Mario Venditti

Dipartimento

Sanità Pubblica e Malattie Infettive

Università “La Sapienza”

Roma

Infezioni da MDR:

aspetti clinico epidemiologici

e prospettive di terapia

ECDC. Point prevalence survey on antimicrobial use in

European acute care hospitals. 2011-2013

Resistenza antibiotica: 1940-2000

penicillina

S. aureus pen-resistente

meticillina

ampicillina

cephalo I gen

gentamicina

MRSA/ MRSE

Bacilli Gram nega ampi res

cephalo II genrazione

ureidopenicilline

Chinoloni & carbapenem

Myco MDR

S. pneumoniae pen res

VRE, GISA, GISE

ESBL, cipro-R

1940 1950 1960 1970 1980 1990 2000

Daptomicina &

linezolidMDR/XDR/P

DR

Che cosa è un germe MDR?

Multidrug-resistant, extensively drug-resistant and pandrug-

resistant bacteria: an international expert proposal for interim

standard definitions for acquired resistance

Magiorakos AP et al Clin Microbiol Infect 2012; 18: 268–281

Definitions for MDR, XDR & PDR

The bacterial isolate is

non-susceptible to at

least 1 agent in >=3

antimicrobial categories

of agents….

“nuovi” e “vecchi” batteri

AR & MDR

Vecchi Batteri

Corynebacterium jeikeium

Corynebacterium striatum

Pediococcus &

Leuconostoc & E

casseliflavus

Staphylococcus

haemolyticus

Erysipelothrix rusiopathiae

Lactobacillus spp

S. maltophilia

Nuovi Batteri

MRSA & VRE

Lin R/MR Cons

ESBL +

enterobacteriaceae

MDR K. pneumoniae ( &

other enterobacteriaceae)

MDR P aeruginosa

MDR A. baumanii

complex

Caso clinico • Paziente di sesso maschile, 63 anni.

• Ipertensione arteriosa essenziale.

• Encefalopatia multinfartuale.

• Malattia di Parkinson.

• Disturbo depressivo non altrimentispecificato.

Decorso clinico

All’ingresso in reparto:

• Febbrilcola… alterazione di VES ….. EO & rx

torace : nulla di rilevante…… esame urine: non

leucocituria ….. Urinocoltura positiva per E. coli

• UTI sostenuta da E. coli→ Ciprofloxacina e.v per

10 giorni. Dimesso in 13a giornata, trattamento

ambulatoriale con Cefditoren pivoxil

(cefalosporina di terza generazione).

?

Apri la parente

Infectious Diseases: A Friend in NeedBouza E Clin Infect Dis 2014

• Petersdorf RG. Training, cost containment,

and practice: effect on infectious diseases. Rev

Infect Dis 1986; 8:478–87.

• Kaplan K. Training of infectious disease

specialists. Rev Infect Dis 1987; 9:226–7.

• Ervin FR. The bell tolls for the infectious

diseases clinician. J Infect Dis 1986; 153:183–8.

• Beeson P. The natural history of medical

subspecialties. Ann Intern Med 1980; 93:624–6.

Distribution of antimicrobial guidelines (AG):

Useful but not enough for an antibiotic stewardship

• Evaluate the impact of distribution of AG on anti-infectious

prescriptions (AIP) in pts with BSI. Cost evaluation of AIP with

and without intervention of an ID specialist.

• The first evaluation of AIP was performed from January to May

2008 in Douai hospital, France, at day 4 after the initial blood

sample using French guidelines (FG). An AG based on FG was

distributed in June 2008 to all Medical Doctors. A second

evaluation of AIP was performed from July 2009 to October 2010

after AG distribution. In May 2009, an ID specialist arrived. He

re-evaluated at day 4 the initial AIP and modified it if necessary

based on the bacteriologic results and the AG

• In the second period, the overall cost of AIP was estimated at

44,000 Euros with the infectious disease specialist intervention

and at 51,000 Euros without.

Lemaire X et al Presse Med. 2014. [Epub ahead of print]

Role od the ID specialist in ASP

ID specialists:

• …. recommends appropriate antibiotic choices,

duration of therapy, and route of delivery and by

monitoring to minimize adverse drug reactions.

• …. facilitates care transitions from the inpatient

setting through outpatient parenteral antibiotic

therapy programs and provision of care

management oversight.

Infectious Diseases Specialty Intervention Is Associated With

Decreased Mortality and Lower Healthcare Costs Schmitt S et al Clinical Infectious Diseases 2014;58(1):22–8

Summary Statistics of Patient Condition

Risk-Adjusted Outcomes for Stays With and

Without Infectious Diseases InterventionsSchmitt S et al Clinical Infectious Diseases 2014;58(1):22–8

Risk-Adjusted Outcomes for Stays Receiving

Early Versus Late Infectious Diseases InterventionsSchmitt S et al Clinical Infectious Diseases 2014;58(1):22–8

chiusa la parente

Decorso clinico

All’ingresso in reparto:

• Febbricola… alterazione di VES ….. EO & rx

torace : nulla di rilevante…… esame urine: non

leucocituria ….. Urinocoltura positiva per e. coli

(non riportata conta UFC/ml)

• UTI sostenuta da E. coli→ Ciprofloxacina e.v per

10 giorni. Dimesso in 13a giornata, trattamento

ambulatoriale con Cefditoren pivoxil

(cefalosporina di terza generazione).

?

Apri la parente

Risk Factors for MRSA

• Antibiotic exposure1-4

• Cephalosporins2,3

• Quinolones2,5,6

References

1. Law MR et al. Epidemiol Infect. 1988;101:623-629.

2. Asensio A et al. Infect Control Hosp Epidemiol. 1996;17:20-28.

3. Peacock JE et al. Ann Intern Med. 1980;93:526-532.

4. Hershow RC et al. Infect Control Hosp Epidemiol. 1992;13:587-593.

5. Harbarth S et al. Clin Infect Dis. 2000;31:1380-1385.

6. Evans ME et al. J Antimicrob Chemother. 1998;41:285-288.

• Invasive devices1, 2

• Length of hospitalization1-3

• ICU stay2, 4

• Surgical procedures3

References

1. Law MR et al. Epidemiol Infect. 1988;101:623-629.

2. Asensio A et al. Infect Control Hosp Epidemiol. 1996;17:20-28.

3. Crowcroft N et al. J Hosp Infect. 1996;34:301-309.

4. Peacock JE et al. Ann Intern Med. 1980;93:526-532.

Factors associated with carriage of C difficileRiggs et al Clin infect Dis 2007

Univariate logistic analysis

POSSIBILE SELEZIONE DI PATOGENI ANTIBIOTICO RESISTENTI IN REPARTI AD

ELEVATO RISCHIO INFETTIVO. I.

POSSIBILE SELEZIONE DI PATOGENI ANTIBIOTICO RESISTENTI IN REPARTI AD

ELEVATO RISCHIO INFETTIVO. I.

Cefalosporina 3^ genCefalosporina 3^ gen

CR P.aeruginosaCR P.aeruginosa Klebsiella-ESBL+

E.coli-ESBL+

Enterobacter

Citrobacter

Klebsiella-ESBL+

E.coli-ESBL+

Enterobacter

Citrobacter

MSSAMSSA EnterococcusEnterococcus

imipenemimipenem

IR AcinetobacterIR AcinetobacterS.maltophiliaS.maltophilia

MRSAMRSA

abusoabuso

vancomicinavancomicina

selezioneselezione

GISAGISA VREVRE

IR P.aeruginosa

< selezione di P/T,A/S e A/a.Cl

FQ

Possibile selezione di BGN antibiotico-resistenti

nei reparti ad alto rischio infettivo

abuso cefalo III gen & chinoloni

Cef -R P.aeruginosa Klebsiella ESBL+

E.coli ESBL+

Enterobacter

Citrobacter

Maggior impiego Carbapenem

Carba-R P.aeruginosa S.maltophilia Carba-R Acinetobater

Enterobacter, Klebsiella spp, E. coli, Proteus spp

VIM1 o KPC positive……

Compreso ertapenem

Maggior impiego di pip/tazo+/- tigeciclina, aminoglicosidi

& fosfomicina trometanolo

Chiusa la parente?No!! Allora che gli si

somministra al nostro

paziente in caso di

vera infezione urinaria

da E. coli

• Ceftriaxone (‘o rocefin?)

• Imipenem (‘o tienam?)

• Ciprofloxacina

• Fosfomicina

• Cotrimoxazolo

• Gentamicina

• Insomma che gli volete somministrare…

• …..E cosa no!

i.v/i.m/os?

Current suggestions: intestinal

decontamination from KPC; cUTIs

(FQ & III gen ceph sparing therapy;

low induction of C difficile)

broad spectrum anti aerobic G-

(including intermediate activity

activity vs KPC).

Gentamicin

Così mi scrive il mitico dr

Tascini………

Caro Mario

ho trattato con gentamicina 2 mg/kg dose unica

giornaliera una UTI da KPC MIC genta 2

mg/L, paziente creatinina 2, piede diabetico:

concentrazione di picco nel siero 7 mg/L, valle

nel siero 2 mg/L. oncentrazione di picco nellle

urine (prese con catetere in contemporanea al

siero) 70 mg/L, valle nelle urine 50

mg/L…….A me sembra buono. Che ne dici?

Carlo

Effects of Gentamicin Monotherapy for the Initial Treatment of Community-Onset Complicated Non-

Obstructive Acute Pyelonephritis Due to Enterobacteriaceae in Elderly and Non- Elderly WomenSeong-Heon Wie et al Antimicrob Agents Chemother 2014 early on line

Clinical outcomes of women with community-onset complicated non-obstructive acute

pyelonephritis treated with gentamicin monotherapy as initial empirical antibiotics

Biofilm formation and susceptibility to gentamicin and colistin of

extremely drug-resistant KPC-producing Klebsiella pneumonie

Neparstek J Antimicrob Chemother. 2014 Apr;69(4):1027-34• We characterized biofilm formation of KPC + K pneumoniae

(ST 258) and determined biofilm susceptibility to gentamicin and

colistin….

• Forty-six KPC-Kpn clinical isolates were studied ….

• Antibiotic effect on biofilm formation was evaluated and

susceptibility within biofilm was determined by the minimal

biofilm elimination concentration (MBEC) method…..

• Genta-R isolates (MIC ≥ 32 mg/L) showed a dramatic increase

in resistance within the biofilm), whereas Genta-S isolates (MIC

<32 mg/L) retained their susceptibility

• Resistance to colistin in biofilm was less prominent

• Gentamicin susceptibility of this endemic lineage is retained in

its biofilm state, supporting the use of this antibiotic in the

clinical scenario.

Decorso clinico

All’ingresso in reparto:

• Febbrilcola… alterazione di VES ….. EO & rx

torace : nulla di rilevante…… esame urine: non

leucocituria ….. Urinocoltura positiva per e. coli

(non riportata conta UFC/ml)

• UTI sostenuta da E. coli→ Ciprofloxacina e.v per

10 giorni. Dimesso in 13a giornata,

trattamento ambulatoriale con Cefditoren

pivoxil (cefalosporina di terza generazione).

?

Farmaci pr cui è possibile una

vera terapia sequenziale

i.v. os

• Macrolidi

• Fluorochinoloni

• Cotrimoxazolo

• Metronidazolo

• Linezolid

• rifampicina

Decorso clinico

• In 20ª giornata ritorna al PS:

Confusione mentale, febbre con valori massimi di

temperatura fino a 39,5° C, ipotensione, G.B.

24000/μl, creatininemia 3,6 mg/dl, albuminemia

2,2 g/dl, lattatemia 4,0 mmol/l. Peristalsi assente,

TC distenzione delle anse intestinali con livelli

idroaerei. Sindrome insorta a domicilio con

diarrea. Dalla ampolla rettale si ottengono delle

feci……

Ricerca C. difficile su feci POSITIVA

Vanco 500 mg/6h topica &

metro iv & piperacillina

tazobactam …osserva, osserva,osserva,

osserva….

Decorso clinico

All’ingresso in reparto:

• Febbrilcola… alterazione di VES ….. EO & rx

torace : nulla di rilevante…… esame urine: non

leucocituria ….. Urinocoltura positiva per e. coli

(non riportata conta UFC/ml)

• UTI sostenuta da E. coli→ Ciprofloxacina e.v per

10 giorni. Dimesso in 13a giornata, trattamento

ambulatoriale con Cefditoren pivoxil

(cefalosporina di terza generazione).

?

Apri la parente

Casi di infezione da C. difficile in un ospedale di Roma

0

2

4

6

8

10

12

14

May

2012

Jun

2012

Jul

2012

Aug

2012

Sep

2012

Oct

2012

Nov

2012

Dec

2012

Jan

2013

Feb

2013

Mar

2013

Apr

2013

May

2013

Jun

2013

n° of cases

n°of deaths

Guastalegname M,Grieco S,Giuliano S,Falcone M,Caccese R, Diambrosio M, Talini G & Venditti M. Infection 2014

A cluster of fulminant Clostridium difficile colitis in an Intensive

Care Unit in ItalyGuastalegname M,et al Infection 2014

Colectomy should be performed to treat

CDI in any of the following situations:

• perforation of the colon

• systemic inflammation and

deteriorating clinical condition not

responding to antibiotic therapy; this

includes the clinical diagnoses of toxic

megacolon and severe ileus.

TRATTAMENTO CHIRURGICO

Operate before

lactate exceeds

5.0 mmol/L

ESCMID GUIDELINES 2013

Diverting Loop Ileostomy and Colonic Lavage

An Alternative to Total Abdominal Colectomy for the Treatment

of Severe, Complicated Clostridium difficile Associated Disease

Neal M et al . Annals of Surgery r 254: 423, 2011

chiusa la parente

Decorso clinico

Osserva, osserva, osserva, osserva……..

Ileo, megacolon tossico, shock settico →

trasferimento in ICU intubazione

orotracheale, reintegro volemico,

norepinefrina.

In 23ª giornata trasferimento nella UTI

del ns ospedale:

Colite grave complicata da C. difficile:

- tre emocolture e nuovo test per tossine di C

difficile

- metro 500 mg e.v. ogni 8 ore + vanco 125

mg via SNG ogni 6 ore.

-Intervento chirurgico di colectomia totale.

-Decesso 24 ore dopo l’intervento chirurgico.

- In 23ª giornata: tre emocolture positive per

Klebsiella pneumoniae KPC + (conferma

fenotipica della produzione di carbapenemasi

con il test di sinergia con acido boronico).

- In 23ª giornata: una emocoltura positiva per

Enterococcus faecium.

Cosa cresce dalle

emocolture effettuate

in 23 ma giornata poco

prima dell’exitus?

Fulminant community onset healthcare associated C

difficile infection complicated by KPC BSI infectionGiuliano S, Guastalegname M, Ienco M, Falcone M & Venditti M BMC Infectious Diseases 2014

Redefining ESKAPE…as ESCAPE

Peterson LR. Clin Infect Dis. 2009;49:992.

E Enterococcus faecium

S Staphylococcus aureus (MRSA)

C Clostridium difficile

A Acinetobacter baumannii

P Pseudomonas aeruginosa

E Enterobacteriaceae

Acknowledges the growing virulence of C. difficile

Enterobacteriaceae captures K. pneumoniae, Enterobacter spp., and other resistant species including Escherichia coli and Proteus spp.KPC

Elementi di riflessione di AS

• Il trattamento della CDAD a

rischio di complicazione

• Il paziente settico vs il paziente con

infezione ma non settico

• Il trattamento delle infezioni da

MDR & off label & era post-

antibiogramma

C. difficile is the most common pathogen causing

health care–associated infections

Reported causative pathogens according to type of infection

Magill SS et al, N Engl J Med 2014;370:1198-208

Burden of Clostridium difficile Infection in USLessa et al, N Engl J Med. 2015;372:825-34

Fattori di rischio di ricorrenza di colite da C difficile

• Età> 65 aa

• Precedente colite da C difficile

• Insufficienza renale

• Gravi comorbidità

• Concomitante uso di terapia antibiotica

sistemica

• Inibitori di pompa protonica ed altri antiacidi

• Precedenti ricoveri ospedalieri

• Combinazione di età > 65 aa, concomitanti

antibiotici e gravi comorbidità

Kine et al Lancet 2001; Bauer CMI, 2009, Bauer Lancet 2011; Hu Gastroenterology, 2009; Bauer CMI

2011; Kwok Am J Gastroenterol 2012; Eye Clin Infect Dis 2012

fidaxomicina

Characteristics of patients with CDI and subsequent

Candida spp. bloodstream infectionGuastalegname M, Russo A, Giuliano S, Falcone M and Venditti M, Clin Infect Dis 2013

Patient

number, sex,

age, ward of

hospitalzation

Cause of

hospital

admission

Previous

antimicrobial

chemotherapy

Antimicrobial

regimen for

primary CDI

CDI

Relapse

(time to

relapseb)

Antimicrobial

regimen for

CDI relapse

CDI to

candidemi

a, days

Candidemia

risk

factors

Candida species

and Antifungal

chemotherapy

Clinical

outcome

1, female,

76.

Medical

ward A

HCAP Pip/tazo,

cipro

oral

vanco

Yes

(24)

oral

vanco +

iv metro

16 PICC

TPN

Type 2

DM

C glabrata

Fluconazole

cure

2, female,

84.

Medical

Ward B

Acute

heart

failure

Ceftriaxon

e

oral

vanco

Yes

(37)

oral

vanco +

iv metro

44 PICC

TPN

Chronic

renal

failure,

steroids

C albicans

Micafungin

Death

at

day 3

of

Mica

3, Male,

87.

Medical

Ward C

Pyelo

nephritis

Levofloxa Oral

vanco

(125 mg

qid)

Yes

(21)

oral

vanco

+

iv metro

10 PICC

TPN

Chronic

renal

failure

C albicans

Anidula

cure

4, male,

82.

Medical

Ward C

Hypokali

emia

Levofloxa Oral

vanco

(125 mg

qid)

Yes

(32)

oral

vanco

+

iv metro

13 PICC

TPN

C

parapsilosis

Anidula

Death

at day

13 of

anidu

• Retrospective, observational, case-control study of

patients who were admitted from January 2013 to

December 2013 in three large Hospitals in Rome:

Policlinico Umberto, San Giovanni, Policlinico Gemelli.

• All patients with a documented CDI infection and

subsequent candidemia were included in the study.

• During the study period were recorded 35 consecutive

cases of candidemia subsequent to CDI. The cases were

compared to 105 patients with CDI, but not

microbiological and clinical evidence of candidemia

during hospitalization.

Risk factors and clinical outcomes of candidaemia

in patients treated for Clostridium difficile infectionRusso A, Falcone M, Murri R, Fantoni M, Carfagna P, Sanguinetti M, Posteraro B, Venditti M Clin Microbiol Infect 2015

Risk factors and clinical outcomes of candidaemia in patients treated

for Clostridium difficile infection

50

Russo A, Falcone M, Murri R, Fantoni M, Carfagna P, Sanguinetti M, Posteraro B, Venditti M Clin Microbiol Infect 2015

Clinical characteristics and outcomes of pts with Clostridium/Candida

infection as compared with controls: multivariate analysis

Severe C difficile infection is associated with the

development of candidemia? A multicenter case-control

study Russo A, Falcone M, Murri R, Fantoni M, Carfagna P, Sanguinetti M, Posteraro B, Venditti M CMI 2015

51

Agents of BSI after 393 episodes of CDAD Falcone M, Russo A, Carfagna P , Goldoni P ,Vullo V & Venditti M Antimicrob Agents Chemother early on line 2015

Pathogens CDAD/BSI+ (n=72)

Enterobacteriaceae 14(19%)

Enterococcus spp 10(14%)

Candida spp 34(47%)

- C albicans 15(44%)

- C glabrata 9(26%)

- C tropicalis 5(15%)

- other spp 5(15%)

Polimicrobial BSI 14(19%)

C albicans+E faecalis 6(43%)

C tropicalis+E feacium 1(7%)

KPC-K pneumoniae+E. faecalis 3(21%)

KPC-K pneumoniae+E. faecium 1(7%)

KPC-K pneumoniae+C glabrata 2(14%)

KPC-K pneumoniae+C tropicalis 1(7%)

Out of 38

bacteria isolates,

26(68%) were

MDR!

72 BSIs after 395 CDI: wards of hospitalization Falcone M, Russo A, Carfagna P , Goldoni P ,Vullo V & Venditti M Antimicrob Agents Chemother early on line 2015

Multivariate analysis: factors associated with development of BSI

Falcone M, Russo A, Carfagna P , Goldoni P ,Vullo V & Venditti M Antimicrob Agents Chemother early on line 2015

BSIs secondary to CDI: risk factors and outcomes

Clinical and demographic characteristics of CRKP carrier cohort vs. ALL BSI

and GNR BSI groupsAmit S et al Clin Microbio Infection 2015

P=.0

4

microbial synergism

as a cause of

bloodstream

infection:

steps?

Step 1

Microbiota

alterantion

Fidaxomicin: effects on colonic

microflora

• Data from the fidaxomicin phase 2a clinical trials in patients treated

for C. difficile infection

Colonic levels of B. fragilis before (Day 0) and after treatment (Day 10)

Louie et al. Antimicrob Agents Chemother 2009;53:261–3

7,0 7,37,4

3,6

0

2

4

6

8

10

Day 1 Day 10

Mea

n l

og

10

CF

U p

er

gra

m o

f fa

eces

Fidaxomicin 200 mg bid Vancomycin 125 mg qid

CFU, colony-forming units

Day 0

Reduced Acquisition and Overgrowth of VRE and Candida spp in Patients

Treated With Fidaxo Versus Vanco for C difficile InfectionNerandzic MN et al Clinical Infectious Diseases 2012;55(S2):S121–6

% of pts with negative pretreatment cultures for VRE and Candida spp who acquired VRE or

Candida spp in stool during treatment

Effect of fidaxo vs vanco on susceptibility to intestinal colonization

with VRE in mice

Deshpande et al Antimicrob Agents Chemother April18, 2016 on line early

Effects of vanco of pts that previously received antimicrobial therapyEdlund C et al Cin Infect Dis 1997

Effect of fidaxo vs vanco on susceptibility to intestinal colonization

with K. pneumoniae in mice

Deshpande et al Antimicrob Agents Chemother April18, 2016 on line early

Comparison of translocation of different types of

microorganisms from the intestinal tract of burned mice.

Staphylococcus & E coli translocated only to MLNs,

Serratia, Klebsiella & P aeruginosa trasnslocated evenly to all tissues

BUT

K. pneumoniae was the most efficient microorganism in

translocating to extraintestinal sites, being the

unique bacterium presenting a very low clearance

in the liver and spleen.

Eaves-Pyles T et al. Shock 2001

microbial synergism

as a cause of

bloodstream

infection:

steps?

Step 2:

Intestinal

mucosa

alteration

Effects of C. difficile on intestinal

mucosa and immune system.

C. difficile infection (CDI) is characterized by anintense inflammatory response provoked by toxinhyperproduction [1].

Inflammatory damage persists despite the

administration of appropriate antibiotic therapy [2].

Toxin production is directly involved in intestinal

mucosal epithelium injury [3, 4] and exerts mucosal

immunity impairment also by modification of

neutrophils morphology and function [5].1 Madan R et al. Trends Mol Med 2012. 2 El Feghaly RE et al. Clin Infect Dis 2013. 3 Nam HJ et al. J Biol Chem 2010. 4 Chumbler NM et al. PLoS

Pathog 2012. 5 Brito GA et al. J Infect Dis 2002.

Vanco Treatment’s Association with Delayed Intestinal Tissue

Injury, Clostridial Overgrowth, and Recurrence of CDI in Mice Warren CA et al Antimicrobial Agents and Chemotherapy 57: 689–696, 2013

histopathology scores of cecal tissues of uninfected mice, infected mice, mice infected

and treated with vanco, and mice infected treated with nitazoxanide

Lam et al, Int J Antimicrob Agents 2013; 42:553-8.

Effect of vancomycin dose on treatment outcomes in severe CDI.

Tigecycline exhibits inhibitory activity against C. difficile in

the intestinal tract of hospitalised patients Kundrapu S et al International Journal of Antimicrobial Agents 45 (2015) 424–426

Faecal concentrations of C. difficile toxins A and B

stratified by therapy with vanco or fidaxo Thabit et al. Ann Clin Microbiol Antimicrob (2016) 15:22

Elementi di riflessione di AS

• Il trattamento della CDAD a rischio di

complicazione

• Il paziente settico vs il paziente con

infezione ma non settico

• Il trattamento delle infezioni da MDR

& off label & era post-antibiogramma

• Calcolo reale del costo dell’impiego dei

farmaci “innovativi”

Determinants of mortality in patients with

severe infection

Vital organ invasion by

growing bacteria

Duplication time

30’

Host inflammatory

response

• Exoproteins

• CW components

(LPS, LT, etc..)

Early active antibiotic (PK/PD)

To avoid

inflammatory response

Antibiotics in critically ill patients: a systematic review of the PK of b-lactamsGonçalves-Pereira and Póvoa Critical Care 2011, 15:R206

Heterogeneity of volume of distribution in litres of b-lactams in ICU patients

Concentration–time profiles of three

different dosing regimens of meropenemDaikos CMI 2011

Considerations for Higher Doses of Dapto in Critically ill Elderly Patients with

MRSA-BSIFalcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infetc Dis 2013;57(11):1568–76

Histogram with kernel density overlay line plot of individual patient (n=50) dapto clearance

Considerations for Higher Doses of Dapto in Critically ill Elderly Patients

with MRSA-BSIFalcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infetc Dis, 2013;57(11):1568–76

Box and whisker plot of dapto AUC0-24 by the weight-based dose used in the population

Comparison of clinical characteristics and outcomes of patients with augmented dapto CL

compared to those with normal CL Falcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, 2013;57(11):1568–763

Cumulative Fraction of Response in Patients Without SepsisFalcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, early on line, 2013

Cumulative Fraction of Response in Patients With SepsisFalcone M, Russo A, Venditti M, Novelli A, Pai MP, Clin Infect Dis, 2013;57(11):1568–76

Letalità a 21 giorni in 97 batteriemie da

enterobacteriaceae in rapporto

alla terapia antibiotica iniziale con agenti attivi in vitro

Antibiotico n. casi % sopravvissuti p

Aminoglicoside 20 75 0.40

BL/BL inibitore 33 87 0.24

Carbapenem 28 96 .01

Ciprofloxacina 16 50 <.001

Tumbarello M et al Antimicrob Agents Chemother 51:1987, 2007

OK!

KO!

b-Lactam/b-Lactam Inhibitor Combinations for the Treatment of Bacteremia Due

to ESBL–Producing Escherichia coli: A Post Hoc Analysis of Prospective CohortsRodrıguez-Bano et al CID 2012:54

9.7% versus 19.4% 9.3% versus 16.7%

Kaplan-Meier curves for mortality in the Empirical Therapy Cohort and the

Targeted Therapy Cohort according to treatment regimens for ESBL+

enterobacteriaceae bacteremias. Rodriguez B & Increment study group AAC , on line early May 2, 2016

From Italy:Petrosillo N, Tumbarello M, Venditti M, Viale

P … almeno un 25% della casisistica.....

0

5

10

15

20

25

30

35

40

45

50

Aminoglycosides R

Fluoroquinolones R

3rd gen.

Cephalosporins R

Carbapenems R

Klebsiella pneumoniae

EARS-NET 2003-2011- ITALY

carbapenem

I due meccanismi determinanti il fenotipo di

carbapenem-resistenza di K. pneumoniae nel nostro

Ospedale

KPC

Logistic regression analysis of risk factors for CR-KP BSI

development in rectal carriers

83

Risk factors for carbapenem-resistant K pneumoniae BSI among rectal

carriers: a prospective observational multicentre studyGiannella M et al Clin Microbiol Infect 2014 early on line

Attributable mortality rate for carbapenem-resistant

Klebsiella pneumoniae (KPC+) bacteremiaBorer A Infect Control Hosp epidemiol 30: 972, october 2009

• 32 casi vs 32 controlli (Età, sesso, malattia di base,

LOS, Charlson score, Mc Cabe score: simili o uguali.

Infezione non batteriemica )

• Confusione mentale (p=.011), ipotensione refrattaria a

terapia (p=.033), MOF (p=.002), sepsi grave (p=.051)

più frequenti per i casi di batteriemia da K. pneumoniae

KPC+.

• Mortalità cruda: 72% per i casi di batteriemia da K.

pneumoniae KPC+ vs 22% nei controlli

• Mortalità attribuibile per i casi di batteriemia da K.

pneumoniae KPC+: 50%

Observational study in two hospitals located in a high-prevalence area (Athens, Greece) including

205 patients with CP-Kp BSIs. For definitive treatment, 103 patients received combination therapy

and 72 monotherapy. A significantly higher mortality rate was observed in patients treated with

monotherapy than in those treated with combination therapy (44.4% versus 27.2%; P=0.018).

Combo vs motherapy vs KPC BSI……Daikos et al AAC 2014

Multivariate analysis of risk factors for inhospital

mortality in patients with infection due to CR-KP*

OR(95% CI) P

COPD 8.98(2.09-38.59) 0.003

Hosp. in ICU 15.76(33.35-74.10) <0.001

BSI 11.42(2.68-48.63) 0.001

Colistin-R KP 5.54(1.40-21.91) 0.01

High rate of colistin resistance among patients with carbapenem-resistant Klebsiella

pneumoniae infection accounts for an excess of mortality Capone A, Giannella M, Venditti M, Tarasi A, …Carattoli A, Petrosillo & SEERBIO-GRAB network, Clin Microbiol Infection, 2012

• Inter-hospital spread (7 roman hospitals) of two major clones, ST512 and ST258.

• 36.1% and 20.4% of strains were also resistant to colistin and tigecycline, respectively

•infection was diagnosed in 91 patients who received appropriate antibiotic treatment and

combination therapy, in 73.6% and 59.3%, respectively

•Inhospital mortality was 25%

* Adjusted for appropriate antibiotic therapy, combination therapy and removal of the

infectious source

Predictors of outcome in ICU patients with septic shock caused by

KPC–producing K. pneumoniaeFalcone M , Russo A, Giordano A, Morelli A & Venditti M Clin Microbiol Infect. 2016 Feb 3

Kaplan-Meier curves about survival of patients with Coli S vs Coli R KPC

infection with septic shock

Predictors of outcome in ICU patients with septic shock caused by KPC+ K. pneumoniaeFalcone M , Russo A, Giordano A, Morelli A & Venditti M Clin Microbiol Infect. 2016 Feb 3

Kaplan-Meier curves about survival of patients with or without

control of removal source of infection

Predictors of outcome in ICU patients with septic shock caused by KPC+ K.

pneumoniaeFalcone M , Russo A, Giordano A, Morelli A & Venditti M Clin Microbiol Infect. 2016 Feb 3

Kaplan-Meier curves about survival of patients with or ≥2 in vitro active antibiotics

Carbapenem sparing antibiotic regimens for infections

caused by KPC Klebsiella pneumoniae infections in ICUSbrana F et al Clin Infect Dis 2012

Associazioni utilizzate:

Tigeciclina 100 mg x 2* + Gentamicina 5-7 mg/kg +/- Fosfomicina 3 gr x 3

Tigeciclina 100 mg x 2* + Colistina 4.5 M x 2* +/- Fosfomicina 3 gr x 3

Tigeciclina 100 mg x 2* + Colistina 4.5 M x 2* +/- Gentamicina 5-7 mg/kg

Site of infection, in vitro suscebtibilty to tygecycline according different

methods, and outcome

Outcomes of critically ill ICU patients treated with fosfomycin for infections due to

PDR and XDR carbapenemase-producing Gram-negative bacteria Pontikis et al Int J Antimicrob Agents Chemother on line early, 2013

• Bacteraemia and VAP were the main infections.

• Carbapenemase-producing K. pneumoniae and P. aeruginosa

were isolated in 41 and 17 cases, respectively.

• All isolates exhibited an XDR or PDR profile, being

fosfomycin-susceptible by definition.

• Fosfomycin was administered iv at a median dose of 24 g/day

for a median of 14 days, mainly in combination with colistin or

tigecycline.

• Clinical outcome at Day 14 was successful in 54.2% of

patients, whilst failure, indeterminate outcome and

superinfection were documented in 33.3%, 6.3% and 6.3%,

respectively.

• All-cause mortality at Day 28 was 37.5%. Bacterial

eradication was observed in 56.3% of cases.

Impact of targeted treatment with gentamicin on survival at 30 days

in pts with severe infection caused by carba/coli-resistant K.

pneumoniae (log-rank test 11.9, P.0.001).Gonzolez Padilla et al J Antimicrob Chemother early on line Oct 2014

Impact of treatment with suboptimal targeted treatment, optimal targeted treatment

without genta and optimal targeted treatment with genta on survival at 30 days in pts with

severe infection caused by carba/coli-resistant K. pneumoniae (log-rank test 17.3, P,0.001)Gonzolez Padilla et al J Antimicrob Chemother early on line Oct 2014

First report of successful ertapenem plus doripenem treatment of a colistin-

resistant KPC-producing K pneumoniae bacteremic VAPCeccarelli G, Falcone M, Mezzatesta ML, Stefani S & Venditti M Antimicrob Agents Chemother 2013

First report of successful ertapenem plus doripenem treatment of a colistin-

resistant KPC-producing K pneumoniae bacteremic VAPCeccarelli G, Falcone M, Mezzatesta ML, Stefani S & Venditti M Antimicrob Agents Chemother 2013

Sinergismo

colistina +ertapenem +meropenem +

gentamicina

P. aeruginosa:

antibacterial resistance mechanisms

• Extended spectrum beta-lactamases

• Carbapenemases

• Presence of efflux pumps

• Decrease in cell wall permeability

MDR P aeruginosa BSIs: risk factors and

mortalityTumbarello M et al Epidemiology and infection 2011

Rates of resistance to variuos antipseudomonal agents

Combination therapy?

• Often recommended to increase the likelihood that

at least one drug is active, perhaps to achieve an

additive or synergistic effect, and to reduce

emergence of resistance

• Classic combination is HD pip/tazo plus GM or

Tobra. Some substitute ciprofloxacin for the AG,

but there is little supportive data

• In vitro and animal models indicate enhanced

efficacy with combination therapy but meta-

analyses and large observational trial found no

mortality benefit from adding an AG to

betalactams

The Sanford Guide 2014

Acinetobacter spp.: percentage of invasive isolates resistant to carbapenems, 2012

Sinergismo Colistina/Tigeciclina con RifampicinaAcinetobacter Baumannii

3

0,125

MHB agar MHB agar supplementato con 8 mg/L di rifampicina

Colistina breakpoint 2 mg/L - Rifampicina livelli di picco sierico 4-32mg/L

2

0,094

Dr Enrico Tagliaferri: esperienza personale

Coli+rifa vs coli alone for severe MDR

Acinetobacter infectionsDurante mangoni E et al CID 2013

Addition of vancomycin to colistin and meropenem in a septic shock

syndrome associated to MDR Acinetobacter bacteremiaCeccarelli G, Oliva A, Visca A, D’Ettorre G & Venditti M BMC Infect Dis. 2015 Sep 30;15:393.

103

Time–kill studies for vanco, colistin, colistin plus vanco against MDR A. baumannii

0.125xMIC(16 mg/L) VAN+1xMIC COL

Ceccarelli G, Oliva A, Visca A, D’Ettorre G & Venditti M BMC Infect Dis. 2015 Sep 30;15:393.

ISAC. International S aureus collaborative group.

Retrospective analysis (2006-10) of 3394 episodes of MRSA BSI from

Europe and USA (ECCMID 2013)

% survival at day 14 day 90

median (range) 84(91 –78) 72(78-63)

Difference 12% 15%

Differences in mortality among 10 hospitals were

significant after adjusting for age, MRSA, foci or

nosocomial acquisition

S1 vs S8

P=0.0001

Diagnostic strategies for rapid identification of MRSA

BSIs at the Gemelli hospital

TTP, time to positivity; BSI, bloodstream infection ; ID,

identification; AST, antimicrobial susceptibility testing

Automated instrumentBlood

cultures

Detection of

positivity

Record TTP

Time

01

02

03

04

05

0

Tim

e t

o g

row

th d

ete

ctio

n (

ho

urs

)

Enterococci Stafilococchi Streptococci Enterobacteriaceae Non fermenters

Culture-based

methods

Gram staining

ID/ AST

Direct

methods

Bruker

BioTyper ID

ASTGenomera

20h x ID

30h x

AST

Elementi di riflessione di AS

• Il trattamento della CDAD a rischio di

complicazione

• Il paziente settico vs il paziente con

infezione ma non settico

• Il trattamento delle infezioni da MDR

& off label & era post-antibiogramma

Nuovi e vecchi antibiotici per

batteri MDR

Vecchi antibiotici Nuovi antibiotici

Colistina

Rifampicina

Vancomicina

Fosfomicina

Cefazolina

Macrolidi

Ciprofloxa/levofloxa & Co

Carbapenem?

Minociclina

Gentamicina

Dapto,Orita/Tela & Dalba

Ceftarolina & ceftibrole

Tedizolid

Fidaxo & sons

ceftazidime-avibactam

Ceftolozane-tazobactam

Imi-MK7655; Mero-RPX7009

S-649266

Eravacycline

Plazomycin

New Drugs anti-CRE &

resistance mechanism ID

KPC OXA-48

VIM

Ceftazidime

Avibactam

Imipenem/

Relebactam

Plazomicin

ATM-AVI NDM

Carbavance

(mero/RPX7009)

KPC

KPC

OXA-48

VIM

KPC

OXA-48

KPC

Courtesy of Arena F & Rossolini GM

!