Current treatment of

carbapenemase- producing

Enterobacteriaceae

Gabriel Levy Hara

Infectious Diseases Unit, Hospital Carlos G Durand, Buenos Aires, Argentina

International Society of Chemotherapy (ISC) Antimicrobial Stewardship Working Group

Antimicrobial Agents with in Vitro

Activity against CPE

Aztreonam

(MBL in the absence of

ESBL)

Carbapenems

Gentamicin (AAC 6’)

Colistin

Tigecycline

Fosfomycin

COLISTIN

Polypeptide drug originally used in ’60s, and reintroduced this decade as last resort.

Administered as colistinmethansulfonate (CMS), inactive prodrug, that is variably converted to colistin (up to 10 fold variation).

Potent bactericidal with concentration- dependent activity

Scarce PK/PD studies, specially in critically ill patients.

Inferior Clinical Efficacy of Colistin. Why?

Suboptimal dosing regimen of the drug.

multivariate analysis of survival data showed that a lower total daily dosage of intravenous colistin was associated with increased mortality (Falagas et al. Int. J. Antimicrob. Agents 2010; 35:194 – 199.

Delay in attaining an efficacious drug concentration

Need to give a loading dose (Plachouras et al. Antimicrob. Agents Chemother. 2009; 53:3430 –3436)

Optimal dosing regimen

Once daily, twice daily or three times daily?

Two forms of colistin Colistin sulfate

Topical treatment

Oral (selective gut decontamination)

Colistin methanesulfonate

Inactive pro-drug, variably converted to colistin in vivo

Intravenous

Colomycin injection is prescribed in IU

Coly-Mycin M Parenteral is prescribed in mg of colistin base

CONFUSING!!!Source: http://aida-project.eu/back-ground-information/fact-sheets/

Recent PK/PD studies of colistin

100 mg colistin sulfate base= 240 mg CMS = 3 MUI colistin

150 mg CBA = 400 mg CMS = 5 MUI colistin

Recent PK/PD studies of colistin

Steady-state plasma concentration-time profiles of the prodrug CMS (A) or formed colistin (B) in 105 critically ill patients (89 not on renal replacement,

12 on intermittent HD, and 4 on CRRT).

Garonzik S M et al. Antimicrob. Agents Chemother. 2011;55:3284-3294

Current doses of 300 mg/d of colistin base may be suboptimal, leading to plasma concentrations below cut-off (2 mg/l) during first 24- 48 hs.

High variability of plasma levels between patients (± 20

times).

Predictive model of seric concentrations with different CMS dosing

0

1

2

3

0 12 24 36 48 60 72 84 96

Time after first dose (hours)

Co

listi

n C

on

cen

trati

on

(m

g/L

)

3 MU x 39 MU + 4.5 MU x 212 MU + 4.5 MU x 29 MU (2h infusion) + 4.5 MU x 212 MU (2h infusion) + 4.5 MU x 2

Plachouras et al Antimicrob Agents Chemother 2009

Retrospective, from 2005-10.

76 pts with bacteremia due to carbapenem-resistant GNB (60 admitted to ICU)

Primary objective: to assess if colistin dose is an independent predictor of clinical outcome during 1st week.

Failure= blood cultures still positive or patient’s

death on day 7.

Global efficacy 68%

Mean MIC in both groups: 2 mg/L

Mean dosing: 2.9 mg/kg/d (cured) vs 1.5 mg/kg/d (failures)

Main results

284 responders from 56 countries

12/56 (21.4%) countries without access to colistin.

Only 21% used loading doses!

Suboptimal dosing very common

More frequent indication : Ventilator associated-pneumonia

Main target: Acinetobacter baumannii

Tigecycline

Due to its PK/PD profile, tigecycline is not recommended for treatment of bacteremia, respiratory or other seriousinfections.

The peak serum concentrations with 50 mg twice daily: 0.6 to 0.9 mg/l

MIC distribution is 1- 2 mg/L for the majority of contemporary KPC-producing K. pneumoniae isolates…

… the poor therapeutic efficacy of the drug in serious infections can be explained.

Aminoglycoside in CPE

Aminoglycoside resistance is increasing among CPE.

In susceptible strains, in vitro data have shown rapid bactericidal activity of gentamicin against gentamicin-susceptible strains

When susceptible, use ALWAYS as part of a combination therapy (preferrably along colistin, carbapenems or tygecicline)

Fosfomycin

Naturally occurring phosphonic acid derivative that inhibits cell wall biosynthesis at an earlier stage than β-lactam antibiotics.

In vitro activity against ESBL-producing Enterobacteriaceae (including carbapenem-resistant K. pneumoniae)

Potential for emergence of resistance during therapy .

Should only be used as part of combined therapy.

• 48 pts with XDR/PDR infections caused by K. pneumoniae, P. aeruginosa

• 25 BSIs, 14 VAP, 11 other•Fosfomycin in combination COL, tigecycline, meropenem, gentamicin, PIP/Tazo

Int J Antimicrob Agents 2013 Oct 16.

Carbapenemase-producing K. pneumoniae (n=41) and P. aeruginosa (n=17)

All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition.

Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline.

Outcome of serious XDR/PDR gram(-) infections

Clinical success: 26/48 (54.2%)

Microbiologic success: 27/48 (56.3%)

28-day mortality: 18/48 (37.5%)

Pontikis et al IJAA

Combined therapy against CPE

New CLSI and EUCAST Breakpointsfor Enterobactericeae

CLSI EUCAST

S (≤) R (≥) S (≤) R (≥)

Imipenem 1 4 2 8

Meropenem 1 4 2 8

Doripenem 1 4 1 4

Ertapenem 0.5 1 0.5 1

Pharmacokinetics of three different

dosing regimens of meropenem

Pharmacokinetics of three different

dosing regimens of meropenem

Tzouvelekis LS, Markogiannakis AM, Psichogiou PT et al.

Carbapenemases in Klebsiella pneumoniaeand other Enterobacteriaceae: an evolving

crisis of global dimensions.

Clin Microbiol Rev 2012; 25: 682-707

A systematic search of MEDLINE and compiled 34 studies containing the necessary information to estimate the efficacy of different antimicrobials in relation to their MICs for the infecting organisms.

A total of 298 patients were identified, 161 infected with KPC- and 140 with MBL-producing K. pneumoniae.

Outcomes of 298 infections* caused by carbapenemase-

producing Klebsiella pneumoniae.

A B C D E F G

0

20

40

60

N=36

N=62

N=21

N=36

N=72

N=56

N=14

Treatment regimen

Failu

re (

%)

• Regimen A: combination therapy

with 2 active drugs one of which was

a carbapenem with MIC ≤4μg/ml;

8.3%**

• Regimen B: combination therapy

with 2 active drugs not including a

carbapenem; 29%

• Regimen C: monotherapy with an

aminoglycoside; 24%

• Regimen D: monotherapy with a

carbapenem (MIC ≤4μg/ml); 25%

• Regimen E: monotherapy with

tigecycline; 35.7%

• Regimen F: monotherapy with

colistin; 47.2%

• Regimen G: inappropriate therapy.

54%

*70% bacteremias, 20% VAP+HAP

A vs B p=0.02

A vs E p=0.03

A vs F p<0.0001

A vs G p<0.0001

B vs G p=0.014

C vs G p=0.04

D vs G p=0.03

** Failure rate

Tzouvelekis, et al. CMR 2012; 25: 682

Carbapenem Monotherapy in 50 Patients with

Serious CPE Infections

(Results compiled from 15 studies)

MIC

(μg/ml)

No. of

patients

No. of

successes

No. of

failures % failure

≤ 1 17 12 5 29.4

2 12 9 3 25

4 7 5 2 28.6

8 6 4 2 33.3

> 8 8 2 6 75

Tzouvelekis et al CMR 2012; 25: 682-707

Multivariate Analysis of Factors Associated with all-

cause 30-day Mortality of Patients with KPC BSIs

Variable P OR(95% CI)

Septic shock 0.008 7.17 (1.65-31.03

APACHE <0.001 1.04 (1.02-1.07)

Inadequate

empirical Rx

0.003 4.17 (1.61-10.76)

Definitive Rx

Col+tigecl+merop

0.01 0.11 (0.02-0.69)

Tumbarello M et al. CID 2012; 55: 943

August 2009 – December 2010

Retrospective observational study

205 consecutive patients with either primary or secondary K. pneumoniae BSIs.

Monotherapy vs combination therapy

By severity of underlying disease

By severity of sepsis

Daikos GL et al. AAC April 2014

In this Italian cohort, increase in the incidence of resistance to colistin from 11% in 2011 to 20% in 2013

Only half of the patients with colistin resistant isolates had previously been exposed to colistin

Tumbarello et al

ECCMID 2014

HOWEVER…TAKE CARE ABOUT ABUSING CARBAPENEMS…!

Many current strains with an MIC > 16 mg/L

More carbapenems consumption = more resistance

Selective pressure may prolong colonization with KPC-Kp

Experts belonging to

Argentinean Society of Infectious Diseases (SADI),

International Society of Chemotherapy (ISC) Antimicrobial Resistance Working Group,

Pan American Association of Infectious Diseases (API),

Pan American Health Organization/World Health Organization (PAHO/WHO),

Infection Control African Network (ICAN), Mediterranean Society of Chemotherapy (MSC) Federation of European Societies for

Chemotherapy and for Infections (FESCI).

CONCLUSIONS (I)

Results of the susceptibility tests and localization of the infection must be considered for the individual treatment decisions.

Current dosing regimens of colistin may be suboptimal.

A loading CMS dose of 6 to 9 MU followed by 4.5- 6 MU bid could be recommended with no additional nephrotoxicity.

CONCLUSIONS (II)

Tigecycline is not recommended as monotherapy for treatment of bacteremia, respiratory or other serious infections, unless other options are not available.

Aminoglycosides should not be used as monotherapy for CPE infections

Fosfomycin should be used in high doses (at least 4 grams four times a day) and always in combination

CONCLUSIONS (III)

Combination of a carbapenem with another active drug –colistin, aminoglycosides or tygecicline- may reduce mortality if:

(i) the carbapenem MIC for the infecting organism is 8 mg/L-

(ii) a high-dose prolonged-infusion regimen is administered (i.e, meropenem 2 g every 8 h orimipenem 1 g every 6 -8 h during 3 h)

In turn, do not use carbapenems if MIC is not available or is >8 mg/l!!! (> resistance/ costs!)

If carbapenems resistance: use at least two active drugs, or probably three…:

Colistin+ tygecicline or fosfomycin ± AG

If colistin resistance: always three drugs if possible!!!

Thanks a lot for yourkind attention!!!