combined therapy og gram-positive infections · falagas, mf et al. jac 2006; 57:639. questions...
TRANSCRIPT
![Page 1: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/1.jpg)
Bruno Baršić
ISCVID Dubrovnik 2013
Combined therapy of gram-positive
infections
![Page 2: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/2.jpg)
Objective
Critically evaluate present state of
combined treatment for Gram-
positive infections
![Page 3: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/3.jpg)
Treatment of Staphylococcal IE
Recommended combinations
MSSA NVIE, MRSA NVE ß-lactam (vancomycin) + Gentamicin 3 mg/kg 3-5
days in 2 or 3 doses (ECS, BSAC, AHA optional)
RSIE – IDUs ß-lactams 2 w (glycopeptides 4 w) (AHA
gentamicin optional)
Oral : ciprofloxacin+rifampin
MRSA NVE add gentamicin + rifampin in patients who do not
response on conventional therapy
PVE ß-lactam (vancomycin) + rifampin + gentamicin (2
w) (FQ)
![Page 4: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/4.jpg)
Questions regarding gentamicin use
in the treatment of staphylococcal IE
Need? ( effectiveness ?)
Duration? (3 , 5, ≥14 days)
Dose? (3 or 6 mg/kg?)
Administration? (qd,bid,tid?)
Side effects are certain Nephrotoxicity
Ototoxicity
Obesity
Longer persistence of bacteremia in addicts with RSIE in monotherapy group (13 vs 17 pts) 3.6+-1.3 days vs. 2.6+-
0.9 days
Negative BC on day 2: 1/13 vs 8/16 pts.
Korzenowsky at al. AIM, 1982
![Page 5: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/5.jpg)
Survival rates in clinical trials comparing ß-
lactam monotherapy with combined gentamicin
therapy
0
20
40
60
80
100
120
Su
rviv
al
rate
s (
%)
Monotherapy Combined
![Page 6: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/6.jpg)
Monotherapy vs. Combined gentamicin
All cause mortality
Falagas, MF et al. JAC 2006; 57:639
![Page 7: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/7.jpg)
Questions regarding gentamicin use
in the treatment of staphylococcal IE
Need? ( effectiveness ?)
Duration? (3 , 5, ≥14 days)
Dose? (3 or 6 mg/kg?)
Administration? (qd,bid,tid?)
Side effects are certain Nephrotoxicity
Ototoxicity
Obesity
Longer persistence of bacteremia in addicts with RSIE in monotherapy group (13 vs 17 pts) 3.6+-1.3 days vs. 2.6+-
0.9 days
Negative BC on day 2: 1/13 vs 8/16 pts.
Korzenowsky at al. AIM, 1982
![Page 8: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/8.jpg)
Mean percentile change in endogenous creatinine clearance (EECC) from diagnosis to
hospital discharge in 286 patients with infective endocarditis, grouped by days of gentamicin
treatment.
Buchholtz K et al. Clin Infect Dis. 2009;48:65-71
![Page 9: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/9.jpg)
Kaplan-Meier plot of cumulative survival after hospital discharge for 136 patients with
infective endocarditis by percentage change in endogenous creatinine clearance (EECC)
from diagnosis to hospital discharge.
Buchholtz K et al. Clin Infect Dis. 2009;48:65-71
![Page 10: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/10.jpg)
Time to a clinically significant decrease in creatinine clearance (CrCl).
Cosgrove S E et al. Clin Infect Dis. 2009;48:713-721
![Page 11: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/11.jpg)
Use of gentamicin in the treatment of
MSSA and MRSA IE – ICE PLUS
STUDY
65
69
134 MSSA episodes 48,5 %
Yes No
2222
44 MRSA episodes50.0 %
Yes No
![Page 12: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/12.jpg)
Use of gentamicin in the treatment of
52 episodes of S.aureus IE
11
30
11
No of patients
None <=1 w >1 w
Buchholtz K et al. CID 2009; 48:65
![Page 13: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/13.jpg)
Use of gentamicin for S. aureus
infections
Guidelines for the treatment of MRSA
infections - (CID 2011; 52:285)
Addition of gentamicin to vancomycin is not
recommended for bacteremia or native valve
infective endocarditis
PVE ? (B-III)
Vancomycin failure ? (B-III)
![Page 14: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/14.jpg)
New combinations?
Televancin + aminoglycosides1
Televancin + ß-lactams (penems?1)
Tygecyclin + gentamicin2
Daptomycin + ß-lactams (gentamicin)3?
1Leonard S, AAC, 2013; 2 McConeghy KW, DMID, 2010; 3 Steenbergen JN, JAC 2009
![Page 15: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/15.jpg)
Treatment of S.viridans and S.bovis IE
Gudielines (AHA, ESC, BSAC)
Position of gentamicin
Two-weeks treatment
Infection caused by a strain which penicillin MIC
>0.12 and ≤0.5 mg/L (2 weeks, once daily)
PVE
2 weeks if MIC <0.12 mg(L
6 weeks if MIC>0.12 mg/L
![Page 16: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/16.jpg)
The role of aminoglycosides for the
treatment of IE caused by Gram-
positive bacteria
Falagas, MF et al. JAC 2006; 57:639
![Page 17: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/17.jpg)
Use of gentamicin in the treatment
of S. viridans IE – ICE PLUS
STUDY
175
69
244 episodes – 71.7%
Yes No
![Page 18: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/18.jpg)
Use of gentamicin in the treatment of
106 episodes of streptococcal IE
9
3859
No of patients
None <=1 w >1w
Buchholtz K et al. CID 2009; 48:65
![Page 19: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/19.jpg)
Treatment of Enterococcal IE
Current Gudielines (AHA, ESC,
BSAC)
Penicillin S
ampicillin or penicillin
(vancomycin)
+
gentamicin (1 mg/kg
tid)
(streptomycin for
gentamicin R)
Gentamicin R
E.faecalis
ampicilin+ceftriaxone
imipenem+ampicillin
ampicillin
(BSAC guidelines)
E.faecium
Linezolid
Quinupristin-dalfopristin
![Page 20: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/20.jpg)
Use of gentamicin in the treatment of
enterococcal IE – ICE PLUS STUDY
83
53
136 episodes – 61.0%
Yes No
![Page 21: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/21.jpg)
Other combinations for enterococcal
infections
Ampicillin + ceftriaxone1
Daptomycin+gentamycin
Tigecycline+rifampicin
1Fernandez-Hidalgo, N. CID; 2013
![Page 22: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/22.jpg)
Ampicillin Plus Ceftriaxone Is as Effective as
Ampicillin Plus Gentamicin for Treating
Enterococcus faecalis Infective Endocarditis
0
5
10
15
20
25
%
Outcome
AC AG
0
5
10
15
20
25
New renal failure
% AC
AG
Fernandez-Hidalgo, N.
CID; 2013
![Page 23: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/23.jpg)
Gentamicin Improves the Activities of Daptomycin
and Vancomycin against Enterococcus faecalis In
Vitro and in an Experimental Foreign-Body Infection
Model
Bacterial load of planktonic bacteria
in cage fluid during treatment (black
bars) and 5 days after treatment
(white bars). Values are means ±
standard errors of the means (SEM).
DAP, daptomycin; VAN, vancomycin;
GEN, gentamicin.Tafin UF, J Infection 2011; 55: 4821
![Page 24: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/24.jpg)
Is it time to change guidelines?
Daily routine doesn’t follow guidelines!
![Page 25: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/25.jpg)
Median time of gentamicin treatment
and the incidence of premature
withdrawal
Olaison et al. CID
2002
median 15 days
premature withdrawal
65/75 (86.7%) (before
36 weeks)
Fernandez-Hidalgo N,
CID 2013
median 23 days (IQR,
14–34 days) if no
adverse event; 14
days [IQR, 12–20
days] if AE)
premature withdrawal
56/87 (64.1%)
![Page 26: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/26.jpg)
Gentamicin use in IE
01020304050607080
% o
f p
rescri
bin
g
Administration once-daily
6122,1
16,9
Gentamicin doseused by physicians
(%)
3 mg/kg
4 mg/kg
>=5mg/kg
Beraud G,et al. EJCMID 2012,31:1413
![Page 27: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/27.jpg)
Prescription patterns in the treatment
of IE
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Staphylococcal IE
Streptococcal IE
Enterococcal IE
Other
Literature based
Guideline based
Beraud G,et al. EJCMID 2012,31:1413
![Page 28: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/28.jpg)
Gentamicin use in IE
Deviation from guidelines
0
10
20
30
40
50
60
70
80
% o
f p
rescri
bin
g
Reasons of Inapp. Rx.
0
5
10
15
20
25
Inapp. Appropriate
Mortality
Demonchy E,et al. Med Mal Infect 2011;41:602
p=0.66
![Page 29: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/29.jpg)
2Jung, Young Koh, et al. Critical Care Medicine. 2010; 38:175
Effect of vancomycin plus rifampicin in the treatment of nosocomial methicillin-resistant Staphylococcus aureuspneumonia
p=0.05
In the VR group, resistance
to RFP developed in 14
patients (34.1%). →
Eradication rate 38.5% vs.
88.5% (p=0.002
![Page 30: Combined therapy og gram-positive infections · Falagas, MF et al. JAC 2006; 57:639. Questions regarding gentamicin use in the treatment of staphylococcal IE ... Fernandez-Hidalgo](https://reader031.vdocuments.us/reader031/viewer/2022011922/60422436097bd00f6a576c19/html5/thumbnails/30.jpg)
Conclusions
Effectiveness of gentamicin use for some G+ve
infections is dubious
Harms of gentamicin use are well evidenced
Different physicians’ attitudes to use combined
treatment
Use of rifampicin associated with increase in
resistance
New combinations emerging – clinical data still
missing