Objectives
Intra-abdominal
Infections
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.
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/Travelers Diarrhea
Helicobacter pylori
Pelvic Inflammatory Disease
Viral
Parasitic
Normal GI Microflora
Stomach:
Stomach:
H. pylori
Lactobacilli
Colon:
Bacteroides
Peptostreptococci
Clostridium
Bifidobacterium
Escherichia coli
Klebsiella
Enterobacter
Enterococci
Staphylococci
(Clostridium difficile)
Anatomy of the GI Tract
Stomach
Jejunum, Ileum
Appendix
Large intestine (colon)
Liver, gallbladder and spleen
Retroperitoneal space:
Peritoneal cavity contains:
Appendicitis
Peritonitis
IntraIntra-abdominal Abscess
Diverticulitis
AntibioticAntibiotic-Associated Diarrhea
Total bacterial count 00-108 log organisms/g
Helicobacter pylori
Streptococci
Lactobacilli
Upper Small Intestine:
Total bacterial count 00-105 log organisms/g
Aerobes
Enterococci
Staphylococci
Lactobacilli
E. coli, Klebsiella
Anaerobes
Bacteroides
Ileum
Total bacterial count 103-109 log organisms/g
Aerobes:
Streptococci
Staphylococci
Escherichia coli, Klebsiella
Enterobacter
Anaerobes:
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:
Microorganisms
Chemicals
Irradiation
Foreign body injury
Large Intestine (Colon)
Bacteroides
Peptostreptococci
Clostridium
Bifidobacteria
Aerobes:
Escherichia coli, Klebsiella
Enterobacter
Enterococci
Staphylococci
Peritonitis
Peritonitis
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 (<1%)
S. aureus/MRSA (CAPD)
Treatment
Seiler CA, et al. Surgery. 2000; 127:178-184.
Clinical Symptoms
Abdominal pain
Anorexia (N/V)
Fever (100 to 102 F)
Abdominal distention and tenderness
Hypoactive or faint bowl sounds
Leukocytosis
Enterobacteriaceae
Bacteroides
Enterococci
P. aeruginosa
Microbiology Enterobacteriaceae (63%)
Secondary Peritonitis
Cefotaxime,
Cefotaxime,
pip/tazo
pip/tazo,, amp/sulb
amp/sulb,,
ceftriaxone,
ceftriaxone,
carbapenem,
carbapenem, FQ,
vanco (MRSA)
Pip/tazo
Pip/tazo,, amp/sulb
amp/sulb,,
carbapenem,
carbapenem, tigecycline,
tigecycline,
moxifloxacin,
moxifloxacin,
(amp+ cipro/levo/AG +
metronidazole)
metronidazole)
Peritonitis
Normally:
Normally: 20 to 50 mL transudate
Peritoneal membrane measures approx. 1.7 m2
WBC < 300 cells/mm3
Protein: <3 g/dL
Bacterial peritonitis:
peritonitis: 300 to 500mL inflow/hr
resulting in hypovolemia.
WBC > 300 cells/mm3
Gram stain + for bacteria
Primary Peritonitis
?????Clinical Question?????
Relatively infrequent
25% of patients with alcoholic cirrhosis
60% of all patients on chronic ambulatory
peritoneal dialysis (CAPD) will have at least one
episode in 1st year.
Average incidence in CAPD patients is 1.3 to 1.4
episodes/yr.
Catheter connecting abdominal cavity to exterior
body is a major risk factor.
Recommend dosing for
intraperitoneal administration of an
antibiotic for a CAPD patient with
a Staphylococcus peritonitis
Peritonitis in CAPD
Antibiotics may be given intraperitoneal via the
dialysate: (exchanges every 4 to 6 hrs)
Reasonable empiric therapy
Gentamicin and tobramycin: 8mg/L
Clindamycin: 1 to 3 mg/L
Penicillin G: 50,000 units/L
Cephalosporins: 125 mg/L
Ampicillin: 50 mg/L
Vancomycin: 30 mg/L
Amphotericin B: 3 mg/L
Appendicitis Case
Gentamicin or tobramycin PLUS vancomycin
Ceftazidime PLUS vancomycin
What are the considerations in a ruptured appendix?
Microbial
Therapeutics
Duration: 2 to 3 weeks
Appendicitis Case, cont.
LF, an 18 yr female, was admitted to the hospital with
diffuse abdominal pain, diarrhea, and nausea. Her pain
was localized to the right side of the abdomen.
Cefazolin was initiated and LF was taken to surgery for
a ruptured appendix to be removed.
LF, an 18 yr female, was admitted to the hospital with
diffuse abdominal pain, diarrhea, and nausea. Her pain
was localized to the right side of the abdomen.
Cefazolin was initiated and LF was taken to surgery for
a ruptured appendix to be removed.
Appendicitis
What are the considerations in a ruptured appendix?
Microbial
Highest incidence 1010-19y/o,
male>female
Pathophysiology:
Pathophysiology: Relationship to onset of sx
Staphylococcus? NOT most important
E. coli? Yes
Anaerobes? Yes
Therapeutics
Cefazolin alone? No
Unasyn yes - why?
0-24h after sx onset: obstruction within appendix
inflammation & occlusion of vascular & lymphatic flow
bacterial overgrowth necrosis
>48h after sx onset: perforation (60%)
(60%)abscess/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
Sample Exam Question:
Appendicitis
Acute, nonnon-perforated appendicitis
Perforated appendicitis
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
Piperacillin/tazobactam (Zosyn) +/+/- Aminoglycoside
Tigecycline (Tigecil)
Tigecil) +/+/- Aminoglycoside
Clindamycin + Ampicillin + Aminoglycoside
Clindamycin + Metronidazole
Moxifloxacin + Metronidazole
Appendicitis Case, cont.
Ampicillin/sulbactam (Unasyn) +/+/- Aminoglycoside
Piperacillin/tazobactam (Zosyn) +/+/- Aminoglycoside
Tigecycline (Tigecil)
Tigecil) +/+/- Aminoglycoside
Clindamycin + Ampicillin + Aminoglycoside
Clindamycin + Metronidazole
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.
What organism(s)
organism(s) are most likely to be responsible for the
abscess?
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?
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
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.
encapsulation can prevent immune cells/abx
cells/abx from attacking
contained bacteria, low O2 in capsule
capsuleanaerobes 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
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
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
replacement
heart rate
Monitor urine out put (0.5 ml/kg/hr)
Monitor
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
MUST include aerobic/anaerobic coverage
Agents with Aerobic and Anaerobic activity:
Surgical
Prompt drainage of abscess (secondary peritonitis) and/or
E.
spread of bacteria+toxins into peritoneum
peritoneumperitonitis
Spread of bacteria+toxins into systemic circulation
circulationsepsis,
sepsis,
multimulti-organ failure, death
MUST include aerobic/anaerobic coverage
(one from each of the below categories)
Anaerobic activity:
Chloramphenicol( also includes aerobic Gram +/+/-)
Clindamycin (also includes aerobic Gram +)
Metronidazole (anaerobic coverage only)
Aerobic activity:
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)
Antibiotic Therapy
Factors involved in selection:
Severity of infection, suspected infecting organism(s) and
resistance patterns, efficacy, toxicity (renal dysfunction),
allergies
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
Failure to improve:
Broad spectrum antibiotics can change the
normal GI flora
Evaluating response:
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.
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
Toxins cause inflammation, necrosis, loss of fluid
electrolytes
Pseudomembranous colitis
Antibiotic Associated Diarrhea
Spectrum of disease
Colitis w/o pseudomembrane formation
Pseudomembranous colitis
Malaise, abdominal pain, water diarrhea, nausea, low fever
Severe abdominal pain, perfuse diarrhea, high fever
Symptom onset can occur shortly after start abx
or several weeks after tx stopped
Diagnosis: stool culture of C. diff, presence of
toxin A or B, endoscopy
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
Can add
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
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, <10yo, or if severe case
with sx of systemic toxicity (potential for better cure rate than
metronidazole)
metronidazole)
MUST give PO concentrations in gut aren
arent high
enough with IV
(Per IDSA treatment guidelines)
?????Clinical Question?????
Alternative/Investigational Therapies
Nitazoxanide vs. metronidazole (non(non-inferior)
Musher et al. CID 2006:43:4212006:43:421-7
Rifaximin (follow up tx after vanco in pts with
recurrent CDAD)
Anion binding resins: bind toxins
Cholestyramine and colestipol
Tolevamer
inferior to primary tx,
tx, possible adjunct to vanco for relapse
Promising results, not yet FDA approved
IVIG
Pharmacy consult is ordered for a
patient presenting with
pseudomembranous colitis after recent
therapy with oral cefuroxime -
What is the likely organism
responsible?
What other info do you need
about the patient?
What is the best antibiotic
treatment this patient?
Johnson et al. CID 2007;44:8462007;44:846-8
No sig benefit in pts with refractory disease
?????Clinical Question, cont.?????
What is the likely organism responsible?
E. coli
Clostridium difficile
Shigella
What other info do you need about the patient?
Ht and wt to calculate IBW for accurate dosing tx for C. diff
Is this the first or recurrent episode, severity of sx,
sx, pregnancy
status, allergies, ect.
ect.
Both of the above
This is the pts first episode;
episode; what is the best antibiotic
treatment?
?????Clinical Question, cont.?????
Metronidazole 500mg PO Q 8h x14d
Vancomycin 125mg PO or IV Q 6h x14d
Vancomycin pulse/taper with probiotic overlap
What is the likely organism responsible?
What other info do you need about the patient?
E. coli
*Clostridium difficile
Shigella
Ht and wt to calculate IBW for accurate dosing tx for C. diff
*Is this the first or recurrent episode, severity of sx,
sx, pregnancy status,
allergies, ect.
ect. (these factors influence your tx recommendation)
Both of the above (no, dose is not based on wt)
This is the pts first episode;
episode; what is the best antibiotic treatment?
*Metronidazole 500mg PO Q 8h x14d (yes!)
Vancomycin 125mg PO or IV Q 6h x14d (IV vanco not effective!)
Vancomycin pulse/taper with probiotic overlap (not indicated for first
episode)
References
IDSA: Guidelines for the Selection of AntiAnti-infective Agents for Complicated IntraIntra-abdominal
Infections. CID. 2003; 37(15): 997997-1005.
Goldstein EJC, Snydman DR. IntraIntra-abdominal infections: review of the bacteriology,
antimicrobial susceptibility and role of ertapenem in their therap. JAC. 2004; 53(S2):ii2953(S2):ii29-ii36.
Malangoni MA, Song J, Herrington J, Choudhri S, Pertel P. Randomized Controlled Trial of
Moxifloxacin Compared with PiperacillinPiperacillin-Tazobactam and AmoxicillinAmoxicillin-Clavulanate for the
Treatment of Complicated IntraIntra-abdominal Infections. Annals of Surgery. 2006; 244(2): 204204-211.
UpToDate
UpToDate. Treatment of antibioticantibiotic-associated diarrhea caused by Clostridium difficile.
difficile.
Accessed 3/10/2008.
UpToDate
UpToDate. Anaerobic bacterial infections. Accessed 3/10/2008.
UpToDate
UpToDate. Treatment and prophylaxis of spontaneous bacterial peritonitis.
peritonitis. Accessed
3/10/2008.
UpToDate
UpToDate. Appendicitis in adults. Accessed 3/10/2008.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML. Pharmacotherapy: A
Pathophysiologic Approach, Sixth Ed. 2005.
Gilbert DN, Moellering RC, Eliopoulos GM, Sande MA. The Sanford Guide to Antimicrobial
Therapy, 37th Ed. 2007.
Lin WJ, L WT, Chu CC, Chu ML, Wang CC. Bacteriology and antibiotic
antibiotic susceptibility of
communitycommunity-acquired intraintra-abdominal infection in children. J Microbiol Immunol Infect. 2006; 39:
249249-254.
