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Antibiotics: The old and the new
Massimo Antonelli, MD
Dept. of Intensive Care & Anesthesiology
Università Cattolica del Sacro Cuore
Rome - Italy
Major sites of infection in medical
ICU
PNE
UTI
5%
5%
6%
30%
4%
3%
1%
BSI
OTHR
SST
EENT
CVS
GI
LRI
16%
30%
n= 13,592
Richards MJ, et al. Infect Control Hosp Epidemiol 2000; 21: 510-515
Facts
• Multi-resistant germs are common
• Antimicrobial resistance increases over time
• Inadequate therapy is associated with
Mortality
• Can we adopt specific strategies to decrease
resistance ?
Most Frequently Reported Pathogens from
ICU Patients with Nosocomial Pneumonia
1.
2.
3.
4.
5.
Pseudomonas aeruginosa
Staphylococcus aureus
Enterobacter spp.
Klebsiella pneumoniae
Acinetobacter spp.
Richards MJ et al. Crit Care Med 1999; 887-892.
S. aureus —The Most Frequent
Isolate in EPIC Study
35
30,1
30
28,7
25
19,1
20
17,1
13
15
10
5
0
S. aureus
P.
aeruginosa
Vincent JL, et al. JAMA 1995;274:639-644.
Vincent JL. Int Care Med 2000;26:S3-S8.
CoNS
Fungi
E. coli
MRSA Pneumonia:
Infection-Related Mortality
70
Mortality (%)
60
56,3
54,5
50
38
40
30
20
10
0
Gonzalez, 1999
Rello, 1994
Iwahara, 1994
Multiresistant bacteria are a
problem in VAP
Organism
% of all isolates
P. aeruginosa
31.7
MRSA
11.8
A. baumannii
11.8
H. influenzae
8.4
S. pneumoniae
7.7
MSSA
3.1
(n = 321 isolates from 290 episodes)
Rello J. Am J Respir Crit Care Med 1999; 160:608-613.
Acinetobacter baumannii Resistance
in 118 ICUs of 5 European Countries
Antibiotic
France Portugal Spain
Ceftazidime
70%
81%
76%
Pip/taz
44%
75%
58%
Amikacin
36%
10%
51%
Ciprofloxacin
78%
75%
81%
Imipenem
9%
5%
16%
Pip/taz=piperacillin/tazobactam
Hanberger H et al. JAMA 1999;281:67-71.
Variables indipendently associated with VAP
caused by “Potentially Resistant” bacteria *
Variable
Odds
Ratio
95% CI
p Value
Duration of MV before VAP
episode  7 d (Y/N)
6.01
1.6-23.1
.009
Prior antibiotic use (Y/N)
13.46
3.3-55.0
.0003
Broad-spectrum antibiotics
(Y/N)
4.12
1.2-14.2
.025
* Discriminant value (AUC) = 0.89
Trouillet JL., et al. AM J RESPIR CRIT CARE MED 1998; 157: 531-539
Facts
• Multi-resistant germs are common
• Antimicrobial resistance increases over time
• Inadequate therapy is associated with
Mortality
• We may adopt specific strategies to decrease
resistance: antibiotic rotation ?
Antimicrobial Resistance in
Nosocomial Infections Gram-Negative Pathogens
P aeruginosa Resistant to Imipenem
15
10
5
Klebsiella pneumoniae Not Susceptible to
Third-Generation Cephalosporin
15
10
5
Year
00
20
99
19
98
19
97
96
19
95
19
94
19
19
93
92
19
91
19
19
19
19
Source: NNIS Data.
Clin Chest Med. 20:303-315.
90
0
89
Percent Resistance
01
00
20
99
20
98
19
97
19
96
19
95
19
94
19
93
Year
Year
ICU Patients
Non-ICU Patients
19
92
19
90
91
19
19
19
89
0
19
Percent Resistance
20
01
00
25
20
99
20
98
19
97
19
96
19
95
19
94
19
93
19
92
19
91
19
19
19
19
90
35
30
25
20
15
10
5
0
89
Percent Resistance
P aeruginosa Resistant to Quinolones
Antimicrobial Resistance of Nosocomial
Infections Gram-Positive Pathogens
Methicillin-Resistant CoagulaseNegative Staphylococci
Percent Resistance
01
00
20
99
20
98
19
97
19
19
96
95
94
19
92
93
19
19
19
19
Year
2001
2000
1999
1998
1997
1996
1995
Year
35
30
25
20
15
10
5
0
Source: NNIS data.
Clin Chest Med. 20:303-315.
1994
2001
Vancomycin-Resistant Enterococci
89
ICU Patients
Non-ICU Patients
Percent Resistance
Year
1999
1993
1997
19
1995
91
1993
19
1991
90
1989
1992
0
1991
10
1989
40
30
20
100
80
60
40
20
0
1990
60
50
19
Percent Resistance
Methicillin-Resistant S aureus
Facts
• Multi-resistant germs are common
• Antimicrobial resistance increases over time
• Inadequate therapy is associated with
Mortality
• We may adopt specific strategies to decrease
resistance: antibiotic rotation ?
Mortality Associated With Initial
Inadequate Therapy In Critically Ill Patients
With Serious Infections in the ICU
Initial appropriate
therapy
Alvarez-Lerma,1996
Rello, 1997
Initial inadequate
therapy
Kollef, 1999
Kollef, 1998
Ibrahim, 2000
Luna, 1997
Mortality*
0%
20%
40%
*Mortality refers to crude or infection-related mortality
Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
Ibrahim EH et al. Chest 2000;118L146-155.
Kollef MH et al. Chest 1999; 115:462-474
Kollef MH et al. Chest 1998;113:412-420.
Luna CM et al. Chest 1997;111:676-685.
Rello J et al. Am J Resp Crit Care Med 1997;156:196-200.
60%
80%
100 %
Reducing Inadequate Therapy
Antibiotic Management Through Practice Guidelines
18
Number of Days
16
14
Computer-Generated Regimen
Physician-Generated Regimen
*
†
*
12
10
*
8
6
4
2
0
Duration of Length of ICU Admission Total Length of
Antibiotic ICU Stay
to Discharge
Stay
Therapy
*P<0.001.
†P<0.003.
Evans, et al. N Engl J Med. 1998;338:232.
Risk Factors for Resistance in VAP
• Use of antibiotics within 15 days1
• Duration of hospitalization2
• Duration of mechanical ventilation > 7 days1
1Trouillet
J-L et al. Am J Respir Crit Care Med 1998;157:531-539.
2Lautenbach
E et al. Clin Infect Dis 2001;32:1162-1171.
Facts
• Multi-resistant germs are common
• Antimicrobial resistance increases over time
• Inadequate therapy is associated with
Mortality
• We may adopt specific strategies to decrease
resistance: antibiotic rotation ?
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Antimicrobial Resistance:
Key Prevention Strategies
Antimicrobial-Resistant
Susceptible
Pathogen
Pathogen
Prevent
Transmission
Pathogen
Prevent
Infection
Infection
Antimicrobi
al
Resistance
Effective
Diagnosis
& Treatment
Optimize
Use
Antimicrobial
Use
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Key Prevention Strategies
 Prevent infection
 Diagnose and treat
infection effectively
 Use antimicrobials wisely
 Prevent transmission
Clinicians hold the solution!
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
12 Steps to Prevent Antimicrobial
Resistance: Hospitalized Adults
Prevent Infection
1. Vaccinate
2. Get the catheters out
Diagnose and Treat
Infection
Effectively
3. Target the pathogen
4. Access the experts
Use Antimicrobials
Wisely
5.
6.
7.
8.
9.
10.
Practice antimicrobial control
Use local data
Treat infection, not contamination
Treat infection, not colonization
Know when to say “no” to vanco
Stop treatment when infection is
cured or unlikely
Prevent Transmission
11. Isolate the pathogen
12. Break the chain of
contagion
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
Use Antimicrobials Wisely
Step 6: Use local data
Fact: The prevalence of resistance can vary by local, patient
population, hospital unit, and length of stay.
Actions:
know your local antibiogram
know your patient population
 Link to: NCCLS Proposed Guidance for Antibiogram Development
Antonelli, 1994, Chest; 105:224-28
Risk factors for Early Onset Pneumonia
14,6
Age <= 40
Age 41-65
Age > 65
30
41,7
*
19
Males
Females
29,2
25
Multiple trauma
Head trauma
13,6
30,6
Pulmonary contusion
No pulmonary contusion
14,7
8,7
AIS 1^
AIS 2
AIS 3
26,9
46,7 *
MV > 24 h
MV <= 24 h or none
0
8,2
33,3
10
20
30
*
40
Incidence %
* p-value < 0.05, chi-square test or Fisher's exact test
^ 1: thorax < 4, abdomen any score; 2: thorax > 4, abdomen <= 9; 3: thorax > 4, abdomen > 9
50
Variations in the etiology of VAP
across ICUs
No. isolates 44- 32- 13- 41
29- 35- 25- 20
14- 4- 7- 32
56 - 52- 10- 152
MV<7, AB-
MV<7, AB+
MV>7,AB-
MV>7,AB+
Pseudomonas 6 - 3 - 0 - 0
Acinetobacter 0- 12 - 15- 0
MRSA
0-0-0-0
65 -14 -12 -20
0 - 17 - 24 - 5
0-9- 0-5
43 - 25 - 28- 6
0 - 50 - 28 - 3
0-0-0-3
86 - 23- 30 - 22
0 - 33 -50 - 13
2 - 12 - 0 - 6
90
80
% Organisms
70
60
50
40
Barc.
Mont.
Sev
Paris
30
20
10
0
Rello et al, AJRCCM 1999; 160: 608-13
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
Use Antimicrobials
Wisely
Step 8: Treat
infection, not
colonization
Fact: A major cause of antimicrobial
overuse is “treatment” of
colonization.
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
Step 8: Treat infection, not colonization
Invasive Bronchoscopic Diagnostic Tests Reduce
Antimicrobial Use in Suspected VAP*
Invasive Non-invasive
Diagnosis Diagnosis
Antimicrobial-free
days (at day 28)
11.0
7.5
p < .001
Mortality
16.2%
25.8% p = .022
*413 patients; 31 intensive care units
Fagon JY, et al: Ann Intern Med 2000;132:621-30
12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults
Step 12: Contain your contagion
Impact of Hand Hygiene on Hospital
Infections
Year
Author
Setting
Impact on Infection Rates
1977
1982
1984
1990
1992
Casewell
Maki
Massanari
Simmons
Doebbeling
adult ICU
adult ICU
adult ICU
adult ICU
adult ICU
Klebsiella decreased
decreased
decreased
no effect
decreased with one versus
another hand hygiene
product
1994
Webster NICU
1995
Zafar
1999
Pittet
MRSA eliminated
nursery
MRSA eliminated
hospital
MRSA decreased
ICU = intensive care unit; NICU = neonatal ICU
MRSA = methicillin-resistant Staphylococcus aureus
Source: Pittet D: Emerg Infect Dis 2001;7:234-240
 Link to: Improving hand hygiene
ROTATION ?
The evidence
Kollef Ann Intern Med. 2001;134:298-314.
Antibiotic rotation in the ICU : 10 Reviews, No RCT, 4 cohort studies
Author
Allegrazzi
J Hosp Inf
2002
Raymond
CCM 2002
Punziak
Clin Inf Dis
2001
Gruson
AJRCCM
2000
Level of Type
Evidence of
Infec.
Pts.
Period of Res.
Rotation GNB
Res
GP
S.aureus
VRE
Mortality
II
VAP 226/397
Surg
6 mo.
¯
¯
na
«
II
VAP
1445
1 yr
¯
¯
na
¯
II
Any
1273
6 mo.
na
na
«
na
II
VAP 392/3455 Survell.
driven
¯
¯
na
«
ANTIMICROBIAL RESISTANCES ANALYSIS
Computer Assistance in Infection Control
EXPERT SYSTEM FOR DECISION SUPPORT
PHYSICIAN VALIDATED
COMPUTER SUGGESTED
SURELY
NEGATIVE
SURELY
POSITIVE
MISSING
DATA
DRUGS
AMFOTERICINA
AMIKACINA
AMOXICILLINA
AMOXICILLINA/AC.
CLAVULANICO
AMPICILLINA
AMPICILLINA/SULBACTAM
AZITROMICINA
AZTREONAM
BENZILPENICILLINA
CEFALEXINA
CEFALOTINA
CEFAMANDOLO
CEFAZOLINA
CEFEPIMA
CEFOTAXIMA
CEFOTETAN
CEFTAZIDIMA
CEFTIZOXIMA
CEFTRIAXONE
CIPROFLOXACINA
CLARITROMICINA
CLINDAMICINA
CLORAMFENICOLO
DOXICICLINA
ETAMBUTOLO
FLUCONAZOLO
GENTAMICINA
IMIPENEM ED INIBITORI ENZIM.
ISONIAZIDE
LEVOFLOXACINA
MEROPENEM
METRONIDAZOLO
NETILMICINA
OFLOXACINA
PEFLOXACINA
PIPERACILLINA
PIPERACILLINA/TAZOBACTAM
PIRAZINAMIDE
RIFAMPICINA
SULFAMETOXAZ. E TRIMETOPRIM
TEICOPLANINA
2000
2001
2002
39,35 gr
495 gr
270 gr
2511,94 gr
36,31 gr
1050 gr
336 gr
5529,6 gr
13,65 gr
450 gr
82 gr
2788 gr
1248 gr
633 gr
15 gr
40 gr
1778000 U.I.
64 gr
100 gr
370 gr
544 gr
578 gr
905 gr
186 gr
1710 gr
279 gr
2500 gr
320,5 gr
618 gr
90 gr
35 gr
3 gr
117 gr
99,6 gr
1685,4 gr
1085 gr
57,6 gr
112,5 gr
2464,5 gr
1193 gr
25,5 gr
17,4 gr
24,6 gr
6112 gr
12876,75 gr
100 gr
132,6 gr
195,84 gr
141 gr
140 gr
615 gr
15 gr
0 gr
168000 U.I.
0 gr
0 gr
288 gr
1041 gr
455 gr
414 gr
0 gr
1680 gr
608 gr
1970 gr
269,4 gr
469 gr
120 gr
10 gr
8 gr
137 gr
254,45 gr
2520,4 gr
76 gr
52,8 gr
295 gr
3985 gr
518,5 gr
13,5 gr
0 gr
16 gr
4950 gr
9641,25 gr
125 gr
87,4 gr
285,6 gr
187,7 gr
570 gr
495 gr
0 gr
0 gr
0 U.I
0 gr
0 gr
180 gr
373 gr
397 gr
200 gr
0 gr
280 gr
150 gr
1790 gr
107,7 gr
279,5 gr
72 gr
10 gr
4 gr
15 gr
91,8 gr
1091,2 gr
30 gr
24,1
98 gr
2753 gr
784,5 gr
6 gr
0,2 gr
14,4 gr
1360 gr
5805 gr
0 gr
74,4 gr
172,1 gr
76 gr
RESISTANCES 2000 - 2001
AGENT
PSEUDOMONAS
AERUGINOSA
AMPICILLINA CEFAZOLINA CEFTAZIDIME CIPROFLOXACINA GENTAMICINA
98,6%
89,5%
47%
55,3%
68,1%
AGENT
PSEUDOMONAS AERUGINOSA
AGENT
STAPHYLOCOCCUS AUREUS
AMIKACINA AMOXICIL./ AC. CLAVUL.
3%
45,9%
IMIPENEM
27,5%
CLARITROMICINA OXACILLINA TRIMET/SULFAMET
62,4%
67,1%
14,2%
AGENT
STAPHYLOCOCCUS CAPITIS
STAPHYLOCOCCUS EPIDERMIDIS
STAPHYLOCOCCUS HAEMOLYTICUS
STAPHYLOCOCCUS HOMINIS
AGENT
KLEBSIELLA PNEUMONIAE
AGENT
VANCOMICINA
0%
TEICOPLANINA OXACILLINA VANCOMICINA
0%
50%
0%
4,3%
84,6%
0%
16,3%
90,1%
0%
2,2%
65,9%
0%
AGENT
AMPICILLINA PENICILLINA PENICILLINA G VANCOMICINA
ENTEROCOCCUS FAECALIS D
1,9%
3,8%
6,7%
1,2%
ENTEROCOCCUS FAECIUM D
83,3%
19,4%
72,2%
2%
AGENT
SERRATIA MARCESCENS
PIPERAC./TAZOB.
31,6%
GENTAMICINA
1,9%
0%
AMPICILLINA CEFTAZIDIME AMIKACINA IMIPENEM
88,8%
41,6%
30,5%
0%
AMPICILLINA AMIKACINA CEFTAZIDIME PIPERACILLINA IMIPENEM MEROPENEM
100%
18%
63,8%
91,5%
0%
0%
AMPICILLINA CLARITROMICINA AMIKACINA CIPROFLOXACINA MEROPENE IMIPENEM
M
ACINETOBACTER BAUMANNII
COMPLEX
96,6%
83,3%
30%
80%
3,3%
0%
When to start
Sandiumenge , Intensive Care Med 2003 on line
1. Antibiotic therapy should be started immediately
Impact of microbiological investigation on guiding and de-escalating
therapy
2. Antibiotic choice can be targeted, in some cases, on direct staining
3. The antibiotic regimen must be modified in the light of
microbiological findings
Dose and duration
4. Prolonging antibiotic treatment does not prevent recurrences.
What microorganism should be covered
5. Patients with COPD or >1 week of ventilation should receive
combination therapy, due to the risk of VAP due to Pseudomonas
aeruginosa
6. MSSA should be strongly suspected if GCS<8. MRSA is not
expected in the absence of prior antibiotic administration
Sandiumenge , Intensive Care Med 2003 on line
7. Therapy against yeasts is not required, even in the presence of
Candida spp colonization
8. Vancomycin administration for MRSA-related VAP (and for
other Gram–positive pneumonias) is associated with a very poor
outcome
Choice of initial agent
9. Guidelines should be regularly updated and customized to local
patterns
10. The specific choice of agent should be based on the regimen to
which each patient has been exposed previously
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