infezioni intraddominali e candidiasi invasiva · contamination duration blood loss foreign bodies...

Infezioni intraddominali e candidiasi

invasiva

Department of Surgery Division of General Surgery and Organ Transplantation Catholic University of Sacred Heart Policlinico “A. Gemelli”, Rome, Italy

G. Sganga

Patients with more severe underlying diseases

More elderly patients

Immunosuppression

More complicated surgery

Increase in survival rate in critical illness ……and prolonged ICU stay

FACTORS RELATED WITH THE INCREASE OF FUNGAL INFECTIONS

Antineoplastic chemo-radio-therapy Transplant surgery

More complex

therapeutic interventions

for

metabolically and immunologically

more compromised patients

Fungal infections in surgical patients

ICU, intensive care unit; SIRS, systemic inflammatory response syndrome

Postoperative

SIRS

ICU complication

Fungal infection

COMPLICATION

Preoperative

Risk factors

Colonisation

Intraoperative

Contamination

Duration

Blood loss

Foreign bodies

Microbiology of peritonitis

Weigelt J. Clev Clin J Med. 2007;74(Suppl 4):S29–37; Eckmann C, et al. Eur J Med Res 2011;16:115–26.

Primary

peritonitis

Secondary

peritonitis

Tertiary

peritonitis Dialysis

associated

Enterobacteriaceae Enterobacteriaceae Enterobacteriaceae Staphylococci

S. aureus Anaerobic bacteria Anaerobic bacteria Anaerobic bacteria

Enterococci Viridans streptococci Enterococci Enterobacteriaceae

Candida spp Candida spp Candida spp

Non-fermentative

Gram-negative rods

Weigelt/PgS32/Table2

Eckman/Pg117/Table2

Eckman/Pg118/Table3

Bassetti M et al. Intensive Care Med 2015;41:1601-10

Intra-abdominal candidiasis: Multicentre, multinational study

Bassetti 2015/1607/table 3

Candida infections: Risk factors in adults

• Neutropenia

• Central venous catheters

• Candida colonisation

• Broad-spectrum antibiotics

• Length of ICU stay

• Mechanical ventilation

• Haemodyalisis

• Multiple blood transfusions

• Diabetes

• Corticosteroids

• Immunosuppressive agents

• Parenteral nutrition

• Urinary catheters

ICU, intensive care unit; APGAR, appearance, pulse, grimace,

activity, respiration

Vincent JL, et al. Int Care Med 1998;24:206–16.

Vincent 1998/209/Table2

For neonates and children:

o Prematurity

o Low birth weight

o Low APGAR score

o Congenital malformation

Surgical interventions as risk factors for intra-abdominal candidiasis

• Recurrent gastrointestinal perforations1,2

• Anastomotic leakages1,2

• Surgery for acute pancreatitis2

• Splenectomy2

• Transplantation3

1. Eggimann P, et al. Ann Intensive Care 2011;1:37; 2. Calandra T, et al. Lancet 1989;2:1437–40; 3. Martino R and Subira M. Ann Hematol 2002;81:233–43.

Calandra/Pg1438/Col2/Para1/Ln3-6


Martino/Pg233/Col1/Para1//Ln3-9


Eggiman/Pg3/Table2

Eggiman/Pg3/Col1/Para3/Ln3-14

Mortality rate: 23.7%–52.9%1

Risk factors for intra-abdominal Candida infection

Secondary peritonitis

Candida spp isolates

Appendicular4 <5%

Colorectal4 12%

Small bowel3 35%

Upper GI tract4 41%

GI, gastrointestinal; ICU, intensive care unit; TPN, total parenteral nutrition 1. Bassetti M, et al. Intensive Care Med 2013;39:2092–106; 2. Eggimann P, et al. Ann Intensive Care 2011;1:37;3. Sandven P, et al. Crit Care Med 2002;30:541; 4. de Ruiter, et al. J Infection 2009;37:522.

Specific:1,2

Recurrent abdominal surgery GI perforations GI anastomoses leakage Multifocal colonisation by Candida spp

Non-specific:1,2

Central venous catheter (+ eventual TPN) ICU stay Diabetes (and immunosuppression) Prolonged broad-spectrum antibiotics

Candida spp are the most frequent isolates

Sandven/Pg544/Col1/Para2/1-

4 & Pg543/Table 1

Eggiman/Pg3/Table2

Sganga/Abstract/Ln4-6

Basetti/Pg2096/Table 2

DeRuiter/Abstract/results/ln13-15

Significance of Candida recovered from intra-operative specimens in patients with intra-abdominal perforations

110 patients prospectively enrolled

Fungal Recovery Rate

appendicitis 1/28 pts (3.5%)

non appendicitis 32/81 pts (39.5%)

PERIOPERATIVE YEAST OR 11.5 2.3-58.6

VARIABLES ASSOCIATED with DEATH

Sandven et al, Crit Care Med, 2002

Fungal infections:

How the surgeon could help

• Getting the best source control and preventing complications

• Early diagnosis

• Early tratment

Management of the patient with fungal infections

DIAGNOSIS as soon as possible

ANTIFUNGALS as soon as diagnosis is suspected

SURGERY by emergency

Source Control

• It is defined as any single procedure or series of procedures that eliminate

infectious foci, control factors that promote ongoing infection, and correct

or control anatomic derangements to restore normal physiologic function

• In other words…... encompasses all the measures that eradicate the focus

of infection, prevent continuing contamination, and restore functional

anatomic relationships

“SOILING INTO THE ABDOMEN SHOULD BE STOPPED IN ANY WAY”

Source control

Marshall JC, Crit Care Med 2004;32 Suppl 11:5513; De Waele, JJ Langenbecks Arch Surg 2010;395:489 Hartl,W Zentralbl Chir 2011;136:11

«SURGERY: ALWAYS BEFORE DAWN, NEVER AFTER SUNSET»

Extended Indications

Multi-loculated and multiple abscesses (Gerzof)

Abscesses with fistula

Pancreatic fluid collections

Abscesses secondary to appendicitis or acute diverticulitis (von Sonnenberg)

Retroperitoneal abscesses (Lameris)

Pelvic abscesses (Woerthen)

Contra-indications

Infected pancreatic necrosis

Multiple abscesses

Small abscesses

Fungi

Coagulopathy

Percutaneous drainage

•Non-loculated fluid collections

•No communication between abscess and viscus

•Non fungal ethiology

Absolute indications

Radiologia Interventistica negli ascessi addominali

• Aspirato per microbiologia

• Aspirato evacuativo

• Drenaggio percutaneo esclusivo

• Drenaggio pre-chirurgico

Leak, appendiciti, diverticoliti, colecistiti

• Drenaggio post-chirurgico

• Trattamento causa ascesso

Leak biliari, urinari

Sven Ivar

Seldinger

Seldinger’ Technique

Needle 18G

Guide 0,035”

Needle 21G

Guide 0,018”

Seldinger set

Contra-indications


Multiple abscesses

Small abscesses

Fungi

Impossible accesses

Coagulopathy

*

*

*

*

*

Contra-indications


Multiple abscesses

Small abscesses

Impossible accesses

Fungi

Coagulopathy

Surgical Guidelines for the Treatment of Intra-Abdominal Sepsis

Surgical procedures

Open abdomen (laparostomy)

“Open abdomen”

“Zipper, meshes”

“Marsupialization”

VAC Therapy

Relaparotomy

“Directed relaparotomy”

“Non-directed” or “Blind” or “Empiric relaparotomy”

“Scheduled relaparotomy”

Laparotomy

“Radical Surgical Debridment” (Hudspeth, 1975)

“Continuous post-operative peritoneal lavage” (Stephen-Lowenthal, 1979)

CT scan with contrast

Hammond NA, et al. Am Fam Phys 2010;82:766; Emmi V, Sganga G. J Chemother 2009,21 Suppl 1:12; Sartelli,M et al World J Em Surgery 2012;7:15.

...computed tomography is the preferred test in evaluating secondary peritonitis...

“...localized perforated diverticulitis – no free fluid or gas – no signs of diffse peritonitis”

Hammond 2010/766/Abstrac/Para1/ln5-7

Sartelli 2012/3/Table1

Emmie 2009/abstract/para2/ln10-11

Emergency surgery

• No blood cultures were taken before surgery

• Sigmoid resection with primary end to end anastomosis. No pus cultures taken intra-operatively

• No pus cultures were taken

Fifth post-operative day

• Temperature, 39.6⁰C

• HR, 110

• RR, 19

• WBC, 22,000

HR, heart rate, RR, respiratory rate, WBC, white blood cells ESBL, extended-spectrum beta-lactamases; ICU, intensive care unit; MRSA, methicillin-resistant Staphylococcus aureus; MDR, multi drug resistant

Ninth post-operative day: Septic Shock and respiratory insufficiency (ICU)

• The pt was transferred to our hospital

• Resuscitation, mechanical ventilation, fluids, inotropes and vasopressors…evidence of faecal material from drainage......

• …..second look: Hartmann procedure

ICU, intensive care unit; MDR, multi-drug resistant

Blood cultures during septic shock: • E. coli ESBL, E. faecalis MDR, C. tropicalis

“Candida score”

Cristobal L et Al: Crit Care Med, 34(3): 730-737, 2006

1699 ICU patients

Predictors of proven candidal infection: odds ratio

Surgery 2.71 Multifocal colonization 3.04 Total Parenteral Nutrition 2.48 Severe sepsis 7.68

(1-3)-β-D-Glucan

ROC AUC curves of BG, CS, and colonisation index for proven IC cases

AUC, area under curve; BG, (1–3)-β-D-glucan; CS, Candida score; IC, invasive candidiasis; ROC, receiver operating characteristic

Posteraro B, et al. Crit Care 2011;15:R249

Pg7/Figure3

(1-3)-β-D-Glucan Identification of the context of false-positive

test results

• Concurrent bacteraemia

• Use of renal replacement therapy

• Treatment with fungus-derived antibiotics

• Intravenously administered immunoglobulins or albumin

• Exposure to gauze

Levesque E, J Clinical Microb 2015;53:771–776

Pg775/Para2/Ln12-16

Identikit of patient at risk for candida infection personal point of view

A critically ill post-surgical patient with fever on adequate antibiotic therapy

Additional risk factors:

Candida colonization

Relaparotomy/relaparotomies

Open abdomen tecniques (abdominal compartimental syndrome, VAC therapy)

Peritonectomy and hyperthermic intraoperative chemotherapy for peritoneal carcinomatosis*

Bowel perforation

Anastomotic leaks

Previous antibiotic therapy

* Capone A. Et al J Surgical Oncology, 2007

Falcone M et al J Antimicrobial Chemotherapy, 2010

VAC, vacuum-assisted closure

Recommended drugs for invasive candidiasis according to different guidelines

Guidelines Recommendation

IDSA 20161 Fluconazole/echinocandins*

ESCMID 20122 Echinocandins/liposomal amphotericin B/voriconazole**

SITI/ISC 20133 Echinocandins/lipid amphotericin B/azoles†

ITALIC 20134 Echinocandins

*Recommendations for candidaemia in non-neutropenic patients in patients with moderately severe to severe illness (echinochandins) or less severe illness (fluconazole)

**Echinocandins have A-I recommendation. Liposomal amphotericin B and voriconazole have B-I recommendation

†Echinocandins/lipid amphotericin B can be used in critically ill patients or for patients with previous azole exposure. Azoles can be used in non-critically ill patients with intra-abdominal candidiasis due to susceptible strains

ESCMID, European Society of Clinical Microbiology and Infectious Diseases; IDSA, Infectious Disease Society of America; ISC, International Society of Chemotherapy; ITALIC, Italian consensus for invasive candidiasis mangement; SITI, Italian Society of Intensive Care

1. Pappas PG, et al. Clin Infect Dis 2016;62:409–417; 2. Cornely OA, et al. Clin Microbiol Infect 2012;18(Suppl 7):19–37; 3. Bassetti M, et al. Intensive Care Med 2013;39:2092–2106; 4. Scudeller L, et al. Infection 2014;42:263–279

Pappas/Pg503/Col2/Para2 & Pg504/Col2/Para4

Cornely/Pg25/Col1/Para3/Ln1-2

Bassetti/Pg2094/Col1/Para3/L1-3

Bassetti/Pg2093/Col1/Abstract/Results/Ln18-22

Bassetti/Pg2093/Col2/Abstract/Ln6-12

Scudeller/268/Col2/Para6/Ln1-2

Management of intra-abdominal candidiasis

• Prophylaxis in high risk patients:

• Fluconazole in patients with recent abdominal surgery and recurrent gastrointestinal perforation or anastomotic leakage1

• Therapy of documented cases:2

• Echinocandins should be used in critically ill, non-neutropenic, or neutropenic patients

• Fluconazole is an acceptable alternative for patients who have had no recent azole exposure and are not colonized with azole-resistant Candida spp.

1. Cornely OA, et al. Clin Microbiol Infect 2012;18(Suppl 7):19–37; 2. Pappas PG, et al. Clin Infect Dis 2016; 62:409–417.

Cornely/Pg19/Abstract/Ln2-3

Pappas2016/1/col2/para2

Pappas2016/1/col2/para3

Key challenges

• Why echinocandins?1–3

‒ Broad spectrum1–3

‒ Resistance is rare5

‒ Fungicidal – biofilm activity4

‒ Preserve organ function (safety profile)4

‒ Few drug-drug interactions4

• Which echinocandin?

‒ Consider:

Dose adjustments

Drug interactions

Pharmacokinetics

Critically ill patients, e.g., neutropenia

1. Ecalta® (anidulafungin) Summary of Product Characteristics, Sept 2014; 2. Mycamine® (micafungin) Summary of Product Characteristics, 2014; 3. Cancidas®(caspofungin) Summary of Product Characteristics, 2014; 4. Scudeller L, et al. Infection 2014;42:263–279; 5. Kofla G, Ruhnke M. Eur J Med Res 2011;16:159–166;

Scudeller/268/Col2/Para6/ln3-4

Scudeller/269/Col1/Para1/ln1-4

Ecalta SmPC p2/Sect4.5; p3/Sect 4.8;

p4/Sect 5.1; p5/Table2

Kofla 2011 p161/col2/para2

Cancidas SmPC p9/Sect 5.1; p20/Sect 4.5

Mycamine SmPC p9/Sect 5.1; p20/Sect 4.5

Antifungal PK: Drug Distribution

+, ≥50% of serum concentrations. –, <10% of serum concentrations.

*Predicted. 1. Dodds-Ashley ES, et al . Clin Infect Dis. 2006;43:S28-S39.

2. Groll AH, et al. Adv Pharmacol. 1998;44:343-500. 3. Eschenauer G, et al. Ther Clin Risk Manage. 2007;3:71-97.

Liver/ Spleen Kidneys

Gut/gall bladder Lungs

Brain/ CSF Eyes

Bladder/urine

AMB + + + + – – –

5FC + + + + + + +

FLU + + + + + + +

ITR + + + + – – –

VOR + + + + + + –

POS* + + + + – – –

Echino + + + + – – –

Abdominal candidiasis is a hidden reservoir of echinocandin resistance

52%

13% 28%

7%

Types of invasive candidasis among patients at UPMC (2010-2011)

Abdominal candidiasis is a hidden reservoir of echinocandin resistance

• 25 pts with abdominal candidiasis received an echinocandin

for >3 days (median 42 days, range 4 – 438).

• All pts had underlying GI diseases, and 92% (23/25) underwent GI surgery within 30 days preceding the onset of abdominal candidiasis (44% SOT recipients)

• C. glabrata (n=17) was most common, followed by C. albicans (n=7), C. tropicalis (n=2) and C.krusei (n=1). Two patients had mixed Candida infections

• 40% (10/25) of abdominal candidiasis were echinocandin breakthrough infections, which occurred during caspo (n=9) or mica (n=1) therapy.

• Among 10 echinocandin breakthrough infections: C. glabrata (n=6), C. albicans (n=3), C. tropicalis (n=1) and C. krusei (n=1)). One patient had both C glabrata and C. tropicalis

No source control!!

Shields et al Antimicrob. Agents Chemother 2014 Dec;58(12):7601-5

Material and Methods

• Open, non controlled, non randomized, pivotal

study, single center

• So far 8 patients were enrolled. The main

indication was Deep Tissue Candidiasis (mostly C.

albicans) with or without candidemia all with

negative “fundus oculi”

• Dosage of anidulafungin: 200 mg i.v. loading dose,

followed by 100 mg/daily

Plasma and biliary excretion of anidulafungin in Liver transplantation

• The biliary samples have been obtained through

the Kehr T-tube, placed in the biliary tract, every 8

hours

• The samples have been collected before and for all the

anidulafungin therapy duration (range 5-21 days)

• At the same time blood samples have been collected.

Samples have been maintained at -80°C until assayed.

High-performance liquid chromatography with ultraviolet

detector (HPLC/UV) analytical method has been used for

the determination of anidulafungin concentrations

Material and Methods

Anidulafungin 100 mg multiple dose

Penetration into bile fluid in 8 patients

0 4 8 12 160

2

4

6

8Plasma concentration

Bile concentration

Time after anidulafungin dose (h)

Co

nc

en

tra

tio

n (

mg

/l)

Sganga G, Novelli A, data on file 2016

[67] Pagani JL, Revelly JP, Que YA, Eggimann P (2015) The role of biomarkers for starting antifungals in the intensive care unit. Clin Pulm Med 22:286–293.

Therapeutic management of peritonitis: a comprehensive guide for intensivists

P. Montravers, S. Blot, G. Dimopoulos, C. Eckmann, P. Eggimann, X. Guirao, J. A. Paiva, G. Sganga & J. De Waele

Intensive Care Medicine, 2016 Aug;42(8):1234-47

Conclusions

• DIAGNOSIS, adequate, as soon as possibleCT scan

• ANTIFUNGALS, adequate, as soon as possible adequate antimicrobial treatment even before formal diagnosis

• SURGERY, adequate, as soon as possible laparoscopy should be considered in experienced hands

• RE-LAPAROTOMY, adequate, as soon as necessarya la demand re-laparotomy appears more rational than planned re-laparotomy. Consider open abdomen and VAC.

QUICK and ADEQUATE

If the initial multi-bacterial infection is left uncontrolled, often this can

result in invasive candidiasis

infezioni intraddominali e candidiasi invasiva · contamination duration blood loss foreign bodies...

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