Matteo Bassetti, MD, PhD Infectious Diseases Division

Santa Maria Misericordia University Hospital

Udine, Italy

The role of carbapenems in the hospital

Rationale for Antibiotic Optimizaton: Balancing The Needs of Patient and Society

Inappropriate antibiotic therapy associated with higher mortality

Indiscriminate use of broad-spectrum

antibiotics driving resistance

Richards GA. Clin Microbiol Infect. 2005;11(suppl):18-S22.

Impact of inappropriate initial empiric antibiotic selection

1. Ibrahim EH, et al. Chest. 2000; 118:146–55; 2. Valles J, et al. Chest 2003; 123:1615–24; 3. Khatib R, et al. Eur J Clin Microbiol Infect Dis 2006; 25:181–5; 4. Teixeira PJZ, et al. J Hosp Infect 2007; 65:361–7; 5. Garnacho-Montero J, et al. J Antimicrobial Chemother 2008; 61:436–41

0

10

20

30

40

50

60

70

80

Bacteraemia1 Community- acquired

bacteraemia2

S. aureus bacteremia3

Ventilator- acquired

pneumonia4

Bacteraemia in ICU patients5

Mor

talit

y (%

of p

atie

nts)

Appropriate antimicrobial treatment Inappropriate antimicrobial treatment

p < 0.001

p < 0.05

p = 0.02

p < 0.02

p < 0.001

How to be appropriate?

Optimal Empiric Therapy

h  Choice1 -  Patient factors including safety -  Local resistance patterns (antibiogram) -  Prior antimicrobial exposure

h  Appropriate -  All suspected pathogens susceptible to ≥1 of the

administered antibiotics

h  Timely1 -  In one study, patients were 2.1% more likely to die for each

30 minute delay in administration2

h  Adequate dosage1 -  Consistent with pK/pD parameters

1Deresinski S. Clin Infect Dis. 2007;45:S177-S183. 2Barie PS, et al. Surg Infect. 2005;6:41-54.

3. Leibovici L, et al. BMJ. 1999;318:1614-1618.

“The important decision in antibiotic treatment turns out to be the choice between present and future patients”3

Risk factors for ESBL-producing Enterobacteriaceae isolation within 48h of hospital

Risk factor OR (95% CI) P-value Recent hospitalization a 5.69 (2.94–10.99) 0.001

Admission from another health care facility 5.61 (1.65–19.08) 0.006

Charlson comorbidity index > 4 3.80 (1.90–7.59) 0.001

Previous therapy with beta -lactams and/or fluoroquinolones b

3.68 (1.96–6.91) 0.001

History of urinary catheterization c 3.52 (1.96–6.91) 0.001

Age >70 years 3.20 (1.79–5.70) 0.001

a During the 12 months preceding index hospitalization. b Includes treatment with -lactam/-lactamase inhibitor combinations, oxyiminocephlosporins, and/or fluoroquinolones during the 3 months preceding index admission. c During the 30 days preceding index blood culture.

Tumbarello M, Bassetti M et al. Antimicrob Agents Chemother Jul 2011;55:3485–3490

Multivariate analysis

Ben-Ami R, et al. Clin Infect Dis. 2009;49:682-690

Predictors of ESBL Pathogens in Patients with Community-Acquired Infections

Variable Odds Ratio

(95% CI) P All patients (n=983)

Male sex 2.5 (1.7 – 3.7) <0.001

Age ≥ 65 years 2.4 (1.6 – 3.6) <0.001

Admission from LTCF 7.5 (3.5 – 16.3) <0.001

Recent hospitalizationa 2.9 (1.9 – 4.4) <0.001

Recent use of any antibiotica 1.8 (1.2 – 2.6) 0.001

Patients with no recent health care contact (n=795)

Male sex 2.9 (1.8 – 4.7) <0.001

Age ≥ 65 years 3.5 (2.5 – 5.6) <0.001

Recent use of a cephalosporina 3.6 (1.8 – 7.3) <0.001

ESBL-producing K. pneumoniae Bacteraemia

0 5 10 15 20 25 30

Carbapenem

Quinolone

Cephalosporin

Beta-lactaminhibitor

Survivors Non-survivors

50%

40%

36.3%

3.7%

Multivariate analysis of mortality (attributed to bacteraemia)

Carbapenem during the first 5 days : OR ( 95% CI )= 0.06 ( 0.01–0.33); p < 0.001

Paterson D et al. Clin Infect Dis 2004;39:31–37

Crude 14-day mortality (%)

Effect of initial antibiotic therapy on mortality in patients with BSI by ESBL-producing

Enterobacteriaceae

Morta

lity (

%)

Inadequate initial therapy (n=89)

Adequate initial therapy (n=97)

p<0.001

Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987–1994

59,5

18,5

0 10 20 30 40 50 60 70

n=186

Effect of switching initial antimicrobial therapy on mortality

Switching after susceptibility results

p<0.001

Adequate treatment within a few hours

Morta

lity (

%)

n=75 Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987–1994

52

18

0

10

20

30

40

50

60

70

21-d

ay m

orta

lity

(%)

97 ESBL-BSI patients initially treated with

potentially active agents

OR 0.14* 0.55 1.48 4.05** P =*0.01 **<0.001

Tumbarello M et al Antimicrob Agents Chemother 2007; 51:1987-1994

Data from SMART (Study for Monitoring Antimicrobial Resistance Trends) 2005-2007.

ESBL-Producing Gram-Negative Bacilli: A Global Problem

Hawser et al. Int J Antimicrob Agents. 2009;34:585-8.

E. coli 8.1%

K. pneumoniae 16.3%

E. coli 12.2%

K. pneumoniae 37.6%

K. oxytoca 5.3%

E. coli 34.9%

K. pneumoniae 29.8%

K. oxytoca 27.6%

E. coli 4.9%

K. pneumoniae 9.6%

E. coli 21.6%

K. pneumoniae 41.6%

Europe

Africa/Middle East

Asia/Pacific

North America

Latin America

ESBL Prevalence in Nosocomial Enterobacteriaceae in Russia

RosNet Study Group

Sukhorukova M et al. 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Vienna, Austria, April 10 – 13, 2010. Abstract P716

Species 2002-2004 Number (%)

2006-2007 Number (%)

Klebsiella pneumoniae 341 (47.5) 332 (46.3)

Escherichia coli 191 (26.6) 205 (28.6)

Proteus mirabilis 51 (7.1) 40 (5.6)

Enterobacter species 45 (6.3) 75 (10.9)

Serratia marcescens 45 (6.3) 29 (4.0)

Citrobacter species 16 (2.2) 11 (1.5)

Klebsiella oxytoca 8 (1.1) 11 (1.5)

Morganella morganii 7 (1.0) 5 (0.7)

Other Enterobacteriaceae 14 (1.9) 6 (0.8)

Schwaber MJ, Carmeli Y. J Antimicrob Chemother 2007;60:913-920

Mortality with ESBL Production in Enterobacteriaceae Bacteremia A Systematic Review and Meta-Analysis

Schwaber (2006) – Tumbarello (2006) –

Marra (2005) – Endimiani (2005) –

Zaoutis (2005) – Blomberg (2005) – Panhotra (2004) –

Kang (2004) – Kim BN (2002) –

Du (2002) – Kim YK (2002) –

Borer (2002) – Ho (2002) –

Menashe (2001) – Pena (2001) – Ariffin (2000) –

Pooled —

0.55 1.00 2.00 6.59

Relative Risk of Mortality (95% confidence interval)

1.85

Lead

Aut

hor (

year

)

TREATMENT OPTIONS FOR INFECTIONS DUE TO ESBL+

FIRST CHOICE SECOND CHOICE Urinary tract infection

CARBAPENEM Amoxycillin/clavulanate QUINOLONE

Ventilator-associated pneumonia

CARBAPENEM TIGECYCLINE

Bacteremia CARBAPENEM TYCECICLINE

Intra-abdominal infection

CARBAPENEM TYGECICLINE Quinolone

§ Possibility of using piperacillin-tazobactam for ESLB-producing E. coli bloodstream infections originating from the urinary tract

Clinical Guidelines for Intra-Abdominal Infections

Solomkin JS et al. Clin Infect Dis 2010;50:133-164

§  Recommendations for single-agent therapy

§  Recommendations for combination regimens

Mild-to moderate severity*

High risk or severity**

Cefazolin, cefuroxime, ceftriaxone, cefotaxime, ciprofloxacin, or levofloxacin, each in combination with metronidazole

Cefepime, ceftazidime, ciprofloxacin, or levofloxacin, each in combination with metronidazole

Mild-to-moderate severity*

High risk or severity**

Cefoxitin Imipenem/cil Ertapenem Meropenem Moxifloxacin Doripenem

Tigecycline Piperacillin/tazo

Ticarcillin/clav

*including perforated or abscessed appendicitis **severe physiologic disturbance, advanced age, or immunocompromised state

Carbapenems Group 1 Group 2 Group 3

Non-fermentants

No Yes Yes

MRSA No No Yes

Carbapenems Ertapenem Panipenem Tebipenem

Imipenem Meropenem Doripenem Biapenem

Tomopenem Razupenem

Newer carbapenems

Bassetti M et al. Curr Med Chem. 2009;16:564-75

Relative activity of Carbapenems

Gram-Positive Activity

Gram-Negative Activity

Imipenem Ertapenem

Meropenem Doripenem

Organism Ertapenem Imipenem Meropenem MIC50 MIC90 MIC50 MIC90 MIC50 MIC90

E. faecalis 8 ≥16 2 4 8 8 E. faecium >16 ≥16 ≥16 ≥16 32 64 MSSA 0.25 0.5 0.03 0.12 0.06 0.5 MRSA >16 ≥16 16 ≥16 8 32 S. pneumoniae 0.03 0.03 0.016 0.03 0.008 0.5 Acinetobacter spp 16 ≥16 0.5 2.0 0.25 2.0 Citrobacter spp 0.016 0.25 0.5 2.0 0.02 0.06 Enterobacter spp 0.03 0.5 1.0 2.0 0.03 0.13 E. coli 0.016 0.06 0.25 0.5 0.06 0.06 P. aeruginosa 4-8 ≥16 2 4 0.25 4

Spectrum of Carbapenems

In vitro Activity of Antibiotics (% Susceptible) Against ESBL-Producing Organisms

Kozlov RS et al. Final report of IISP No. MK-0826 RUSLS1292, 2009

Ertapenem

h New 1-ß-methyl carbapenem licensed in 2003

h Significantly different properties from existing carbapenems

h Significantly different uses

Carbapenem properties

Ertapenem Imipenem - Cilastatin

Meropenem

Stable to renal DHP1

Yes No Yes

Metabolism Renal I: Hepatic C: Renal

Renal

Protein bound

~94% 20% <10%

Half life 4h 1h 1h

Ertapenem Human Pharmacokinetics

Bioavailability of IM Ertapenem > 90%

2 mg/L

Half-life ~ 4h

1

10

100

1000

0 2 4 6 8 10 12 14 16 18 20 22 24

Time, hr

[Tot

al E

rtape

nem

] PL (

mg/

L)

IV IM

Healthy Volunteers Single 1g dose

Ertapenem free concentration

ESBL

Spneumo pen-R Anaerobic bacteria

Burkhardt O et al. J Antimicrob Chemother. 2007;59(2):277-84

Context Comparator Equivalence Intra-abdominal infection

Pip/Taz 3.375g 6h Yes

Ceftriaxone 2g od + Metronidazole 500mg 8h

Yes

Pelvic infection Pip/Taz 3.375g 6h Yes

Complicated SSTI Pip/Taz 3.375g 6h Yes

Community -acquired pneumonia

Ceftriaxone 2g od Yes

Complicated UTI Ceftriaxone 2g od Yes

RCTs involving Ertapenem

Ertapenem: efficacy in intra-abdominal infections (mata-analysis)

Clinical efficacy

Adverse effects

Falagas ME et al. Aliment Pharmacol Ther 2008; 27, 919–931

Ertapenem in ESBL early VAP

h 20 pts treated with ertapenem

Bassetti M et al JAC 2007

Respiratory culture

Eradicated Persisted

Klebsiella pneumoniae 12/14 [86%] 2/14 [14%]

Enterobacter cloacae 2/2 [100%] 0

Proteus mirabilis 1 / 2 [50%] 1 / 2 [50%]

Citrobacter freundii 0/2 2/2 [100%]

Total 15/20 [75%] 5/20 [25%]

The Primary Goal Espoused in the IDSA/SHEA Antibiotic Stewardship Guideline

§  “The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the

selection of pathogenic organisms (such as Clostridium difficile), and the emergence of

resistance.”

Dellit TH. Clin Infect Dis 2007;44:159-177

Correlation Between Antibiotic Consumption and Resistance in P. aeruginosa

Antibiotic class !Hazard ratios! Ceftazidime !0.8!

Piperacillin !5.2!

Ciprofloxacin !9.2!

Imipenem !44!

Carmeli Y et al. Antimicrobial Agents Chemother. 1999;43:1379-1382.

Lepper PM et al. Antimicrob Agents Chemother. 2002;46:2920-2925.

Correlation Between Imipenem Consumption and Resistance of P. aeruginosa to Imipenem

Imip

enem

resi

stan

ce (%

)

Imip

enem

con

sum

ptio

n (D

DD

s)

Risk Factors for Imipenem-Resistant P. aeruginosa

h  A total of 779 isolated resulting in an incidence of 5.6 cases per 1,000 patient admissions (with an average % resistance of 21.6%)

h  Associated with a high incidence of imipenem-resistant P. aeruginosa by univariate analysis -  Group 2 carbapenems (P <0.0001) -  Aminoglycosides (P = 0.034) -  Penicillins (P = 0.05)

h  Group 1 carbapenems not associated with imipenem-resistant P. aeruginosa (P = 0.2)

Carmeli Y et al. Diagn Microbiol Infect Dis 2011;70:367–372

Impact of Ertapenem on Susceptibility of P. aeruginosa to Imipenem

Goldstein EJC et al. Antimicrob Agents Chemother 2009;53:5122–5126

*

*Autosubstitution of ertapenem for ampicillin-sulbactam in months 19 to 48 of the study

§  Retrospective analysis in a 344-bed community teaching hospital on the effect of ertapenem on susceptibility

*Nicolau DP et al. Int J Antimicrob Agents 2012;39:11-15

§  Suggestion that ertapenem best used as either empirical or directed therapy for infections due to aerobic gram-negative and mixed anaerobic bacteria where coverage of non-fermentative gram-negatives including Pseudomonas is not typically necessary or desirable •  Suspected infections due to ESBL-producing bacteria •  Polymicrobial complicated intra-abdominal infections

where the probability of Pseudomonas is unlikely based on the medication history, clinical course, and demographics of the patient

§  Potential role in de-escalation or step-down therapy from carbapenems when possible, with therapy being changed as necessary once culture data become available

An Example of Optimizing Antibiotic Use Through an ASP: Carbapenem Stewardship*

Carbapenems in VAP

Soo Hoo GW et al. Chest 2005;128:2778-87

h  ICU carbapenem-based regimen

h After D3 therapy based on susceptibility results

h Better empirical cover (81 vs 46%; p<0.01)

When to Expect P. aeruginosa

h  Retrospective analysis from 4 hospitals -  151 patients and 152 controls

h  P. aeruginosa caused 6.8% of 4,114 episodes of Gram-negative bacteremia

h  Risk factors: severe immunodeficiency, OR: age >90, antimicrobials within 30 days, presence of central venous catheter or a urinary device -  If ≥2 had over 25% risk for P. aeruginosa

V Schechner et al, CID 48:580-6, 2009

An Approach to Clinical Therapeutics Centered on the Consideration of P. aeruginosa

Pseudomonas Likely

Pseudomonas Unlikely

Penicillins Piperacillin Ampicillin

Cephalosporins Ceftazidime Cefepime

Ceftriaxone Cefotaxime

Carbapenems Imipenem Meropenem Doripenem

Ertapenem

Fluoroquinolones Ciprofloxacin Moxifloxacin

Potential Benefits of a De-escalation Strategy: Recent Evidence

•  ICU-acquired pneumonia in 137 patients:

─  Safe when the patient is clinically stable by day 5

─  Patients in the de-escalation group showed a significantly

lower mortality rate compared to patients in the

non-de-escalation group o  Day 14, p=0.08 o  Day 30, p=0.03

(Days)

Joung MK, et al. Crit Care. 2011:15;R79.

De-escalation in the ICU: A Retrospective Study

•  All consecutive patients treated with empiric therapy in the ICU for ≥72 hours over a period of 16 months

─  116 patients with 133 infections

─  All infections were examined, not just VAP

─  De-escalation in 60 (45%) of cases

•  De-escalation therapy was associated with a significant reduction of recurrent infection

•  15% vs. 5% (p = 0.02)

•  De-escalation had no effect on mortality

Morel J, et al. Crit Care. 2010:14;R225.

Potential Benefits of a De-escalation Strategy

•  A reduction in overall antimicrobial costs

•  Beneficial impacts on the antimicrobial resistance

profile of the institution

•  Decreased antibiotic-related adverse events

–  Superinfection with resistant bacteria

–  Clostridium difficile

•  No alteration in treatment outcomes

Masterton RG. Crit Care Clin. 2011:27;149-162.

Carbapenem Uses

Ertapenem h 1st line for complicated community-acquired infection h Low risk of Pseudomonas/ Acinetobacter infection h Intra-abdominal infections h Directed therapy h De-escalation drug

Imipenem Meropenem Doripenem

h Serious hospital-acquired infection h High risk of Pseudomonas/ Acinetobacter infection h Directed therapy