How to treat MDR pathogens Tobias Welte Department of Respiratory Medicine and Intensive Care Medizinische Hochschule Hannover, Germany.

How to treat MDR pathogensTobias Welte

Department of Respiratory Medicine and Intensive Care

Medizinische Hochschule Hannover, Germany

Welte – MDR Pathogens, Mar del Plata 11.10.2014Welte – MDR Pathogens, Mar del Plata 11.10.2014


2008 2012 Grading

D. Antibiotic therapy

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 ↑

4.a. Combination empirical therapy for

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 ↑


Standard Treatmentgram 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


Pseudomoas aeruginosaCombination 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.)


Standard Treatmentgram 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


Pseudomonas aeruginosaCombination 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.)


C52H98N16O13 C52H98N16O13

• Introduced into the German market in 1959

• Banned from the German market due to nephrotoxicity in 1981

• Approved again in 2012


MDR Treatment

• Multidrug resistant pathogenes– Carbapenemase producing

Enterobacteriacae– Acinetobacter spp.– Pseudomona aeruginosa


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


Acinetobacter baumanniiAntibiotic 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


Lancet Infect Dis 2013; 9 Jul online

18


Edelmann MV. Lancet Infect Dis 2013; 9 Jul online

18


Attributable Mortality for Carbapenem-Resistant K. Pneumoniae (KPC)

• 32-patient cohort with KPC bacteremia• 32 non-bacteremic KPC control patients matched for time period,

comorbidities, underlying disease, age, and sex

Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6.Borer A, et al. Infect Control Hosp Epidemiol. 2009;30:972-6.

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)

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*P < 0.001


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%

Qureshi ZA et al. AAC 2012;56:2108-13

20



Revival of „old“ drugsColistin

• Combination Therapy (?) with– Colistin

• 9 Mill. E Loading Dose• 4.5 Mill E twice daily as maintenance

therapy• + inhaled colistin ???



Predictors of mortality in patients with bloodstream infections caused by KPC-producing 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


• 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)

Tumbarello M. Clinical Infectious Diseases 2012;55(7):943–50

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Multivariate analysis of factors associated with death among patients with bloodstream infection due to KPC producing

Klebsiella Pneumoniae.

Shock - - 0.0087.17 (1.65-31.03)

Inadequate initial treatment - - 0.003 4.17 (1.61-10.76)

APACHE III score (mean ± SD) - - <0.001 1.04 (1.02-1.07)

Tigecycline & Colistin &

Meropenem- - 0.01

0.11 (0.02-0.69)

Tumbarello M, Viale PL, Viscoli C, Bassetti M et al. Clin Infect Dis, 2012; Oct;55(7):943-50


Why Colistin plus Rifampin ?

• Two-steps, sequential mechanism of action

• Colistin disrupt the outer bacterial cytoplasmic membrane

• Rifampin inhibit DNA-dependent RNA-polymerase at the ribosomal -subunit

• Some preliminary experience on A. baumannii


Colistin + rifampicin: in vivo better outcome!

Control

Colistin

Rifampicin

Both agents

Pantopoulou A et al. Int J Antimicrob Agents. 2007;29(1):51-5


• 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).


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.





Revival of „old“ drugs Tigecyclin

• 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

Ramirez J et al. 2013 Apr;57(4):1756-62.

10


Clinical response in phase 2 Clinical response in phase 2 (study 2000) (study 2000) vs. vs. phase 3 phase 3 (study 311) (study 311) HAP trialsHAP trials

Ramirez J et al. 2013 Apr;57(4):1756-62.


Mean tigecycline (TGC) serum concentrations in subjects with hospital-acquired pneumonia after intravenous infusions.

2000 HAP- TGC Serum concentration 2000 HAP- TGC Serum concentration Ramirez J et al. 2013 Apr;57(4):1756-62.



Inhaled Antibiotics in the ICU

• Retrospective matched case-control study in Greece

• Patients with VAP due gram-negative MDR pathogens

– 43 pts. received AS plus IV colistin – 43 control patients who had received IV

colistin alone• Microbiology

– 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



Inhaled antibiotics for VAPLiu Q et al.Anesthesiology 2012; 117:1335-47


How to treat MDR pathogens Tobias Welte Department of Respiratory Medicine and Intensive Care Medizinische Hochschule Hannover, Germany.

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