empirical antibacterial treatment: glycopeptides and … · 2018-02-21 · glycopeptides in...
TRANSCRIPT
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EMPIRICAL ANTIBACTERIAL TREATMENT:
GLYCOPEPTIDES AND OTHER GRAM-
POSITIVE ANTIBACTERIALS
A.COMETTA, O.MARCHETTI, T.CALANDRA
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BACKGROUND
1. Epidemiological data
in the mid 80’
2. Development of
resistance to
glycopeptides in 90’
20
40
60
80
100
Gram positives
Gram negatives
IATG-EORTC TRIALS 1973-2000
1986-88
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GLYCOPEPTIDES (GP) IN NEUTROPENIC
PATIENTS: OBJECTIVES
1. Should GP be given as upfront empiricaltherapy ?
2. Should GP be given in case of documentedGram positive MDI?
3. Should GP be given in case of persistent feverafter initial broad spectrum empiricalantibiotic therapy?
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GLYCOPEPTIDES IN NEUTROPENIC
PATIENTS: METHODS
• Literature review
– Search
• Medline
• Cochrane
• Pubmed
• Manual search bibliography of referenced publications
• ICAAC, ECCMID, ASH, ASCO, and EBMT 2002-2005
• CDC grading
• Questionnaire on European practices.
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GLYCOPEPTIDES IN NEUTROPENIC
PATIENTS: METHODS
1. Randomized controlled trials
2. Meta-analysis
1. Paul et al JAC 2005; 55: 436-444
2. Vardakas Lancet Infect Dis 2005; 5: 431-439
3. Published guidelines
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GLYCOPEPTIDES IN
NEUTROPENIC PATIENTS
1. Upfront empirical therapy
2. In case of persistent fever after initial
broad spectrum empirical antibiotic
therapy
3. In case of documented Gram positive MDI
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RANDOMIZED CONTROLLED TRIALS WITH THE SAME
ANTIBIOTIC(S) IN THE 2 GROUPS (1)
TeicoplaninCefta103De Pauw 1990
TeicoplaninPipera-amika46Micozzi 1990
747
47
60
N= GlycopeptideAntibioticTrial/year
TeicoplaninCefta-amikaDel Favero 1987
VancomycinTicar-gentaKarp 1986
VancomycinCefta-amikaEORTC 1991
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Diapositiva 7
CA4 ComettaA; 21/09/2005
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RANDOMIZED CONTROLLED TRIALS WITH THE SAME
ANTIBIOTIC(S) IN THE 2 GROUPS (2)
TeicoplaninPipera-amika158Martino 1992
VancomycinCefta102Pico 1993
127
103
N= GlycopeptideAntibioticTrial/year
VancomycinCeftaRamphal 1992
VancomycinCeftaNovakova 1991
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Diapositiva 8
CA5 ComettaA; 21/09/2005
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RANDOMIZED CONTROLLED TRIALS WITH
DIFFERENT ANTIBIOTICS IN THE 2 GROUPS (1)
CeftaImipenem89Riikonen 1991
CeftaCefta-amika75Meunier 1990
87
193
101
N= Antibiotic + GPAntibiotic- no GPTrial/year
CeftaCefta-amikaViscoli 1991
Ticar/clav-amikaTicar-amikaShenep 1988
CeftaImipenemBosseray 1992
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Diapositiva 9
CA6 ComettaA; 21/09/2005
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RANDOMIZED CONTROLLED TRIALS WITH DIFFERENT
ANTIBIOTICS IN THE 2 GROUPS (2)
Pip/tazo-amikaPip-amika104Micozzi 1993
151
71
59
N= Antibiotic + GPAntibiotic-no GPTrial/year
ceftaCarbeni-cephalo-
genta
Granowetter 1988
CeftaPip-gentaKelsey 1992
AztreonamPip-gentaSpencer 1990
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Diapositiva 10
CA7 ComettaA; 21/09/2005
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GLYCOPEPTIDES AS UPFRONT
THERAPY
1. Mortality
2. Success, duration of fever, shock
3. Further infections, breakthrough bacteremia
4. Toxicity
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1. Odds ratios
of mortality
Vardakas Lancet Infect Dis 2005; 5: 431-439
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1/292/29Kelsey 1992
5/754/83Martino 1992
7/646/63Ramphal 1992
7/609/60Novakova 1991
8/509/50Meunier 1990
0/531/48Shenep 1988
3/583/56Micozzi 1993
Glycopeptide
Death/total
No Glycopeptide
Death/total
Trial/year
MORTALITY (1)
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2/987/95Viscoli 1991
24/37719/370EORTC 1991
4/526/51De Pauw 1990
0/3310/69*Pico 1993
Glycopeptide
Death/total
No Glycopeptide
Death/total
Trial/year
MORTALITY (2 )
* Ceftazidime 1g q 8h
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GLYCOPEPTIDES AS UPFRONT
THERAPY
1. Mortality
2. Shock, success, duration of fever
3. Further infections, breakthrough bacteremia
4. Toxicity
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2. Odds ratios of
success without
modification
Vardakas Lancet Infect Dis 2005; 5: 431-439
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Initial addition of vancomycin for the empirical treatment
of Gram-positive bacteremia in neutropenic patients
11%8%Acyclovir
<0.00121%10%Amphotericin B
<0.001
12%10%Other antibiotic
0%22%Vancomycin
Cefta-amika
+ vancomycin
(n = 67)
Cefta-amika
(n = 68)
Modification of
initial empirical
treatment
EORTC-IATCG, J Infect Dis, 1991; 163: 951-958
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2.Time to defervescence
• EORTC : no difference
• Karp: significant difference (median 14 days in
placebo group vs 9 days in GP group)
• Meta-analysis: pooling data from 2 trials: no
difference
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7/569/58Micozzi 1993
1/441/43Bosseray 1992
5/648/63Ramphal 1992
8/526/51Novakova 1991
11/759/63Viscoli 1991
3/362/35Kelsey 1992
42/377 (11%)50/370 (13.5%)EORTC 1991
Glycopeptide
/total
No Glycopeptide
/total
Trial/year
3.BREAKTHROUGH INFECTION (1)
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3. BREAKTHROUGH INFECTION (2)
07 (32%)*Karp 1986
Glycopeptide
/total
No Glycopeptide
/total
Trial/year
5/77 (6.5%)
G+: 2/77
35/146 (24%)
G+ : 29/146
Marie/Pico 1993
* Late onset G+ sepsis
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0/441/45Riikonen 1991
1/461/55Granowetter 1988
1/380/35Kelsey 1990
1/539/48*Shenep 1988
Glycopeptide
n/total
No Glycopeptide
n/total
Trial/year
3. G+ BREAKTHROUGH BACTEREMIA
* CNS: 5. Viridans streptococci: 4 (1 death due to shock)
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4. Odds ratio of adverse effects
A. All adverse effects
B. nephrotoxicity
Vardakas Lancet Infect Dis 2005; 5: 431-439
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19/646/63Ramphal 1992
34/984/95Viscoli 1991
3/440/45Riikonen 1991
2/440/43Bosseray 1992
8/368/35Kelsey 1992
2/750/83Martino 1992
6/334/33Del Favero 1987
Glycopeptide
n/total
No Glycopeptide
n/total
Trial/year
4. ADVERSE EFFECTS (1)
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55 (14%)35 (9%)Hypokaliemia
26 (7%)12 (3%)Rash
85 (22%) 50 (13.5%)Hepatotoxicity
24 (6%)9 (2%)Nephrotoxicity
Glycopeptide
n= 383
No Glycopeptide
n=370
Adverse effect
4.ADVERSE EFFECTS (2) EORTC 1991
EORTC-IATCG, J Infect Dis, 1991; 163: 951-958
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0/330/33Del Favero 1987
0/440/45Riikonen 1991
4/523/51Novakova 1991
3/390/36Meunier 1990
22/3123/29Karp 1986
0/361/35Kelsey 1992
0/750/83Martino 1992
Glycopeptide
/total
No Glycopeptide
/total
Trial/year
4.ADVERSE EFFECTS (3): nephrotoxicity
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GLYCOPEPTIDES IN
NEUTROPENIC PATIENTS
1. Upfront empirical therapy
2. In case of documented Gram positive MDI
3. In case of persistent fever after initial broad
spectrum empirical antibiotic therapy
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Bacteremia due to viridans streptococci in
granulocytopenic cancer patients
10 (2.9%)342Fleishback 2001
36 (4.7%)763IATG-EORTC 2003
24 (4.6%)513Cordonnier 2003
31 (4.3%)733Del Favero 2001
19 (4.6%)409Feld 2000
Bacteremia due to
S.viridans
Pts numberTrial/year
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EORTC-IATCG trial V:
Gram-positive bacteremias
36Other
27
23
21
16
30
21
28
4
Streptococci
viridans
Coagulase-neg. staph.
S. aureus
Ceftazidime +
amikacin +
vancomycin
(n=67)
Ceftazidime
+
Amikacin
(n=68)
EORTC-IATCG, JID, 1991
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Initial addition of vancomycin for the empirical treatment
of Gram-positive bacteremia in neutropenic patients
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
Ceftazidime+amikacin+vancomycin
Ceftazidime+amikacin
Duration of treatment (d)
Proportion febrilepatients
EORTC-IATCG, J Infect Dis, 1991; 163: 951-958
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PATIENTS WITH SKIN AND SOFT TISSUE
INFECTIONS
8151010Superinfection
(%)
8.07.77.57.6Days to
defervescence
7686Infectious
mortality (%)
42423335Success (%)
Comb + V
N=43
Mono + V
N=53
Comb
N=355
Mono
N=367
Dompeling Eur J Cancer 1996; 8: 1332
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GLYCOPEPTIDES IN
NEUTROPENIC PATIENTS
1. Upfront empirical therapy
2. In case of documented Gram positive MDI
3. In case of persistent fever after initial broad spectrumempirical antibiotic therapy:
• Cometta et al CID 2003; 37: 382
• Erjavec et al JAC 2000; 45: 843
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Addition of glycopeptides in
neutropenic cancer patients
62%471Peacock 2002
36%987IATG-GIMEMA 1996
45%867Sanz 2002
31%541Winston 2001
26 %722De Pauw 1994
pts with addition
of glycopeptides
Pts numberTrial/year
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859 febrile neutropenic PtsDay 0
763 eligible pts:
piperacillin/tazobactam96 Pts not eligible
48-60 hours
165 Pts with persistent
fever and FUO, CDI or
Bacteremia due to G+
susceptible to P/T
598 Pts afebrile, or with
exclusion criteria for
randomization
RANDOMIZATION STUDY OF P/T EFFICACY
Cometta. CID 2003; 37: 382
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Randomized patients: defervescence
3.5 (2.7-4.4)4.3 (3.3-4.7)Median time to defervescence
(Days; 95% C.I.)
40 (47%)37 (47%)Pts with defervescence after
change of protocol therapy
42 (49%)36 (45%)Pts with defervescence under
protocol therapy
82 (96%)73 (92%)Pts with defervescence
Vancomycin
N = 86
Placebo
N = 79
Cometta. CID 2003; 37: 382
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Overall time to defervescence
Days
15129630
Rate of febrile patients
1.0
.8
.6
.4
.2
0.0
Placebo
Time zero : administration of vancomycin or placebo
Vancomycin
Cometta. CID 2003; 37: 382
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Outcome of the patients
1 (14)2 (15, 35)Death related to infection
(Day of death)
93Pts with AE definitely or
probably related to AB
31 (36%)30 (37%)Pts given ampho B
34Further G+ bacteremia
Vancomycin
N = 86
Placebo
N = 79
Cometta. CID 2003; 37: 382
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X febrile neutropenic PtsDay 0
124 pts:
imipenem/cilastatin
11 Pts
not eligible
72-96 hours
115 Pts with persistent
fever and FUO, CDI or
Bacteremia due to G+
susceptible to I/C
RANDOMIZATION
Erjavec JAC 2000; 45: 843
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Erjavec et al
outcome of the patients
6 (10.7%)4 (6.9%)Death
25 (44.6%)27 (46.6%)Pts with defervescence
Teicoplanin
N = 56
Placebo
N = 58
Erjavec JAC 2000; 45: 843
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1. Initial empirical glycopeptide in
neutropenic patients (IDSA 2002)
• Development of hypotension or shock
• Known colonisation with MRSA or Peni-R
Pneumococcus
• Positive results for G+ before identification
• Clinically suspected serious cath-related
infection (cellulitis)
• (Institutions with high rate of infections due to
MRSA or Peni-R viridans streptococci )
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RANDOMIZED CLINICAL TRIALS: PROBLEMS
• No double-blind trial except Karp’s and Shenep’s
trials: addition of GP more frequent in the group
initially treated without GP
• More trials with different antibiotics in the 2
groups: role in the occurrence of adverse effects
and further infections?
• Various doses of vancomycin and teicoplanin
• No randomized controlled trial assessing the use of
streptogramin or linezolid
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CONCLUSION 1
I DNot recommendedPersistent fever
I DNot recommendedAt onset of fever
CDC grading
system
Glycopeptide
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CONCLUSION 2
III CrecommendedHypotension or shock
III CrecommendedSkin and soft tissue
infections including
cath-related infections
III CrecommendedKnown colonisation
with MRSA
CDC grading
system
Glycopeptide