ID - antibiotic resistance Flashcards
Mechanism of methicillin resistance in MRSA
Modified penicillin-binding protein – altered target site of beta-lactam binding
- Not enzymatic – can’t be overcome by a beta-lactamase inhibitor (e.g. Augmentin)
Treatment of Severe MRSA Infections
Source control
- Glycopeptides e.g. vancomycin, teicoplanin
- Linezolid
- Tedizolid - improved version of linezolid
- Daptomycin
- Tigecycline
- Ceftaroline
Linezolid
inhibits bacterial protein synthesis; binds to both 30S and 50S ribosomal subunits.
- Broad spectrum of activity against Gram Positive bacteria
- May also suppress toxin production
- Excellent bioavailability (100%), with good bone, lung and CNS penetration
- Resistance remains low despite >20 years use in USA
- Increasingly used for MDR and XTR Tuberculosis
- Major SE: reversible bone marrow depression with prolonged use, irreversible neuropathy, optic neuropathy (rare)
Daptomycin
- cyclic lipopeptide bactericidal antibiotic that causes depolarization of the bacterial cell membrane
- ineffective in respiratory tract infections due to inactivation by pulmonary surfactant (can’t use for pneumonia)
- Needs loading doses and dose adjustment in renal failure
- Important SE’s: myopathy, peripheral neuropathy, eosinophilic pneumonia
- Serial measurements of serum creatine kinase needed
Tigecycline
- Antibiotic category: Glycylcycline; (minocycline derivative - doxy derivative really)
- Protein synthesis inhibitor, binding at the 30s ribosomal subunit,
- predominantly bacteriostatic in action
- Eliminated via biliary tract – therefore limited utility in UTI’s
- Does not require dose adjustment in renal failure or dialysis
- High volume of distribution (it distributes avidly to tissues) results in very low serum concentrations – unsuitable for primary bacteraemia therapy
- Broad gram positive activity (including MRSA, VRE) and gram negative activity (including ESBL’s and AmpC producers), anaerobes, and atypical pathogens
- Potential salvage therapy for severe or refractory C. difficile infection
- Higher risk of treatment failure and death than with other antibiotics, but typically used as drug of last resort when no other options available
Ceftaroline
5 th generation cephalosporin
- High affinity for PBP-2a (the altered binding site that gives methicillin resistance)
- Active against gram +ve bacteria (including coag -ve staphs) and resistant Strep. pneumo
- May be active against vancomycin-resistant E. faecalis but not E. faecium
- Some activity against gram-positive (e.g. oral) anaerobes
- Emerging data on treatment of MRSA bacteremia.
- Combination ceftaroline + daptomycin - earlier clearance of bacteraemia
- Limited activity against gram –ve’s. Not active against Pseudomonas, or AmpC or ESBL producers
- Low side effect profile but a few case reports of eosinophilic pneumonia
- Low protein binding, mainly renal clearance, needs renal dose adjustment
Dalbavancin and oritavancin
“new and improved vancomycin”
* 2 nd generation Lipo-glycopeptide family
* Inhibition of bacterial cell wall biosynthesis
- Dalbavancin has prolonged terminal half-life of 14.4 days and oritavancin has 16 days terminal half life!!!
- Lower MIC’s (improved activity) than vancomycin for most MRSA
- Once weekly administration (!) - convenient and cost-effective for acute bacterial skin and soft tissue infections
Vancomycin in gram negative bacteria
Can not penetrate outer lipid membrane of gram negatives
– so no Gram negative activity
Vancomycin AE
Nephrotoxicity, ototoxicity, “Red Man” syndrome, neutropenia, thrombocytopenia, rash
Vancomycin MOA
Inhibits synthesis of bacterial cell wall by binding to “Dalanyl-D-alanine terminus of the pentapeptide side-chain” preventing cross-linking.
Teicoplanin
- Glycopeptide antibiotic - similar to vancomycin
- Equally effective as vancomycin
- But can be given as slow injection over 5 min, or 30-min infusion or even IM injection
- Longer half-life than vancomycin (~168h vs 11h) so daily dosing
- Nephrotoxicity / ototoxicity relatively rare
- Drug level monitoring not required unless pre-existing renal impairment
- Less “red man syndrome” than vancomycin …but it’s more expensive
Mechanism of Vancomycin resistance (Enterococci)
D-Ala D-Ala -> D-Ala D-Lac
Resistance Genes for Vancomycin
- VanA gene cluster: Vanc & teicoplanin resistance (D-Ala D-Ala -> D-Ala-D-Lac). Very high vanc MIC. Genes found on plasmid or chromosome (transposon). Transferable.
- VanB gene cluster: Vanc. resistant (moderate vanc MIC) but remains teicoplanin sensitive (D-Ala D-Ala -> D-Ala-D-Lac). Genes found on transposon. Transferable.
- VanC gene cluster: Vanc. resistant (low level only) but teicoplanin sensitive D-Ala D-Ala -> D-Ala D-Ser. Occurs naturally, found on chromosome of E. gallinarum & E. casseliflavus. Not transferable.
Issues with VRE
- GI colonisations may persist for years. Decolonisation not possible.
- Easily spread: lasts 60 minutes on hands, 4 months on objects & surfaces
- Difficult to eradicate from hospital environment
- Transferable resistance mechanism (plasmid) to enterococci and other bacteria (e.g. S. aureus = VRSA)
- Clinical infections typically nosocomial and effect vulnerable hosts: e.g.
central lines, urinary catheters, in ICU/dialysis units
- Limited treatment options…previously
VRE Treatment Options
- Penicillin / Amoxicillin / Ampicillin – it may be isolated vancomycin resistance
- Teicoplanin – only for VanB / Van C
- Linezolid
- Daptomycin +/- beta-lactam
- Tigecycline
- Ceftaroline (but not E. faecium)
- Other: nitrofurantoin or fosfomycin (only for uncomplicated UTI)
New name for CRE?
Carbapenemase-Producing Enterobacteriaceae (CPE)
Carbapenemase-Producing Organisms (CPO)
was Carbapenem-Resistant Enterobacteriaceae
