Transcript Folie 1

How to treat MDR pathogens
Tobias Welte
Department of Respiratory Medicine and Intensive Care
Medizinische Hochschule Hannover, Germany
Welte – MDR Pathogens, Mar del Plata 11.10.2014
2008
2012
Grading
1.a. Administration of effective iv ABs within the 1. hour of recognition of septic shock
1B
1B
1.b. Administration of effective iv ABs within the 1. hour of recognition of severe sepsis
1D
1C
2.a. Initial empiric anti-infective therapy of one or more drugs that have activity against
all likely pathogens and that penetrate in adequate concentrations into tissues
presumed to be the source of sepsis
1B
1B
2.b. Antimicrobial regimen should be reassessed daily for potential deescalation
1C
1B
↑
3. Use of biomarkers to assist the clinician in the discontinuation of empiric antibiotics
in patients who initially appeared septic, but have no subsequent evidence of infection
nn
2C
↑
neutropenic patients with severe sepsis
2D
2B
↑
for pts with difficult to treat, MDR bacterial pathogens f.e. Acinetobacter/Pseudomonas
nn
2B
↑
For pts with severe infections associated with respiratory failure and septic shock,
combination therapy with an extended spectrum beta-lactam and either an
aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia
2D
2B
↑
A combination of beta-lactam and macrolide for
patients with septic shock from bacteremic Streptococcus pneumoniae infections
nn
2B
↑
4.B Empiric combination therapy not be for more than 3–5 days. De-escalation to the
most appropriate single therapy as soon as the susceptibility profile is known
2D
2B
↑
5. Duration of therapy typically 7–10 days; longer courses may be appropriate in pts
with a slow clinical response, undrainable foci of infection, bacteremia with S. aureus;
some fungal and viral infections or immunologic deficiencies, including neutropenia
1D
2C
↓
6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic
shock of viral origin
nn
2C
↑
7. Antimicrobial agents should not be used in patients with severe inflammatory states
determined to be of noninfectious cause
1D
UG
↑
D. Antibiotic therapy
↑
4.a. Combination empirical therapy for
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Standard Treatment
gram negatives
• E. coli/Enterobakteriacae
– Ampicillin/Inhibitor Combinations
– 2. and 3. Generation Cephalosporines
– Ertapenem
• Pseudomoas aeruginosa/Acinetobacter
– Piperacillin/Tazobaktam
– 4. Generation Cephalosporines
– Carbapenemes
• St. maltophilia
– Fluorquinolones
– Cotrimoxazol
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Pseudomoas aeruginosa
Combination Therapy
• If combination therapy is required then
combine with
– + Aminoglycosid
• Gentamycin/Tobramycin 6 mg/kg BW per day as a single
dosage (Through Level < 2 mg/L)
• Amikacin 20-25 (-30) mg/kg KG BW per day as a single
dosage
– + Fluorquinolones
• Ciprofloxacin (800-1200 mg tgl.)
• Levofloxacin (1000 mg tgl.)
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Standard Treatment
gram negatives
• E. coli/Enterobakteriacae
– Ampicillin/Inhibitor Combinations
– 2. and 3. Generation Cephalosporines
– Ertapenem
• Pseudomoas aeruginosa/Acinetobacter
– Piperacillin/Tazobaktam
– 4. Generation Cephalosporines
– Carbapenemes
• St. maltophilia
– Fluorquinolones
– Cotrimoxazol
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Pseudomonas aeruginosa
Combination Therapy
• If combination therapy is required then
combine with
– + Aminoglycosid
• Gentamycin/Tobramycin 6 mg/kg BW per day as a single
dosage (Through Level < 2 mg/L)
• Amikacin 20-25 (-30) mg/kg KG BW per day as a single
dosage
– + Fluorquinolones
• Ciprofloxacin (800-1200 mg tgl.)
• Levofloxacin (1000 mg tgl.)
Welte – MDR Pathogens, Mar del Plata 11.10.2014
• Introduced into the
German market in 1959
• Banned from the
German market due to
nephrotoxicity in 1981
• Approved again in 2012
C52H98N16O13
Welte – MDR Pathogens, Mar del Plata 11.10.2014
MDR Treatment
• Multidrug resistant pathogenes
– Carbapenemase producing
Enterobacteriacae
– Acinetobacter spp.
– Pseudomona aeruginosa
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Proportion of Carbapenems Resistant (R) Klebsiella
pneumoniae Isolates in Participating Countries in 2012
http://www.ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/, 19.11.13
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Acinetobacter baumannii
Antibiotic
MIC
Amikacin
4
S
Ciprofloxacin
4
R
Amoxi/clav
>32
R
Tobramicin
>16
R
Ampicillin
>32
R
Tigeciclin
1
S
Cefepime
>64
R
Ceftazidime
>64
R
Gentamicin
>16
R
Imipenem
>16
R
Levofloxacin
>8
R
Meropenem
16
R
Colistin
<0.5
S
Piperacillina/tazobacta
>128
R
Trimetoprim/sulfa
>320
R
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Lancet Infect Dis 2013; 9 Jul online
Welte – MDR Pathogens, Mar del Plata 11.10.2014
18
Edelmann MV. Lancet Infect Dis 2013; 9 Jul online
Welte – MDR Pathogens, Mar del Plata 11.10.2014
18
Attributable Mortality for Carbapenem-Resistant
K. Pneumoniae (KPC)
Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6.
• 32-patient cohort with KPC bacteremia
• 32 non-bacteremic KPC control patients matched for time period,
comorbidities, underlying disease, age, and sex
Study patients
Control patients
Required intensive care
12 (37.5%)
3 (9.4%)
Required ventilator
support
17 (53.1%)
8 (25%)
Required central venous
catheter
19 (59.4%)
9 (28.1%)
Crude Mortality Rate*
23 (71.9%)
7 (21.9%)
 Attributable Mortality for Study Patients: 50% (95% CI, 15.3 – 98.6)
 Mortality Risk Ratio for Study Patients:
3.3 (95% CI, 2.9 – 28.5)
*P < 0.001
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Qureshi ZA et al. AAC 2012;56:2108-13
MDR Pathogenes – Combination Therapy
•
•
•
•
Retrospective analysis of 41 blood culture positive patients with
Carbapenem resistent Pseudomonas
Mortality in the monotherapy group 57.8%
Mortality in a combination therapy group (Carbapenem and one other
antibiotic) 13.3%
Mortality in a combination therapy group (Carbapenem and Tigecyclin
or Colistin) 12.5%
Welte – MDR Pathogens, Mar del Plata 11.10.2014
20
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Revival of „old“ drugs
Colistin
• Combination Therapy (?) with
– Colistin
• 9 Mill. E Loading Dose
• 4.5 Mill E twice daily as maintenance
therapy
• + inhaled colistin ???
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Predictors of mortality in patients with bloodstream infections caused by KPCproducing Klebsiella pneumoniae and impact of appropriate antimicrobial treatment
• 53 patients
• Overall mortality was 52.8% and infection mortality was 34%
• In the appropriate mortality due to infection occurred in 20%
– 20/20 in combination:
favourable infection outcome
– 7/15 given appropriate monotherapy died (p 0.001).
• In univariate analysis, risk factors for mortality were:
– age (p <0.001)
– APACHE II score at admission and infection onset (p <0.001)
– severe sepsis (p <0.001)
• Variable for survival:
–
–
–
–
appropriate antimicrobial treatment (p 0.003)
Combinations of active antimicrobials (p 0.001)
catheter-related bacteraemia (p 0.04)
prior surgery (p 0.014)
Zarkotou O et al. Clin Microbiol Infect. 2011;17:1798-803
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Tumbarello M. Clinical Infectious Diseases 2012;55(7):943–50
•
•
•
•
Multicenter retrospective cohort study, in 3 large Italian teaching hospitalsbetween 1
January 2010 and 30 June 2011
125 patients with bloodstream infections (BSIs) caused by KPC-producing Kp isolates
(KPC-Kp) diagnosed
30-day mortality rate was 41.6%
– monotherapy (54.3%
– combined drug therapy 34.1%; P = .02).
30-day mortality was independently associated with
– Postantibiogram therapy with a combination of tigecycline, colistin, and meropenem
was associated with lower mortality (OR: 0.11; P = .01)
Welte – MDR Pathogens, Mar del Plata 11.10.2014
21
Multivariate analysis of factors associated with death among
patients with bloodstream infection due to KPC producing
Klebsiella Pneumoniae.
7.17 (1.65-31.03)
Shock
-
-
0.008
Inadequate initial treatment
-
-
0.003
4.17 (1.61-10.76)
APACHE III score (mean ± SD)
-
-
<0.001
1.04 (1.02-1.07)
0.11 (0.02-0.69)
Tigecycline & Colistin &
-
-
0.01
Meropenem
Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, 2012; Oct;55(7):943-50
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Why Colistin plus Rifampin ?
• Two-steps, sequential mechanism of action
• Colistin disrupt the outer bacterial
cytoplasmic membrane
• Rifampin inhibit DNA-dependent RNApolymerase at the ribosomal -subunit
• Some preliminary experience on A.
baumannii
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Colistin + rifampicin: in vivo better outcome!
Pantopoulou A et al. Int J Antimicrob Agents. 2007;29(1):51-5
Both agents
Rifampicin
Colistin
Control
Welte – MDR Pathogens, Mar del Plata 11.10.2014
• Multi-drug resistance was defined as resistance of the
isolate to anti-pseudomonal penicillins, cephalosporins,
carbapenems, quinolones and aminoglycosides.
• All the patients were treated with colistin sulphomethate
sodium (Bellon; Rhone-Poulenc Rorer, France)
administered intravenously at the dosage of 6 million units
(100 000 U/kg) divided into three doses associated with
intravenous rifampicin (10 mg/kg every 12 h).
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Clinical characteristics and outcome
The mean duration of treatment with intravenous
colistin and rifampicin was 17.7 (+10.4) days (range
7–36).
 Clinical and microbiological responses were
observed in 22 of 29 cases (76%)
 Overall infection-related mortality was 21% (6/29).
 Three of the 29 evaluated patients (10%) developed
nephrotoxicity when treated with colistin, all of whom
had previous renal failure. No cases of renal failure
were observed among patients with normal baseline
renal function.

Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Revival of „old“ drugs
Tigecyclin
Ramirez J et al. 2013 Apr;57(4):1756-62.
• Phase II-Study in patients with hospital acquired pneumonia
– Tigecyclin 75 mg twice daily
– Tigecyclin 100mg twice daily
– Imipenem/Cilastatin 1g three times a day
• Primary Endpoint: Advers Events
– No significant difference between the groups
• Secondary Endpoint: Clinical Cure
– Both tigecyclin groups were non inferior to Imipenem/Cilastatin
– High dose tigecyclin was in trend more effective than low dose tigecyclin
and imipenem/cilastatin
Welte – MDR Pathogens, Mar del Plata 11.10.2014
10
Clinical response in phase 2 (study 2000) vs.
phase 3 (study 311) HAP trials
Ramirez J et al. 2013 Apr;57(4):1756-62.
Welte – MDR Pathogens, Mar del Plata 11.10.2014
2000 HAP- TGC Serum concentration
Mean tigecycline (TGC) serum concentrations in subjects with hospitalacquired pneumonia after intravenous infusions.
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Ramirez J et al. 2013 Apr;57(4):1756-62.
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Inhaled Antibiotics in the ICU
•
•
Retrospective matched case-control
study in Greece
Patients with VAP due gram-negative
MDR pathogens
–
–
•
Microbiology
–
–
–
•
43 pts. received AS plus IV colistin
43 control patients who had received IV
colistin alone
Acinetobacter baumannii (66 cases
[77%])
Klebsiella pneumoniae (12 cases [14%])
Pseudomonas aeruginosa (8 cases
[9.3%])
No significant differences between the
2 groups were observed regarding
–
–
–
eradication of pathogens (P = 679)
clinical cure (P=.10)
mortality (P=.289).
Kofteridis D. et al. Clinical Infectious Diseases 2010; 51(11):1238–1244
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Inhaled antibiotics for VAP
Liu Q et al.Anesthesiology 2012; 117:1335-47
Welte – MDR Pathogens, Mar del Plata 11.10.2014
Welte – MDR Pathogens, Mar del Plata 11.10.2014