Pierluigi Viale Infectious Disease Unit Teaching Hospital S. Orsola – Malpighi Bologna

Terapia antimicrobica

nelle infezioni intra-addominali

Congresso Nazionale SITA Torino 27-28 settembre 2018

Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study Sartelli M et al. World J Emergency Surgery 2012, 7:36

2,152 patients 1,701 (79%) affected by CA-IAIs 451 (21%) affected by HA-IAIs

INTRA ABDOMINAL INFECTIONS – SUBJECTS UNDER DISCUSSION

THE THREAT OF MDR GRAM NEGATIVES

CHALLENGES IN CANDIDA INFECTIONS

THE ROLE OF ENTEROCOCCUS SPP

OPPORTUNITIES FOR ANTIBIOTIC STEWARDSHIP

Carbapenem Therapy Is Associated With Improved Survival Compared With Piperacillin-Tazobactam for Patients With Extended-Spectrum β-Lactamase Bacteremia Tamma PD et al, Clin Infect Dis 2015,60:1319-25

A total of 331 unique patients with ESBL bacteremia were identified. One hundred three (48%) patients received PTZ empirically and 110 (52%) received carbapenems empirically. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. The primary outcome was time to death from the first day of bacteremia.

Probability of survival censored at day 14

Carba-Carba

Pip/tzb-Carba

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of BSIs due to ESBL-Producing Enterobacteriaceae Gutiérrez-Gutiérrez B et al - Antimicrob Agents Chemother. 2016;60:4159-69

Multinational, retrospective cohort study, enrolling 627 patients with mono microbial BSI due to ESBL-E were studied

K-M CURVES for SURVIVAL

Patients were randomly assigned 1:1 to piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician.

Adult patients were eligible for enrollment if they had at least 1 positive blood culture with E. coli or Klebsiella spp that was nonsusceptible to ceftriaxone or cefotaxime, but remained susceptible to piperacillin-tazobactam and meropenem according to local laboratory protocols.

The primary efficacy outcome was all-cause mortality at 30 days after randomization.

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E. coli or K. pneumonia Bloodstream Infection and Ceftriaxone Resistance. A Randomized Clinical Trial Harris PNA et al, JAMA. 2018;320:984-994

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumonia Bloodstream Infection and Ceftriaxone Resistance. A Randomized Clinical Trial Harris PNA et al, JAMA. 2018;320:984-994.

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E. coli or K. pneumonia Bloodstream Infection and Ceftriaxone Resistance. A Randomized Clinical Trial Harris PNA et al, JAMA. 2018;320:984-994

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E. coli or K. pneumonia Bloodstream Infection and Ceftriaxone Resistance. A Randomized Clinical Trial Harris PNA et al, JAMA. 2018;320:984-994

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients with E. coli or K. pneumonia Bloodstream Infection and Ceftriaxone Resistance. A Randomized Clinical Trial Harris PNA et al, JAMA. 2018;320:984-994

Increased relative abundance of carbapenemase-producing Klebsiella pneumoniae within the gut microbiota is associated with risk of bloodstream infection in long-term acute care hospital patients. Shimasaki T et al Clin Infect Dis. 2018 Sep 18.

A total of 2,319 samples from 562 admissions (506 patients) were collected, of which 255 (45.4%) were colonized with KPC-Kp and 11 (4.3%) had KPC-Kp BSI

Demographic and Clinical Characteristics of KPC-Kp colonized patients (N=255)

Age (Years), mean ± SD 63.2 ± 15.9 LOS in days, median (IQR) 40 (27-65) Mechanical ventilation 98 (38.4) Central venous catheter 130 (51.6) Indwelling urinary catheter 159 (62.4) Charlson Score, median (IQR) 3 (2-5) Diabetes mellitus 123 (48.2%) Congestive heart failure 82 (32.2) Stroke 72 (28.2) Decubitus ulcer 193 (75.7) ESRD on hemodialysis 35 (13.8) Antibiotic use, n (%) 235 (92.2) Carbapenem 102 (40.0) Bl/BLI 69 (27.1) Vancomycin iv 133 (52.2) Metronidazole 49 (19.2)

Increased relative abundance of carbapenemase-producing Klebsiella pneumoniae within the gut microbiota is associated with risk of bloodstream infection in long-term acute care hospital patients. Shimasaki T et al Clin Infect Dis. 2018 Sep 18.

ROC curve analysis of the relation between relative abundance of KPC-Kp and subsequent KPC-Kp BSI

RR for BSI = 4.2 95% CI 1.3-14.0

P = 0.01

Increased relative abundance of carbapenemase-producing Klebsiella pneumoniae within the gut microbiota is associated with risk of bloodstream infection in long-term acute care hospital patients. Shimasaki T et al Clin Infect Dis. 2018 Sep 18.

Clinical predictors HR (95% CI) P value Age in years 0.99 (0.97-1.02) 0.549 Charlson comorbidity index 0.90 (0.74-1.09) 0.277

Any medical device use 1.05 (0.25-4.48) 0.943

Any antibiotic exposure 0.70 (0.24-2.07) 0.519

Carbapenem 2.19 (1.06-4.55) 0.036

Bl/BLI 0.66 (0.23-1.90) 0.436

Vancomycin IV 0.79 (0.38-1.66) 0.537

Metronidazole 0.50 (0.12-2.12) 0.351

Risk factors associated with ≥22% relative abundance of KPC-Kp in the gut microbiota

Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing E.coli and K. pneumoniae: a pooled analysis of Phase 3 clinical trials. Popejoy MW et al, J Antimicrob Chemother 2017; 72: 268–272

In vitro ACTIVITY

Clinical cure rates for patients with ESBL-ENT (including CTX-M-14/ 15) were

consistently higher with ceftolozane/tazobactam than with comparators.

In cIAI Clinical cure rates were 98.1% for ceftolozane/tazobactam and 88.5%

for meropenem (P> 0.05)

Furthermore, 18 of 19 patients with a ceftolozane/tazobactam MIC > 2 mg/L

achieved clinical cure with ceftolozane/tazobactam

Efficacy of ceftolozane/tazobactam against urinary tract and intra-abdominal infections caused by ESBL-producing E.coli and K. pneumoniae: a pooled analysis of Phase 3 clinical trials. Popejoy MW et al, J Antimicrob Chemother 2017; 72: 268–272

A ROLE FOR INNOVATIVE BL-BLIs? A BASIC EXAMPLE OF A HIERARCHICAL PATTERN OF CHOICES 1. Patients without sepsis «ancient» BL-BLIs

2. Patients with RF for mortality new BL-BLIs

3. Patients admitted to ICU carbapenems

CPE treatment – UNMET NEEDS

the «MIC creep» of carbapenems undermines their therapeutic

backbone role

the colistin resistance hinders its use in combo regimens

the low reliability of standard chemosensitivity tests hampers

their interpretation

The management of new options (ceftazidime/avibactam, meropenem/

vaborbactam, imipenem/relebactam, aztreonam/avibactam, plazomycin) is not yet

completely defined

Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by KPC–producing K. pneumoniae Tumbarello M et al, Clin Infect Dis in press

Cases were eligible for inclusion in the cohort if the patient (1) was ≥18 years old; (2) had had a culture-confirmed KPC-Kp infection; and (3) had received ≥72 hours of CAZ-AVI salvage therapy (with or without other antimicrobials). A total of 138 pts were retrospetively enrolled. In a sub group of 104 bacteremic patients findings of were compared with those on a matched cohort of patients whose bacteremic KPC-Kp infections had been managed in the participating centers receiving ≥72 hours of salvage therapy regimens that did not include CAZ-AVI (controls). Case-control matching was based on (1) the number of days (± 1 day) from bacteremia onset to the initiation of salvage therapy and (2) Pitt bacteremia scores (± 1 point). Data on survivor and nonsurvivor subgroups in the combined group of bacteremia patients (cases plus controls) were analyzed to identify predictors of 30-day mortality. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died.

Flowchart of patients’ inclusion process

Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by KPC–producing K. pneumoniae Tumbarello M et al, Clin Infect Dis 2018 Jun 9

Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by KPC–producing K. pneumoniae Tumbarello M et al, Clin Infect Dis 2018 Jun 9

Thirty-day survival rates of CAZ-AVI–treated bacteremic patients according to concomitant drugs used as combination therapy or to CAZ-AVI monotherapy

Istituto di Farmacologia Clinica - UniUD

CUMULATIVE RESPONSE PROBABILITY OF CEFTAZIDIME AVIBACTAM 2.5 G Q8H vs. P. aeruginosa CF ISOLATES

PK/PD TARGET ATTAINMENT ANALYSES TO DETERMINE OPTIMAL DOSING OF CEFTAZIDIME-AVIBACTAM FOR THE TREATMENT OF

ACUTE PULMONARY EXACERBATIONS IN PATIENTS WITH CYSTIC FIBROSIS Bensman TJ et al. Antimicrob Agent Chemother 2017 Oct; 61: e00988-17

INTRA ABDOMINAL INFECTIONS – SUBJECTS UNDER DISCUSSION

THE THREAT OF MDR GRAM NEGATIVES

CHALLENGES IN CANDIDA INFECTIONS

THE ROLE OF ENTEROCOCCUS SPP

OPPORTUNITIES FOR ANTIBIOTIC STEWARDSHIP

INTRA ABDOMINAL CANDIDIASIS – open questions

a single definition gathering togheter different conditions

to treat or not to treat ?

empirical or targeted management ?

which role for biomarkers in the diagnosis?

which drugs ?

Association between source control and mortality in 258 patients with intra-abdominal candidiasis: a retrospective multi-centric analysis comparing intensive care versus surgical wards in Spain. Lagunes L et al Eur J Clin Microbiol Infect Dis 2017; 36:95–104

A retrospective, multicenter, cohort study, performed at surgical wards and intensive care units of three University Hospitals in Spain between 2010 and 2014, with the aim of improving understanding of the interaction between source control, early antifungal therapy, and use of vasoactives in patients with intra-abdominal candidiasis. 258 pts identified.

Independent risk factors for 30-day mortality in ICU and surgical ward patients

SURVIVALS

Association between source control and mortality in 258 patients with intra-abdominal candidiasis: a retrospective multi-centric analysis comparing intensive care versus surgical wards in Spain. Lagunes L et al Eur J Clin Microbiol Infect Dis 2017; 36:95–104

Antifungal stewardship in IAI – a proposal

BEST Sslection of surgical ICU patients at

highest risk for IC

Start AGGRESSIVE antifungal treatment

Early de-escaltion or early discontinuation according with BIOMARKERS/FAST MICROBIOLOGY

and OUTCOME

INTRA ABDOMINAL INFECTIONS – SUBJECTS UNDER DISCUSSION

THE THREAT OF MDR GRAM NEGATIVES

CHALLENGES IN CANDIDA INFECTIONS

THE ROLE OF ENTEROCOCCUS SPP

OPPORTUNITIES FOR ANTIBIOTIC STEWARDSHIP

Quality of antimicrobial prescriptions in surgery

• (Prophylaxis not considered)

• 25-30% inappropriate prescriptions

• Reasons – Not first line drug(s) (local guideline) 20-40% – Inadequate dosing 10-20% – Inadequate duration 70-90% – Oral route possible 20-30%

Data by Retamar P et al, HVM PPS Studies, 2013-2016

Trial of Short-Course Antimicrobial Therapy for Intra-abdominal Infection Sawyer RG et al N Engl J Med 2015; 372:1996-2005

518 patients with complicated intraabdominal infection and adequate source control ewere randomly assigned to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections.

Trial of Short-Course Antimicrobial Therapy for Intra-abdominal Infection Sawyer RG et al N Engl J Med 2015; 372:1996-2005

Trial of Short-Course Antimicrobial Therapy for Intra-abdominal Infection Sawyer RG et al N Engl J Med 2015; 372:1996-2005

Protocol violation 18% 27%

Longer-duration antimicrobial therapy does not prevent treatment failure in high-risk patients with complicated intra-abdominal infections Hassinger TE et al, Surgical Infect 2017; 18

Patients enrolled in the Study to Optimize Peritoneal Infection Therapy trial were evaluated retrospectively to identify risk factors associated with treatment failure, which was defined as the composite outcome of recurrent IAI, surgical site infection, or death.

The STOP-IT trial included 517 patients enrolled The overall rate of treatment failure was 22.1%. Four variables showed significant association with failure • steroid use, • hospital acquired infection, • APACHE) II score >15, • colonic source of infection

Both the presence and the number of risk factors were associated independently with treatment failure, but treatment duration was not