Mario Venditti - SIMI Mario.pdf · Mario Venditti Dipartimento Sanità Pubblica e Malattie...
Transcript of Mario Venditti - SIMI Mario.pdf · Mario Venditti Dipartimento Sanità Pubblica e Malattie...
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
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