stafilococco aureo ed enterococco of potential conflicts of interest emanuele durante mangoni, md...
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Stafilococco aureo ed Enterococco
Emanuele Durante Mangoni, MD PhD
Napoli
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Disclosure of potential conflicts of interest
Emanuele Durante Mangoni, MD PhD
• My Institution has received research funding for my group from MSD, Pfizer
• I have received personal fees or participated in advisory boards or have been in the speaker’s bureau of Pfizer, MSD, Angelini, Bio-Merieux, Abbvie, Sanofi-Aventis, Medtronic, and DiaSorin.
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S. aureus – prevalence of methicillin resistance
EDCD Surveillance Report 2016
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2011: 7 years old
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Treatment options for MR Staphylococci
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30-day mortality
24% for MRSA BSI *
* ANZCOSS dataset
Vancomycin weaknesses:
1) slow bacterial killing
2) poor tissue penetration (e.g. lung)
3) slow clearance of bacteraemia
4) high mortality
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How Vancomycin performs compared to other
anti-MRSA Agents
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MRSA Pneumonia: Zephyr Study Outcomes
Clin Infect Dis 2012; 54:621–9.
Nephrotoxicity:
Vancomycin 18.2%
Linezolid 8.4%
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Daptomycin has equal activity against BSI due to met-S AND met-R Staph. aureus
Fowler V Jr et al, NEJM 2006
p = 0.74p = 0.28
DAPTO COMPARATOR
median time to clearance of bacteremia
MRSA 8 9 p = 0.25
MSSA 4 3 p = 0.28
6 mg/kg/d
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Primary study outcome: Infection Related Length Of Stay
No difference between DAPTO and VANCO
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NEPHROTOXICITY OF VANCOMYCIN vs DAPTOMYCIN
Cosgrove SE et al. Clin Infect Dis. 2009;48:713-21
Vancomycin is as much nephrotoxic as
Gentamycin
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21 pts bacteremic at the time of Dapto start
19 (91%) cleared bacteremia after a median of 4 days [2-8]
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Daptomycin does not impair renal function
International Journal of Antimicrobial Agents 48 (2016) 61–68
Renal impairment Incidence
RIFLE R
RIFLE I7.9%
0.9%
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Tailoring Vanco vs Alternative Agents for MRSA infectionsfrom MIC values to clinical judgement
VANCOMYCINOPTIMISED DOSAGE
NO KIDNEY DISEASENO CHRONIC COMORBIDITIES
ABILITY TO MEASURE THROUGH LEVELSNEED TO REDUCE COSTS
ALTERNATIVE RX
KIDNEY DISEASEMEDICAL COMORBIDITIES
OUTPATIENT THERAPY IN STABLE CASES WEALTHIER HOSPITAL ENVIRONMENT
EDM 2015, personal opinion
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Vancomycin-based combinations
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Clinical Infectious Diseases 2016; 62(2):173–80
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Clinical Infectious Diseases 2016; 62(2):173–80
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87 patients: 48 MRSA, 39 MSSA
Infection 2011; 39(6): 549-554
Aminoglycoside(n = 49)
No aminoglycoside(n = 38)
RR (95%C.I.) p value
duration of bacteremia 5 days 5 days Na 0.49
6-month all-cause mortality 51% 42.1% 1.17 (0.81−1.69) 0.41
complications of IE 71.4% 73.7% 0.95 (0.64−1.43) 0.82
recurrence within 6 months 8.2% 23.7% 0.51 (0.22−1.17) 0.04
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Cosgrove SE et al. Clin Infect Dis. 2009;48:713-21
MS and MR S. aureus
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Aminoglycosides for MRSA Infections:Use with caution or avoid
• Elderly
• Chronic kidney disease K/DIGO >3
• Endocarditis with heart failure
• Use of diuretics
• Iodinated contrast media for coronary angiography
EDM 2015, personal opinion / experience
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Rifampin
Penetration into biofilm and abscesses
Kills organisms in stationary phase
Rapid emergence of resistance during monotherapy and with high bacterial loads
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Prospective, randomized, controlled, open-label trial 22 patients: Vancomycin 1 g every 12 hours (mono -therapy) 20 patients: Vancomycin 1 g every 12 hours + rifampin 600 mg orally once daily (combo)for 28 daysMRSA infective endocarditis – All NVE
OutcomesMonotherapy Combination therapy p value
Cure rate 18 [82%] 18 [90%] >0.20 (NS)Duration of bacteremia 7 days 9 days >0.05 (NS)
Vancomycin trough concentrations were 11.4 µg/mL and 10.4 µg/Ml (p=0.20)
Ann Intern Med 1991; 115(9): 674-680
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Rifampin
N = 42
No Rifampin
N = 42
P-Value
APACHE II score 17 13 0.08
LIE 33% 7% 0.003
Duration of bacteremia 5.2 days 2.1 days 0.002
Emergence of Resistance 21% 0% < 0.001
Increased LFTs 23% 2% 0.014
Drug Interactions 52% 0% < 0.001
Survival 79% 95% 0.048
NVEMRSA 79%
RIF add aftermedian 3 days
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MRSA MRSE
h-VISA
Infect Dis Ther (2015) 4:51–65
Rifa+Dapto/Vanco: best combination vs staph biofilm
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a prior to antibiotic exposure
MRSE embedded in biofilm SEM images are at 1000× magnification
b after 72 h of DAP + RIF exposure
Infect Dis Ther (2015) 4:51–65
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Rifampin use in MRSA Infections
• Biofilm-associated infection
• When prosthesis remains in place
• Not in acute, bacteremic cases
• Not in chronic liver disease patients, epilepsy, polypharmacy
• When drug-drug interactions are not an issue
• Start rifampin after bacterial burden has decreased / blood cult. cleared
EDM 2015, personal opinion, based on existing evidence
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New / Innovative Options against MRSA
• Ceftaroline - Ceftobiprole
• Dalbavancin
• Fosfomycin-based combinations
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Ceftaroline - Ceftobiprole
• 5th gen cephalosporins, excellent safety
profile
• Bind to the altered transpeptidase PBP2a
(mecA gene product)
• Allow to treat MRSA infections and rare
penicillin-resistant pneumococci with a
beta-lactam
• Bactericidal, PD T>MIC
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Efficacy was evaluated in 126 patients
MRSA BSI sources: lower respiratory tract (32.5%) infective endocarditis (24.6%)
Clinical success was observed for 86 (68.3%) of the patients in the efficacy population, with 28 (22.2%) experiencing in-hospital mortality
Pts with cleared BSI on CEFT: 115 (91.3%)
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Safety was evaluated in 211 patients
Adverse reactions were uncommon: Clostridium difficile infection 6 patients (2.8%) Rash 7 patients (3.3%) Neutropenia 3 patients (1.4%)
Mean time from CEFT start to neutropenia: 16 days
median duration of ceftaroline therapy: 11 days (IQR, 5-15 days)
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Ceftaroline use & safety
• 600 mg q12h, normal renal function eGFR>50
• <50-30 mL/min: 400 mg q12h
• <30 mL/min: 300 mg q12h
• <15 ml/min or HD: 200 mg q12h (after HD)
• IV infusion over 60’
• CDI may occur; 10% develop a positive
direct Coombs test
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Ceftobiprole use & safety
• 500 mg q8h, normal renal function eGFR>50
• <50-30 mL/min: 500 mg q12h
• <30 mL/min: 250 mg q12h
• <15 ml/min or HD: 250 mg q24h (after HD)
• IV infusion over 120’
• CDI may occur; few patients may develop
hypersensitivity reactions
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Summary: Ceftaroline / Ceftobiprole
• Are an option for salvage treatment
• Rapidly clear bacteremia
• Well tolerated
• Standard dose may not be optimal for MRSA BSI / IE
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Summary: Dalbavancin
• Is an option for parenteral outpatient rx
• Use upfront in ABSSSI not yet BSI
• Due to spectrum of activity and biofilm penetration, deserves
consideration for cardiovascular prosthesis infections
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bactericidal with a broad spectrum including:- Gram-positives (e.g. Enterococcus faecalis and Staph aureus) - Gram-negatives (e.g. E. coli & Klebsiella)
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Fosfomycin disodium IV PK
• High serum concentrations with 2 - 4 g every 6 h
• Adequate penetration into various tissues, including lung, central
nervous system, and bone
• Rapid onset of resistance, always combine in serious infections
• Vials of 2, 4 and 8 g
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Fosfomycin disodium: Safety
• It is a very well tolerated drug
• AE are mostly GI: nausea, vomiting and diarrhea
• Skin rashes
• AE occur in 5% of patients
• With a (recommended) daily dose of intravenous fosfomycin up to 8–16
g, the amount of sodium administered can range from 2.6 to 5.3 g per
day (1 g of fosfomycin delivers 330 mg [14.4 mEq] of sodium).
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synergism between these antibiotics against MRSA is associated with
changes in the proportion of specific membrane penicillin-binding
proteins (PBP) induced by fosfomycin, specifically PBP2a in the MRSA
membrane, which can regress, leading strains to regain their
susceptibility to beta-lactams
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3 patients with left-sided staphylococcal
endocarditis (1 with MSSA prosthetic
aortic valve endocarditis and 2 with MRSA
native-valve endocarditis) were
successfully treated with high-dose
intravenous daptomycin (10 mg/kg/day)
plus fosfomycin (2 g every 6 h) for 6
weeks.
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This combination was tested in vitro against
7 MSSA, 5 MRSA, and 2 intermediately
glycopeptide-resistant S. aureus isolates and
proved to be synergistic against 11 (79%) strains
and bactericidal against 8 (57%) strains.
This combination deserves further clinical study.
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Summary: Fosfomycin combinations
• Very valuable option to compound other molecules
• No solid clinical end point data yet
• Sodium and water overload may be an issue in
decompensated patients (cong heart failure, adv cirrhosis)
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HLGR E.faecalis – prevalence of resistance
EDCD Surveillance Report 2016
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VR E.faecium – prevalence of resistance
EDCD Surveillance Report 2016
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ESC 2015 guidelines for Enteroccal Endocarditis
Habib G. Eur Heart J 2015
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Fernández-Hidalgo N. Clin Infect Dis 2013
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Fernández-Hidalgo N. Clin Infect Dis 2013
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Treatment choices for MDR Enterococci (Amp-R, HLGR, VRE)
Site of infection First choice Alternative Comments
Bacteremia / Endocarditis Daptomycin >10 mg/kg/day
Linezolid, 600 mg bid
Daptomycin + Ampicillin
Daptomycin + Ceftaroline
Daptomycin + Linezolid
Urinary tract infections Nitrofurantoin, 100 mg qid
Fosfomycin, 3 g od, 2 doses
Ampicillin HD + Gentamycin
Intra-abdominal infections Tygecycline, LD 100 mg > 50 mg bid Teicoplanin, 12 mg/kg/day
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Treatment of Vanco-R / Amp-R enterococcal IE (current guidelines)
Baddour LM. Circulation 2015
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Unadjusted
30d mortality
Adjusted
Antimicrobial Agents and Chemotherapy 2014; 58(2):734–739
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Treatment of MDR Staph. aureus & Enterococci: SUMMARY
A conservative, GL-based-approach relies rx on Vanco and Ampi
There are still limited data supporting the superiority of alternative
treatments / combinations
The new options can be used though a cautious, patient-tailored
approach, and can have some important advantages in terms of safety
and easy of administration
We do have rescue treatment options for ‘clinically’ recalcitrant infections
We need more and more RCT on whose results base our daily practice