Sindrome di Fournier

Fulvio Crippa

Il Ruolo dell’Infettivologo

DEFINIZIONE Lesioni necrotizzanti che possono estendersi

rapidamente alle fasce e ai muscoli sottostanti e portare ad una massiccia distruzione tissutale

INCIDENZA Negli USA dai 500 ai 1500 casi per anno con una

incidenza di 0.04 casi per 1000 persone/anno negli USA

NSTIs

Cornia PB et al, Expert Opin Pharmacother, 2008

NSTIs

1871

descritte per la prima volta come “hospital gangrene”

1951

introduzione del termine “necrotizing fasciitis” per

descrivere alcune NSTIs

attualmente esistono differenti sistemi di

classificazione, comunque con questo termine

necrotizing soft-tissue infections (NSTIs) comprende

tutte le SSSIs necrotizzanti per le quali esiste un

unico approccio diagnostico e terapeutico

Anaya DA and Dellinger EP, CID, 2007

NSTIs

Cornia PB et al, Expert Opin Pharmacother, 2008

CARATTERISTICHE Importanza del dolore (maggiore rispetto a quanto

suggerito dai segni obiettivi)

SIRS, SEPSI, SEPSI GRAVE, SHOCK SETTICO

Crepitii all’esame obiettivo (oppure aria nei tessuti alla radiografia)

Petecchie, ecchimosi, bolle

Rapida progressione dell’infezione

Definizione: La FN è un’infezione dei tessuti molli aggressiva che evolve in una necrosi rapidamente progressiva e destruente delle fasce con alterazione dei piani anatomici.

Sedi: infezione secondaria (biopsia cutanea, lacerazione, morso di insetto, puntura di siringa – tossicodipendenti ev, VZV, ferita chirurgica, ascesso cutaneo, ulcere per insufficienza venosa cronica)

Kihiczak GG et al, JEADV, 2006

Fascite necrotizzante (FN)

Variante di FN che si sviluppa a livello genitale Comorbidità: soprattutto diabete mellito, nel 20% non

si riconosce una causa scatenante Infezione perianale o retroperitoneale che si diffonde attraverso i piani fasciali ai genitali

– IVU e successivo interessamento delle ghiandole perituretrali, scroto e pene

– traumi in regione genitale: ingresso di microrganismi nel sottocute

– post emorroidectomia

Iniziale gangrena superficiale, limitata alla cute e al sottocute, che si estende alla base dello scroto.

L’infezione può estendersi al perineo e alla parete

addominale anteriore.

Stevens DL et al, CID, 2005

Gangrena di Fournier

The evaluation of microbiology and prognosis of Fournier’s gangrene in past five years

• Retrospective cohort study that was designed to study the trends in microbiology and prognosis of FG.

• From the PubMed database, articles published in the recent 5 years (from Jan1st , 2009 to Dec 31st ,2013) were reviewed.

• A total of 19 articles (each with n > 30 and with thorough data descriptions in the topic of Fournier's gangrene), were enrolled in this study

Tang et al. SpringerPlus (2015) 4:14 DOI 10.1186/s40064-014-0783-8

American Journal of Surgery The microbiology of necrotizing soft tissue infections

David Elliott, Joseph A Kufera, Roy A.M Myers Volume 179, Issue 5, Pages 361–366

• 198 patients with documented NSTI revealed 182 patients with sufficient microbiologic information for analysis.

• These 182 patients grew an average of 4.4 microbes from original wound cultures, although a single pathogen was responsible in 28 patients.

• Eighty-five patients had combined aerobic and anaerobic

growth

• Beta-hemolytic streptococci are the most frequent solitary pathogens.

• The most common bacterial species overall include

– Bacteroides/Prevotella

– Streptococci

– Gram-negative enterobacteriaceae (E coli, K pneumonia, Proteus mirabilis).

– Enterococci and staphylococcal species are also commonly found

La gangrena origina dalla trombosi dei vasi sanguigni, che causa un intenso dolore locale.

La cute interessata appare eritematosa ed indurita; se il trattamento è ritardato evolve velocemente in bolle emorragiche con zone di necrosi focale.

Nichols RL and Florman S, CID, 2001

GANGRENA da Streptococco β emolitico di gruppo A

Pathogenesis

• Necrotizing fasciitis develops as the infectious organisms proliferate and extend from the subcutaneous tissue along superficial and deep fascial planes.

• Bacterial enzymes and toxins may play a part in

this process. • The bacterial factors thought to be important in

NF include surface proteins and toxins.

Steptococcal (Flash Eating Bacteria) exotoxins

• Hemolysins, Streptolysins O and S, Leukocidines.

• Surface proteins M-1 and M-3 increase the adhesion of streptococci to tissues and prevent phagocytosis by neutrophils.

• Streptococcal pyrogenic exotoxins (SPEs) A, B, and C and streptococcal superantigen (SSA) cause the release of cytokines.

Soft Tissue Damage

• Impact on host phagocytes and a contribution to the paracellular translocation of GAS.

• SLS-associated gene A (sagA) mRNA and the associated 'pleiotropic effects locus' (pel) mRNA affect virulence through their impact on the expression of other virulence genes.

• SLS also functions as a signalling molecule, and it has been proposed to contribute to iron acquisition from the host.

Streptolysin S

• Enhanced resistance to neutrophil-mediated killing is accomplished through the upregulation of multiple factors that facilitate neutrophil extracellular trap (NET) destruction

– extracellular streptodornase D (Sda1)) – Apoptosis by streptolysin O (SLO), interleukin-8 (IL-8)

degradation IL-8 protease (SpyCEP) – reduced resistance to antimicrobial peptides by streptococcal

inhibitor of complement (SIC) and the hyaluronic acid capsule. – Fibrinogen-binding proteins help capture plasminogen, which is

converted to plasmin by bacterial streptokinase. – The protease activity of plasmin aids bacterial colonization of

host tissues.

• Many of these virulence factors are upregulated in group

A Streptococcus (GAS) strains with a mutation in the covRS operon, leading to hypervirulence.

• Exotoxins may bind to T-cell receptors, causing an overwhelming production of TNF, IL-1, and IL-6, setting in motion a destructive process that may lead to subsequent organ failure and toxic shock syndrome.

• TNF has been clearly associated with streptococcal toxic shock syndrome.

NSTIs: diagnosi

Valore LRNEC score, punti

PCR, mg/L

<150 0

>150 4

GB, cells/mm3

<15 0

15-25 1

>25 2

Hb, g/dL

>13.5 0

11-13.5 1

<11 2

Na, mmol/L

≥135 0

<135 2

Creatinina, mg/dL

≤1.6 0

>1.6 2

Glicemia, mg/dL

≤180 0

>180 1

Wong Ch et al,

Crit care Med, 2004

LRINEC score

LRINEC score

Rischio LRINEC score Probabilità di NSSSIs (%)

Basso ≤ 5 <50

Intermedio 6-7 50-75

Alto ≥ 8 >75

Wong Ch et al, Crit Care Med, 2004

Esami colturali

Materiale maggiormente attendibile per l’isolamento colturale dell’agente eziologico:

• emocolture per aerobi e anaerobi prima dell’inizio della terapia antibiotica

• tessuto raccolto durante intervento chirurgico

Fung HB et al, Drugs, 2003

Imaging

Rx: presenza di gas nei tessuti sottocutanei

TC: causa dell’infezione (ascesso profondo), presenza di gas nei tessuti sottocutanei (maggior sensibilità rispetto all’Rx)

RM: estensione del processo infettivo, guida del debridement chirurgico in caso di FN

Anaya DA and Dellinger EP, CID, 2007

Imaging

Gli studi presenti in letteratura sull’uso dell’imaging per la diagnosi precoce delle SSSIs hanno evidenziato che l’ispessimento della fascia superficiale con o senza enhacement si associa a NSSSIs

Limiti:

• confronto tra sito di infezione e sito controlaterale sano, ma non tra infezione necrotizzante e non necrotizzante

• tali metodiche presentano alta sensibilità, ma bassa specificità.

Anaya DA and Dellinger EP, CID, 2007

Fournier’s Gangrene: Management and Mortality Predictors in a Population Based Study

Mathew D. Sorensen,* John N. Krieger, Frederick P. Rivara, Matthew B. Klein and Hunter Wessells

From the Harborview Injury Prevention and Research Center (MDS, FPR), Department of Urology (MDS, JNK, HW) and Division of Plastic Surgery, Department of Surgery (MBK), University of Washington School of Medicine, Seattle, Washington

0022-5347/09/1826-2742/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION

• Teaching and nonteaching hospitals differ substantially in the populations, case definitions, and severity and management of Fournier's gangrene.

• Hospitals where more patients with Fournier's gangrene were treated had lower mortality rates, supporting the rationale for regionalized care for this rare disease.

Treatment

Linezolid vs Vancomycin in treatment of

complicated skin and soft tissue infection

Patients with CSSSIs were randomised (1:1) to receive

linezolid or vancomycin (592 received linezolid vs 588

receveid vancomycin)

In the ITT population 92.2% vs 88.5% of patients treated

with linezolid and vancomycin respectively were clinically

cured 7 days after stopping therapy (p: 0.057)

For patients with MRSA infection:

linezolid outcomes (88.6%) were superior vancomycin

outcomes (66.9%)

Weigelt J et al, Antimicrob Agents Chemiot, 2005

Linezolid reduces lenght of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven

methicillin-resistent Staphylococcus aureus (MRSA)

1200 patients hospitalised with CSSSIs due to MRSA

compared with vancomycin linezolid treatment was

associated with:

- significantly shorter lenght of stay (p<0.01)

- decrease antibiotic duration therapy (p< 0.0001)

Kamal MFI et al, Int J Antimicrob Agents, 2005

Daptomycin vs vancomycin for complicated skin and skin

structure infections: clinical and economic outcomes

53 patients with CSSSIs at risk for MRSA were treated with

daptomycin and matched with a cohort of 212 patients with

vancomycin

the proportions of patients with clinical improvement or

resolution of their infections on days 3 and 5 were 90% vs

70% and 89% vs 81% in the daptomycin group vs the

vancomycin group (p<0.01) and 100% at the end of therapy

in both groups

among patients with complete resolution of their infections

(77% patients with daptomycin vs 42% with vancomycin,

p<0.05), median duration of ev therapy was 4 and 7 days

respectively (p< 0.001). Devis SL et al, Pharmacoth, 2007

Efficacy and safety of tigecycline monotherapy compared with vancomycin plus aztreonam in patients with complicated skin and skin structure infections:

results of a phase 3, randomized, double-blind trial

573 pazienti ospedalizzati con CSSSIs causate da MSSA e MRSA

tigeciclina in monoterapia vs vancomicina + aztreonam: • efficacia clinica: 83% vs 82% (p=0.87) • eradicazione microbiologica: 78% vs 77% (p=0.81)

- 76% vs 81% per MRSA - 86% vs 84% per MSSA

tigeciclina abbrevia la durata della degenza di circa 1 g rispetto all’associazione vancomicina+aztreonam (p=0.019)

Sacchidanand S et al, Int J Infect Dis, 2005

Treatment

• Treatment of Fournier gangrene involves the institution of broad-spectrum antibiotic therapy. The antibiotic spectrum should cover staphylococci, streptococci, the Enterobacteriaceae family of organisms, and anaerobes.

• A reasonable empiric regimen might consist of ciprofloxacin and clindamycin. Clindamycin is particularly useful in the treatment of necrotizing soft-tissue infections because of its gram-positive and anaerobic spectrum of activity.

• In animal models of streptococcal infection, clindamycin has been shown to yield response rates superior to those of penicillin or erythromycin, even in the context of delayed treatment.

Treatment

• Other possible choices include ampicillin/sulbactam, ticarcillin/clavulanate, or piperacillin/tazobactam in combination with an aminoglycoside and metronidazole or clindamycin. Vancomycin can be used to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA).

• In cases associated with sepsis syndrome, therapy with intravenous immunoglobulin (IVIG), which is thought to neutralize superantigens (eg, streptotoxins A and B) believed to mitigate the exaggerated cytokine response, has been shown to be a good adjuvant to appropriate antibiotic coverage and complete surgical debridement.

• If initial tissue stains (ie, potassium hydroxide [KOH] stain) show fungi, add an empiric antifungal agent such as amphotericin B or caspofungin.

http://www.guideline.gov/content.aspx?id=34103#Section420

Fournier's gangrene. In: Guidelines on urological infections.

Fournier's gangrene. In: Grabe M, Bjerklund-Johansen TE, Botto H, Wullt B, Çek M, Naber KG, Pickard RS, Tenke P, Wagenlehner F. Guidelines on urological infections. Arnhem, The Netherlands: European Association of Urology (EAU); 2011 Mar. p. 76-8.

Suggerimento

Nature Reviews Microbiology

9, 724-736 (October 2011)

doi:10.1038 nrmicro2648

Molecular insight into invasive group A streptococcal disease

Jason N. Cole1,2, Timothy C. Barnett2, Victor Nizet1,3 & Mark J. Walker2

Cornerstones of Therapy

• Early recognition

• Aggressive surgical debridement

• Resuscitation

• Broad-spectrum antibiotics