Objectives

Intra-abdominal Infections

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Describe pathogenesis & clinical characteristics of intraintra-abdominal infections Identify most likely etiologic organism(s) organism(s) Review appropriate drug therapy

Marnie Peterson, Pharm.D., Ph.D., BCPS College of Pharmacy [email protected] ©2006 Marnie Peterson. This presentation is provided to facilitate the learning of participants within this course. It may not be modified, reproduced and/or circulated for other means without the permission of the author.

Intra-abdominal Infections

Intra-abdominal Infections

Infections contained within the peritoneum or retroperitoneal space. „

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Duodenum Pancreas Kidneys

GI microflora depends on the anatomic site! Upper Intestine: Streptococci Enterococci Staphylococci E. coli Klebsiella Bacteroides Ileum: Streptococci Staphylococci Escherichia coli Klebsiella Enterobacter Bacteroides Clostridium

Food Poisoning/Traveler’ Poisoning/Traveler’s Diarrhea

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Helicobacter pylori

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Pelvic Inflammatory Disease Viral Parasitic

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Normal GI Microflora „

Stomach: „

Stomach: H. pylori Lactobacilli Colon: Bacteroides Peptostreptococci Clostridium Bifidobacterium Escherichia coli Klebsiella Enterobacter Enterococci Staphylococci

(Clostridium difficile)

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Anatomy of the GI Tract „

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Stomach Jejunum, Ileum Appendix Large intestine (colon) Liver, gallbladder and spleen

Retroperitoneal space: „

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Peritoneal cavity contains: „

Appendicitis Peritonitis IntraIntra-abdominal Abscess Diverticulitis AntibioticAntibiotic-Associated Diarrhea

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Total bacterial count 00-108 log organisms/g „ „ „

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Helicobacter pylori Streptococci Lactobacilli

Upper Small Intestine: „ „

Total bacterial count 00-105 log organisms/g Aerobes „ „ „ „

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Enterococci Staphylococci Lactobacilli E. coli, Klebsiella

Anaerobes „

Bacteroides

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Ileum

Total bacterial count 103-109 log organisms/g Aerobes:

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Streptococci Staphylococci Escherichia coli, Klebsiella Enterobacter

Anaerobes:

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Normal GI Microflora

Bacteroides Clostridium

Peritonitis Inflammation of the serous lining of the peritoneal cavity due to:

Total bacterial count 1010-1012 log organisms/g Anaerobes:

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Microorganisms Chemicals Irradiation Foreign body injury

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Large Intestine (Colon)

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Bacteroides Peptostreptococci Clostridium Bifidobacteria

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Aerobes:

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Escherichia coli, Klebsiella Enterobacter Enterococci Staphylococci

Peritonitis

Peritonitis „

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Primary Peritonitis

Primary No focus of disease is evident Bacteria transported from blood stream to peritoneal cavity (Cirrhosis, CAPD)

Secondary Acute perforation of the GI tract (gastric, diverticular (diverticulitis), appendix (appendicitis), gallbladder, tumor perforations) [66%] „ PostPost-operative peritonitis [24%] „ PostPost-traumatic peritonitis [10%]

S. pneumoniae (15%) Enterococci (6(6-10%) anaerobes (female Pathophysiology: Pathophysiology: Relationship to onset of sx

Staphylococcus? NOT most important E. coli? Yes Anaerobes? Yes

Therapeutics „ „

Cefazolin alone? No Unasyn yes - why?

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0-24h after sx onset: obstruction within appendix Æ inflammation & occlusion of vascular & lymphatic flow Æ bacterial overgrowth Æ necrosis >48h after sx onset: perforation (60%)Æ (60%)Æabscess/peritonitis

Early sx: sx: dull, nonnon-localized RLQ pain, indigestion, bowel irregularity, flatulence Later sx: sx: pain/tenderness more localized, N/V „

Fever >103F, leukocytes >15000: perforation likely

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Sample Exam Question:

Appendicitis „

Acute, nonnon-perforated appendicitis „

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Perforated appendicitis „ „ „

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cefazolin + metronidazole

For initial treatment in a pt with a ruptured appendix and no other contributing factors, which of the following is an incorrect choice?

Cover enteric gram – rods and anaerobes (2nd/3rd generation ceph or FQ) + metronidazole Cefoxitin, Cefoxitin, piperacillin/tazobactam, piperacillin/tazobactam, ampicillin/sulbactam, ampicillin/sulbactam, imipenem

Antibiotics are started before surgery, continued for 7710 days Switch to PO based on patient status

Sample Exam Question: „

For initial treatment in a pt with a ruptured appendix and no other contributing factors, which of the following is an incorrect choice? „

Ampicillin/sulbactam (Unasyn) +/+/- Aminoglycoside

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Piperacillin/tazobactam (Zosyn) +/+/- Aminoglycoside

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Tigecycline (Tigecil) Tigecil) +/+/- Aminoglycoside

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Clindamycin + Ampicillin + Aminoglycoside

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Clindamycin + Metronidazole

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Moxifloxacin + Metronidazole

Appendicitis Case, cont. „

Ampicillin/sulbactam (Unasyn) +/+/- Aminoglycoside

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Piperacillin/tazobactam (Zosyn) +/+/- Aminoglycoside

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Tigecycline (Tigecil) Tigecil) +/+/- Aminoglycoside

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Clindamycin + Ampicillin + Aminoglycoside

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Clindamycin + Metronidazole

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Moxifloxacin + Metronidazole

Appendicitis Case, cont. „

LF improved postpost-operatively & completed 7d course of PO cephalexin. cephalexin. 4d after completing antibiotics she felt diffuse pain over the appendectomy site. Abdominal CT scan revealed a peritoneal abscess. Abscess was drained & fluid sent to the lab.

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What organism(s) organism(s) are most likely to be responsible for the abscess? „ „ „

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Likely MRSA, not covered by cephalexin Gram negative bacteria not covered by 1st generation cephalosporins Anaerobic bacteria not covered by cephalexin

Was the cephalexin an appropriate choice of abx for LF? „ „ „

No, LF should have remained in the hospital for 77-10 days with IV tx No, there was not appropriate coverage with a 1st generation ceph Yes, but metronidazole should have been added for anaerobic coverage

Intra-abdominal Abscess

What organism(s) organism(s) are most likely to be responsible for the abscess? „ „ „

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Likely MRSA, not covered by cephalexin: cephalexin: MRSA not most likely here *Gram negative bacteria not covered by 1st generation cephalosporins: cephalosporins: Gram –’s likely involved and cephalexin has limited gram – coverage *Anaerobic bacteria not covered by cephalexin: cephalexin: anaerobes likely involved, cephalexin not good choice for anaerobes

Was the cephalexin an appropriate choice of abx for LF? „ „ „

No, LF should have remained in the hospital for 77-10 days with IV tx: tx: no, outpatient tx is okay with appropriate abx choice *No, there was not appropriate coverage with a 1st generation ceph: ceph: not adequate coverage of gram –’s and anaerobes Yes, but metronidazole should have been added for anaerobic coverage: an agent with anaerobe coverage should be added, but also need gram gram coverage

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Intra-abdominal Abscess „

Abscess: purulent collection of fluid, necrotic debris, bacteria, inflammatory cells that is walled off/encapsulated by adjacent healthy cells in an attempt to keep pus from infecting neighboring structures. „

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encapsulation can prevent immune cells/abx cells/abx from attacking contained bacteria, low O2 in capsuleÆ capsuleÆanaerobes thrive here!

Result of chronic inflammation, develop over daysdays-yrs Located within peritoneal cavity or visceral organs May range from a few milliliters to a liter in volume

Intra-abdominal Abscess „

Ruptured abscess „ „

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Presentation: nonspecific low grade or spiking fever, abdominal pain/discomfort +/+/- distension Labs: leukocytosis, leukocytosis, +/+/- positive blood cultures, +/+/hyperglycemia Ultrasound, GI contrast study, or CT scan may be used for evaluation

Management of IntraIntra-Abdominal Infections

IntraIntra-abdominal Abscess „

Microbiology „

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Combination of modalities: „

usually mixed infection: aerobes & anaerobes within the same abscess

debridement

coli „ Klebsiella „ Enterococci „ B. fragilis „ Clostridium

„ Resection of perforated colon, small intestine, ulcers „ Repair of trauma

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replacement heart rate „ Monitor urine out put (0.5 ml/kg/hr) „ Monitor

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Ampicillin/sulbactam (Unasyn) (enterococci) Piperacillin/tazobactam (Zosyn) (enterococci) enterococci) Imipenem/cilistatin (Primaxin) Meropenem (Merrem (Merrem)) Ertapenem (Invanz) Invanz) Aminoglycoside + clindamycin or metronidazole Tigecycline (Tygacil) Tygacil) Moxifloxacin (Avelox) Avelox) (active against 83% of Bacteroides strains) „

(+ metronidazole: metronidazole: per IDSA guidelines CID 2003:37 997)

Appropriate antimicrobial therapy

Empiric Antibiotic Therapy

Empiric Antibiotic Therapy „

Support of Vital functions: „ Blood pressure/fluid

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MUST include aerobic/anaerobic coverage Agents with Aerobic and Anaerobic activity:

Surgical „ Prompt drainage of abscess (secondary peritonitis) and/or

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spread of bacteria+toxins into peritoneumÆ peritoneumÆperitonitis Spread of bacteria+toxins into systemic circulationÆ circulationÆsepsis, sepsis, multimulti-organ failure, death

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MUST include aerobic/anaerobic coverage (one from each of the below categories) Anaerobic activity: „ „ „

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Chloramphenicol( also includes aerobic Gram +/+/-) Clindamycin (also includes aerobic Gram +) Metronidazole (anaerobic coverage only)

Aerobic activity: „ „

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Aminoglycosides: „ gentamicin, tobramycin (Gram negatives only) BetaBeta-lactams: „ Cefotaxime (Claforan) „ Ceftriaxone (Rocephin) „ Aztreonam (Azactam) (Gram negative only) Quinolones: „ Ciprofloxacin (Cipro) (Mostly Gram negative) „ Levofloxacin (Levaquin) (Gram +/+/- and some anaerobic coverage) „ Moxifloxacin (Avelox) Avelox) (Gram +/+/- and anaerobes) Vancomycin/Linezolid/Synercid (Enterococci, MRSA)

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Antibiotic Therapy „

Factors involved in selection: „

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Severity of infection, suspected infecting organism(s) and resistance patterns, efficacy, toxicity (renal dysfunction), allergies

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Increases in Candida or GramGram-negative bacteria Proliferation of antibioticantibiotic-resistant organisms „ Pseudomembranous colitis from over proliferation of toxintoxin-producing anaerobe, Clostridium difficile. difficile.

Improvement in 2 to 3 days Switch to oral antibiotic therapy

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Failure to improve: „ „ „

Broad spectrum antibiotics can change the normal GI flora „

Evaluating response: „

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Antibiotics and GI flora

Resistant organisms Recurrent surgical infections Other infections: (urinary tract infections, pneumonia)

Pseudomembranous Colitis “Antibiotic Associated Diarrhea” Diarrhea”

Antibiotic Associated Diarrhea Antibiotic therapy (broad spectrum agents: clindamycin, clindamycin, ampicillin, ampicillin, 3rd generation cephalosporins are most common) Disruption of normal colonic flora C. difficile colonization (gram +, spore forming anaerobe) Release of toxins A (enterotoxin ), B (cytotoxin ), & binary toxin (enterotoxin), (cytotoxin), CDT (associated w/ recent outbreaks) Damage to colonic mucosa (pseudomembranous (pseudomembranous plaques), inflammation, intestinal fluid secretion

Pseudomembranous Colitis „ „

Clostridium difficile: difficile: toxin mediated disease „

Toxin A (major) „ Overproduction

in tcdC gene.

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in outbreak strains of C. difficile due to deletion

Toxin B (minor) Binary toxin CDT „ associated

with recent outbreaks (NEJM 2005; 353: 2433) with binary toxin are often resistant to quinolones

„ C. difficile strains

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Toxins cause inflammation, necrosis, loss of fluid electrolytes

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Pseudomembranous colitis

Antibiotic Associated Diarrhea „

Spectrum of disease „

Colitis w/o pseudomembrane formation

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Pseudomembranous colitis

„ Malaise, abdominal pain, water diarrhea, nausea, low fever „ Severe abdominal pain, perfuse diarrhea, high fever

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Symptom onset can occur shortly after start abx or several weeks after tx stopped

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Diagnosis: stool culture of C. diff, presence of toxin A or B, endoscopy

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C. diff risk if abx use in past 2 months

FIRST LINE: „ Metronidazole (Treatment of Choice) „ 250mg PO QID or 500mg PO/IV TID x 1010-14 days ALTERNATIVE: (if not responding to metronidazole or recurrences) „ Vancomycin „ 125mg PO QID x 1010-14 days +/+/- rifampin 600mg PO BID „

Always stop the drug responsible for causing the infection as soon as possible!

Pseudomembranous colitis

Pseudomembranous colitis

RECURRANCES: „ „

1st: Retreat with either metronidazole or vancomycin, vancomycin, dosed as above, x 1010-14d >2nd:Vancomycin taper/pulse therapy „ 125mg PO QID x7d, then 125mg PO BID x7d, then 125mg PO QD x7d, then 125mg PO QOD x7d, then 125mg PO every 3 days x14d

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3 week course of probiotics (Saccharomyces boulardii 500mg PO BID) starting during final week of taper and continued for 2 weeks after vanco taper „

Metronidazole vs. vanomycin

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counteract disturbances & reduce risk of colonization by pathogenic bacteria

Similar in nonnon-severe cases with time to resolution of diarrhea, side effects, and relapse rates „ 2020-25% recurrence, not related to tx choice, dose or duration Metronidazole: Metronidazole: cheaper, preferred due to concern of VRE Vancomycin: Vancomycin: okay if pt is pregnant,