes, legionalla, leprosy, TB Good tissue penetration and B/A Two step resistance (c.f. 1 for cipro) C.difficile QT prolongation