Pierluigi Viale Clinica di Malattie Infettive Policlinico S. Orsola – Malpighi

VII Congresso Nazionale SIMPIOS

Rimini, 9-11 maggio 2016

Corso precongressuale

«Enterobatteri produttori di carbapenemasi»

CENNI DI TERAPIA

64-year-old female, intestinal transplanted+12 pancreatitis with peri-pancreatic fluid collection KPC-Kp isolated

The isolate was resistant to aminoglycosides but susceptible to tigecyclineand colistin . The patient was started on a combination of tigecycline andcolistin and completed a 14-day course

+ 36 HAP KPC-Kp isolated from BALThe isolate was now resistant to tigecycline but susceptible to colistin . Thepatient was started on a combination of colistin and extended-infusionmeropenem with a good clinical response

+ 65 severe sepsis blood cultures KPC-Kp isolatedThe isolate remained susceptible to colistin. The patient was started on acombination of colistin, tigecycline and meropenem. Although she wasemodynamically stable, her blood cultures remained positive for more than 6days despite this combination of antibiotics.

+ 72 the patient was switched to a combination of colistin, meropenem , andertapenem . She initially responded to this regimen but developedbreakthrough bacteremia 12 days later. The isolate had now becomeresistant to colistin

Successful Treatment of Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumoniae Bacteremia Camargo JF et al , Antimicrob Ag Chemother 2015; 59:5903–5908.

Treatment with a combination ofintravenous CAZ-AVI (1,000 mg/250mg i.v. q8h based on therecommended dose determined bycreatinine clearance and ertapenem(1 g i.v. q24h) was then started.

The patient responded well, withsterilization of her blood cultureswithin 24 h of this regimen.

She completed a course of 2 weeksand by the end of therapy, for thefirst time since her admission, wastransferred out of the intensive careunit

Diego, 50-year-old

Clinical history:• HCV-related cirrhosis complicated with a large portal vein thrombosis• Chronic renal failure • Type 2 diabetes mellitus

On September 20, 2015

Liver and kidney transplantation at our hospital

In the early post-transplant course:• portal vein thrombosis worsening• digestive bleeding from esophageal varices• refractory ascitis

• Colonization with KPC on day 8

TIPS implant

On postoperative day 16

• Fever (TC max 39°C)• Hypotension• Positive blood cultures for KPC producing K. pneumoniae (KPC-Kp)

Combination treatment with:

• Colistin [9 milion international unit (MIU) first day then 4.5 MIU i.v. q12h]

• HD meropenem (2 g in 1 h then 1.5 g i.v. q6h by extended-infusion)

Favorable clinical responseBlood cultures negativisation

On postoperative day 45

• Fever and Hypotension • Severe leucopenia• Positive blood cultures for PDR-KPC producing K. pneumoniae (KPC-Kp)

A combination antibiotic therapy was started with:• HD meropenem• Ertapenem (1 g i.v. q24h)• Colistin

In the following days:• Persistent fever (TC 39°C)• Persistent blood cultures positivity for the PDR KPC-Kp

Abdominal CT scan showed thrombus re-organization PET/CT scan ruled out pylephlebitis and/or TIPS infection

Escalation (Desperation) therapy:• Rifampin addiction• Replacing colistin with gentamicin

8 days after ... (+55)

• Persistence of Severe clinical conditions • Persistence of blood-cultures positivity

• Ceftazidime-Avibactam• (2000 mg/500 mg i.v. q8h)

• Ertapenem (1 g i.v. q12h)

After 48 h: clearance of blood cultures

After 14 days: stop therapy and discharge from the intensive care unit

At 2 month of follow-up: patient stable and free of new infectious symptoms

Susceptibility to CAZ-AVI was tested using the disc diffusion assay, obtaining a zone diameter of 25 mm.

Combination Reciprocal serum inhibitory

titre (SIT)

Reciprocal serum

bactericidal titre (SBT)

Trough Peak Trough peak

COL, MER, ERT 2 4 2 2

GEN, MER, ERT NB 4 NB 4

CAZ-AVI, ERT 8 8 8 8

Serum inhibitory and bactericidal titres

of three different regimens against the isolate

Giannella M et al, submitted

Treating infections caused by carbapenemase-producing Enterobacteriaceae.Tzouvelekis LS et al Clin Microbiol Infect 2014;20:862-72.

Twenty clinical studies (including those describing the largest cohorts of CPE-infected patients) were reviewed.

The data summarized here indicate that treatment with a single in vitro activeagent resulted in mortality rates not significantly different from that observedin patients treated with no active therapy, whereas combination therapy withtwo or more in vitro active agents was superior to monotherapy, providing aclear survival benefit (mortality rate, 27.4% vs. 38.7%; p <0.001).

Combo with Carba

MonoInappropriate Combo Combo without Carba

Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapyand mortality in a multicentric study.

Tumbarello M et al on behalf of ISGRI-SITA, J Antimicrob Chemother. 2015 ;70:2133-43

A 3-year (2011-2013) retrospective cohort study in 5 large Italian teaching hospitals.The cohort included 661 adults with bloodstream (BSIs, n=447) or non-bacteraemicinfections caused by a KPC Kp isolate. All had received >48 h of therapy (empiricaland/or non-empirical) with >1 drug to which the isolate was susceptible.

14-day mortality rate: 34.0%

Independent predictors of 14-day mortality

BSI (OR, 2.09; P<0.001)

presentation with septic shock (OR, 2.45; P=0.001)

inadequate empirical antimicrobial therapy (OR, 1.48; P=0.04)

chronic renal failure (OR, 2.27; P<0.001)

high APACHE III scores (OR, 1.05; P<0.001)

colistin-resistant isolates (OR, 2.18; P=0.001)

Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapyand mortality in a multicentric study.

Tumbarello M et al on behalf of ISGRI-SITA, J Antimicrob Chemother. 2015 ;70:2133-43.

Number of patientsNon-survivors

All combo mono OR (95% CI) P

Total (%) 34.0 30.2 38.4 0.69 (0.49-0.97) 0.03

Infection characteristics

BSI 38.7 32.0 51.3 0.45 (0.29-0.68) <0.001

Low-risk BSI 31.1 25.7 44.8 0.42 (0.16-1.16) 0.06

High-risk BSI 41.0 34.1 52.8 0.46 (0.29-0.74) <0.001

Non-BSI infections 24.3 22.2 25.2 0.85 (0.39-1.78) 0.65

Isolate sensitivity

Colistin-resistant 47.0 42.6 50.0 0.74 (0.35-1.58) 0.40

Tigecycline-resistant 33.5 31.9 36.1 0.83 (0.40-1.74) 0.59

Gentamicin-resistant 39.8 36.2 44.9 0.70 (0.31-1.57) 0.34

Merop MIC ≤8 32.5 27.9 40.4 0.57 (0.32-1.03) 0.04

Merop MIC ≥16 mg/L 34.9 32.0 37.6 0.78 (0.51-1.19) 0.22

Inadequate empirical atb 39.4 33.5 47.7 0.55 (0.35-0.86) 0.006

Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case-control-control study.

Giacobbe DR et al,on behalf of ISGRI-SITA, Clin Microbiol Infect 2015 21:1106

To assess risk factors for Col-R, 142 patients with Col-R KPC-Kp BSI were compared to twocontrols groups: 284 controls without infections caused by KPC-Kp (control group A) and 284controls with colistin-susceptible (ColS) KPC-Kp BSI (control group B).

Factors associated to Col-R KPC-KP - First Multivariate analysis (cases vs. g. A) previous colistin therapy, previous KPC-Kp colonization, ≥3 previous hospitalizations, Charlson score ≥3 neutropenia Factors associated to Col-R KPC-KP - 2nd multivariate analysis (cases vs. g. B)previous colistin therapy, previous KPC-Kp colonization Charlson score ≥3

30-day mortality of Col-R KPC-Kp BSI 51%.

CPE management – UNMET NEEDS

Data advocating the superiority of combo regimens are all derived fromobservational, uncontrolled studies. Therefore randomized clinical trials aimedat comparing Mono vs Combo and Different combo regimen could be stronglyneeded, if feasible.

It remains an open question whether the addition of a third agent is warrantedwhen the carbapenem MIC is high

It has to be defined the PD breakthrough for carbapenems

Of concern is the increasing number of reports documenting CPE resistance tocolistin and tigecycline considered “salvage” agents for therapy. How thesepandrug-resistant cases can be best managed remains an open question.

How can we predict the efficacy of any combo regimen?

Are there settings or patients where an empirical anti CPE treatment should beprescribed?

CPE management – UNMET NEEDS about the BEST AVAILABLE THERAPY

Of concern is the increasing number of reports documenting CPE resistance tocolistin and tigecycline considered “salvage” agents for therapy. How thesepandrug-resistant cases can be best managed remains an open question.

EXTENDED USE OF GENTAMYCIN BASED REGIMENS ?

DOUBLE CARBAPENEM?

FOSFOMYCIN ?

COTRIMOXAZOLE ?

HIGHER TIGECYCLINE DAILY DOSES?

TRIPLE COMBO REGIMENS?

CARBAPENEM SPARING REGIMENS?

Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae Gonzalez-Padilla M et al, Antimicrob Chemother 2015; 70: 905–913

Retrospective cohort study examining 50 cases of sepsis caused by carbapenem-resistantK. pneumoniae ST512 producing KPC-3, SHV-11 and TEM-1.

Tigecycline and fosfomycin were active against 36 (72.0%) and 10 (20.0%) isolates,respectively. With regard to gentamicin, 18 isolates (36.0%) were susceptible (MIC ≤2mg/L), 31 (62.0%) showed intermediate susceptibility (MIC > 2 to ≤4 mg/L) and 1(2.0%) was resistant (MIC >4 mg/L). All isolates showed resistance to other antibioticsincluding colistin and meropenem (MIC >32 mg/L for all isolates).

Optimal empirical treatments were used in only six patients (12%). Targeted treatmentwas optimal in 37 patients (74%).

Gentamicin was targeted in 29 pts (58%), as mono in 8 and in combo regimens in 21

The 30 day crude mortality rate was 38% (19/50 patients)

Mortality in the group of patients with optimal targeted treatment containinggentamicin was 20.7%, (7.7% for MIC ≤2 mg/L -31.2% for MIC > 2 to ≤4mg/L) compared with 37.5% of patients with optimal targeted treatmentwithout gentamicin (P < 0.21).

Gentamicin therapy for sepsis due to carbapenem-resistant and colistin-resistant Klebsiella pneumoniae Gonzalez-Padilla M et al, Antimicrob Chemother 2015; 70: 905–913

the impact of targeted treatmentwith gentamicin on survival at 30 days

High dose tigecycline in critically ill patients with severe infections due to MDRO De Pascale G et al Crit Care 2014;18:R90

Retrospective study involving 100 ICU pts with microbiologically confirmed infection; 54received TGC at a standard dose and 46 at a high dose (100 mg every 12 h). Carbapenem-resistant A. baumannii (blaOXA-58 and blaOXA-23 genes) and K pneumoniae (blaKPC-3 gene)were the main isolated pathogens (n = 79). Overall ICU mortality 57%

Logistic regression analysis of factors associated with clinical cure (48%) in 63 VAP pts

OR 95% CI P-value

SOFA score at infection occurrence 0.66 0.51, 0.87 0.003

Initial inadequate treatment 0.18 0.05, 0.68 0.01

High-dose tigecycline group 6.25 1.59, 24.57 0.009

ANTIBIOTIC CRISIS : WHICH ANSWERS?

New drugs

Alternative therapies

Improved microbiological diagnosis

Infection Control strategies

Anti-Microbial Stewardship

ANTIMICROBIAL STEWARDSHIP – a clinical vision

How to save carbapenems avoiding any risk for the patient

ESBL Enterobacteriaceae

Is there a residual role of BL-BLI or are we condemned to use always

carbapenems?