Visceral Infection

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Intra-abdominal Infections

Resident’s Lecture

Edward L. Goodman, MDMay 1, 2006



Outline

• Pathogenesis of IAI

• Magnitude of problem

• Questions and Controversy• Antimicrobial Regimens



Complicated Intra-Abdominal

Infections

DefinitionExtends beyond the hollow

viscus of origin into the

peritoneal space

Associated either with

abscess formation or

peritonitis

Requires either operative or

percutaneous intervention to

resolve Solomkin J et al. Clin Infect Dis. 2003 Oct 15;37(8):997-1005.

Mazuski J et al. Surgical Infections. 2002. 3(3):161-173.

Medical Illustration Copyright © 2005

Nucleus Medical Art,

All rights reserved. www.nucleusinc.com




Infection Types• Wide variety of

conditions

–Perforatedgastroduodenal ulcers

–Biliary tract infections

–Small bowelperforations

–Complicated

appendicitis (with

abscess or perforation)Goldstein E. Clin Infect Dis 2002 Sep 1;35(Suppl 1):S106-11.

Medical Illustration Copyright © 2005

Nucleus Medical Art,

All rights reserved. www.nucleusinc.com




Infections:Common PathogensFacultative and Aerobic Gram-Negatives

Escherichia coli Klebsiella spp Pseudomonas

aeruginosaProteus sppEnterobacter sppother gram-negatives

71.3%14.3%14.1%

5.2%5.1%

12.3%

Gram-Positive Organisms

Streptococcal sppEnterococcus faecalisEnterococcus faeciumEnterococcus sppStaphylococcus aureus

38.0%11.6%3.4%7.8%3.5%

Solomkin J et al: Intra-abdominal infections. In: Schwartz SI, Shires GT, Spencer FC, et al: Principles of Surgery , 7th ed. New York: McGraw-Hill Book Co., 1999:1541-42.

Anaerobic organisms

Bacteroides fragilis other Bacteroides Clostridia spp

Prevotella sppPeptostreptococcus spp Fusobacterium sppEubacterium sppOthers

34.5%71.0%29.2%

12.0%16.7%8.6%

16.5%19.4%

Incidence of various bacteriain 702 patients with intra-

abdominal infections



PathogenesisWeinstein, Onderdonk et al. JID 1975;132:282-286

• Animal models mimic clinical condition – Gelatin capsules with rat feces implanted in peritoneal

cavity of rat

– Early peritonitis: 37% mortality

– Late abscesses in survivors: 100% incidence

• Antimicrobial Probes – Gentamicin: acute mortality 4%; abscess in 98% of

survivors

– Clindamycin: acute mortality 35%; abscess in 5% of survivors

– Combination: 7% mortality;6% abscess



Magnitude of ProblemBarie et al. Surg Infect 2004;5(4):365-73

• 465 patients 1991-2002 Major NYC Hosp

– Viscus perforation

– Peritonitis (78%) or abscess (22%)

– Community acquired 72%, Hospital Acquired

28%

• 74% organ dysfunction

• 23% mortality



Which Patients Require Therapeutic

Administration of ABX?

• Considered prophylactic and given <=24

hours

– Bowel injuries that are repaired within 12

hours

– Acute perforation of stomach, duodenum and

proximal jejunum in absence of antacid

therapy or malignancy (is there anyone not on Protonix®?)

– Acute appendicitis without gangrene,

perforation, abscess or peritonitis



Require ABX?

• Acute cholecystitis often not infected

– If infection strongly suspected

• Empiric therapy directed against enteric GNR

– Not necessary to cover enterococcus

– Not necessary to cover anaerobes unless biliary-bowel

anastamosis

• Infected pancreatic necrosis = colonic flora – Prophylactic antibiotics for non infected

pancreatic necrosis are “controversial” (i.e., GI vs

ID)



Identification of High Risk Patients(who need broader spectrum Rx)

• High risk of death/complications

– High APACHE II score

– Poor nutritional state

– Significant cardiovascular disease – Inability to obtain source control

– Immunosuppressive therapy or condition

• Certain acute and chronic diseases

– e.,g, acute leukemia, dialysis

– Prolonged preop hospital stay

– Prolonged preop (>2 days) antimicrobials



Duration of Therapy

• Until resolution of clinical signs – Normal temp and WBC (?CRP)

– Return of GI tract function

• If persisting clinical evidence of infection at5-7 days – Sono/CT

• If diagnostic, obtain source control by draining andcontinue ABX and modify based on abscess culture

• If negative for abscess, consider D/C ABX



When are Cultures Indicated?

• Uncomplicated, perforated or gangrenous appendixwithout abscess: no impact on outcome when culturesobtained

• Abscesses, peri-colonic infections: failure rates higher if

empiric ABX don’t cover aerobic flora• Community epidemiology differs

• Anaerobic susceptibility: – Unnecessary if predictably potent coverage with metronidazole,

carbapenems, beta lactam inhibitors used• Resistance a concern with clindamycin, cefamycins, piperacillin

alone, most quinolones

– Indicated if persisting anaerobic isolates, bacteremias or prolonged therapy indicated



Health Care Associated (HCA)

Infections (Nosocomial)

• Infections occurring after initial surgery are

HCA and may harbor resistant flora

• If empiric therapy does not include

coverage against subsequently recovered

resistant flora, morbidity higher

• Often require empiric combination therapy

– To cover MRSA, (VRE), MDR GNR



Complicated IA Infections

Infecting Flora by Onset Location• Community-acquired infections

• Enteric GNB, facultative bacilli, and β-lactam-susceptible GPC,obligate anaerobic bacilli (distal small-bowel and colon-derivedinfections and for more proximal perforations when obstruction is

present) – E coli , B fragilis

• Healthcare-associated infections (post-op/nosocomial)

• Prolonged pre-op LOS or > 2 days pre-op antibiotics• Usually more resistant flora

– Pseudomonas, Enterobacter and Proteus spp, MRSA, Enterococci,and Candida spp

• Knowledge of local susceptibility patterns critical

Solomkin J et al. IDSA Guidelines Clin Infect Dis. 2003 Oct 15;37(8):997-1005.

GNB=gram-negative bacilli

GPC=gram-positive cocci

LOS=length of stay



What Should be Cultured?

• Blood cultures often no benefit in

community acquired IAI (CA-IAI)

• Intra-abdominal specimens

– Should be representative of the process

– Rarely need more than one or two

– Should always be sent for anaerobic as well

as routine

• Anaerobic transport system

• SWABS ARE NEVER APPROPRIATE



When Should Gram Stain be

Done?

• CA-IAI: not indicated

• HCA-IAI: indicated to help guide empiric

coverage

– If GPC clusters seen, cover for MRSA



Indication for Anti-fungal Rx

• Candida species isolated in 20% of acute

perforations of GI tract

• Anti-fungal therapy not indicated in most except:

– Recent immunosuppressive therapy – Postop or recurrent IAI

• Choice of therapy

–C albicans – fluconzole

– Non albicans – caspofungin, voriconazole, AMB



Indications for Enterococcal

Coverage

• Not indicated for enterococci as part of

mixed flora in CA-IAI

– Numerous comparative trials have shown no

benefit from covering enterococcus

• Indicated in

– HCA-IAI

– Pure culture of enterococci

– Bacteremia with enterococci



Antimicrobial Regimens

• IDSA Practice Guidelines 2003

• Newer regimens

– Tigecycline CID 2006

– Moxifloxacin (FDA) 2005



Recommended Regimens:

2003 IDSA cIAI Guidelines

Adapted from Solomkin J et al. IDSA Guidelines. Clin Infect Dis. 2003 Oct 15;37(8):997-1005.

Mild-to-moderate InfectionsHigh-severity Infections

Single agent regimen

• Ampicillin/sulbactama

• Ticarcillin/clavulanic acid• Ertapenem

• Piperacillin/tazobactam

• Imipenem/cilastatin• Meropenem

Combination regimen

• Cefazolin or cefuroxime +metronidazole

• Fluoroquinolone (FQ)-basedtherapy + metronidazole

• Cefotaxime, ceftriaxone,ceftizoxime, ceftazidime,cefepime + metronidazole

• Aztreonam + metronidazole

• FQ + metronidazole

a



Moxifloxacin MonotherapyFDA Web Site 11/30/05



Study Moxifloxacin IV/PO vs. Piperacillin/Tazobactam

(PIP/TZO) IV⇒

Amoxicillin/Clavulanate (AMOX/CLA)PO

Design Prospective, randomized, multi-center, multinational,double-blind, active control, Phase III trials in patientswith complicated intra-abdominal infection (cIAI)

Comparator Moxifloxacin 400 mg sequential IV/PO versus PIP/TAZ3.375 gm IV q6h⇒AMOX/CL 800/114 mg PO q12h

Location[years]

71 centers: in the US (62), Canada (7) and Israel (2);[2000-2003]

Definition

cIAI

Requiring operative procedure or percutaneous

drainage. Purulence/ exudate, inflamed or necrotictissue confirmed at time of surgery.

Treatment 5-14 days

10Outcome Clinical response at test-of-cure (TOC) (-10%) 25-50

after entry into the study

Moxifloxacin Study Design

Data on File, Schering Corporation. Study #100272.

Malangoni M et al. ICAAC 2004. Washington DC. Abstract #L-990.



Moxifloxacin Study in cIAI

Patient Populations (N=681)Population MoxifloxacinIV/POn (%)

PIP/TAZ IV⇒ AMOX/CL PO

n (%)

Randomized 339 342

Safety 329 (97%) 327 (96%)

Efficacy Valid 183 (54%) 196 (57%)

Microbiologically

Evaluable Patients(MBE)

150 (44%) 163 (48%)





79.878.2

50

55

60

65

70

75

80

85


Clinical Response (TOC)†

C l i n i c a l R e s p

o n s e ( T O C )

( % P a t i e n t s )

n=153/196n=146/183

Moxifloxacin IV/PO PIP/TZO IV

AMOX/CLA PO

p=NS; 95% Confidence Interval ( 7.6, 9.2)

Efficacy-valid population†Primary endpoint




78.0 77.3

0

10

20

30

40

50

60

70

80

90

100

Microbiologic response includes eradication and presumed eradication at TOC in the

MBE population (N=313)

B

a c t e r i o l o g i c a l R e s p o n s e

a t T O C ( % P a t i

e n t s )

p=NS; 95% Confidence Interval (-9.9%, 8.7%).

Moxifloxacin IV/PO

117/150 126/163n =

PIP/TZO IV

AMOX/CLA PO



Moxifloxacin

IV/POPIP/TZO IV

AMOX/CLA PO


Bacteriological Response



77.0

85.4

76.772

0

10

20

30

40

50

60

70

80

90


Microbiologic Success

M i c r o S u c c e s s

( T O C )

( % P a t i e n t s )

69/9067/87 36/5035/41

E coli B fragilis

Microbiologic success includes eradication and presumed eradication at TOC in the

MBE population (N=313)

n =



Moxifloxacin

IV/POPIP/TZO IV

AMOX/CLA PO

p=NS



Adverse Event Moxifloxacin(N=329)

n (%)

PIP/TZO IVAMOX/CLA PO

(N=327)n (%)

Any treatment-emergent adverse event

(AE)

276 (83.9) 271 (82.9)

Died 6 (1.8) 7 (2.1)

Serious AE 63 (19.1) 66 (20.2)

Premature discontinuation due to AE 34 (10.3) 28 (8.6)

Any drug-related adverse AE (≥2%) 82 (24.9) 90 (27.5)Diarrhea 16 (5) 26 (8)

Nausea 16 (5) 13 (4)

Gamma glutamyl transferase increase 8 (2) 5 (2)


Malangoni M et al. ICAAC 2004. Washington DC. Abstract #L-990.Safety Population


Overall Safety Profile



Tigecycline for Complicated IAI

• Pooled date from 2 phase 3 studies

comparing Tigecycline to Imipenem-

cilastatin in 1642 adults



Caveats on Newer Regimens

• Moxifloxacin

– Anaerobic resistance to FQ may emerge

– Limited experience

– Nothing published yet

• Tigecycline

– Nausea/vomiting limiting factor in our

experience

– Literature: 44%

2003 IDSA IAI G id li



2003 IDSA cIAI Guidelines

Overall Antimicrobial Management

• Fluid resuscitation required prior to initiating antibiotic torestore adequate visceral perfusion and ensure drugdistribution

• Empirical coverage initiated upon suspicion of cIAI

• Duration of therapy should be continued until resolution of clinical signs of infection:

– Afebrile

– Normalization of WBC count

– Return of gastrointestinal function

• If infection persists beyond 5-7 days:

– Diagnostic investigation required (CT or ultrasound) and/or additional intervention for source control

– Ensure treatment regimen provides appropriate coverage

Solomkin J et al. IDSA Guidelines Clin Infect Dis. 2003 Oct 15;37(8):997-1005.



Bibliography

• Babinchak T, Ellis-Grosse E et al. The Efficacyand Safety of Tigecycline for the Treatment of Complicated Intra-Abdominal Infections:

Analysis of Pooled Clinical Trial Data. Clin Inf

Dis 2005;41 (Suppl 5):S354-67• Barie PS, Hydo LJ, Eachempati. Longitudinal

Outcomes of Intra-Abdominal InfectionComplicated by Critical Illness. Surg Infect2004;5(4):365-73

• Goldstein EJC. Intra-Abdominal AnaerobicInfections. Clin Inf Dis 2002;35(Suppl ):S106-11



Bibliography

• Schering-Plough Company Data on File(personal communication)

• Solomkin JS, Mazuski JE, Baron EJ et al.Guidelines for the Selection of Anti-Infective

Agents for Complicated Intra-abdominalInfections. Clin Infect Dis 2003;37:997-1005

Access on ID Society.org. Practice Guidelines

•Weinstein WM, Onderdonk AB, Bartlett JG,Louie TJ, Gorbach SL. Antimicrobial therapy of experimental intraabdominal sepsis. J Infect Dis1975;132:282-6

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