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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007 S29
JOHN A. WEIGELT, MD
Department of Surgery, Division of Trauma/Critical Care,
Medical College of Wisconsin,
Milwaukee, WI
Empiric treatment options in the management
of complicated intra-abdominal infections
■ ABSTRACT
Complicated intra-abdominal infections remain a
major challenge for surgeons and internists because
of their association with high morbidity and mortality.
For optimal outcome, these infections require a com-
bination of appropriate and timely surgical source
control and adjunctive broad-spectrum antimicrobial
therapy. This review discusses criteria for choosing
empiric antimicrobial therapy, outlines available
treatment options, and highlights new antimicrobial
therapies for these infections.
■ KEY POINTS
Source control for complicated intra-abdominal
infections remains the most important component of
successful treatment. Proper selection of empiric
antibiotic therapy is adjunctive but important in the
overall treatment approach.
Selection of empiric antimicrobial therapy for
complicated intra-abdominal infections depends on the
severity of illness and how the infection was acquired.
The diverse bacteriology of complicated intra-
abdominal infections and the emergence of bacterial
resistance make the antimicrobial treatment of these
infections an important clinical challenge.
Emerging resistance of many gram-negative enteric
pathogens and
Bacteroides fragilis
continues to
stimulate the search for effective new antimicrobials.
B
ecause of their association with high rates of
morbidity and mortality, intra-abdominal
infections remain one of the major challenges
facing surgeons and internists. Although
approximately 80% of intra-abdominal infections are
acquired outside of the health care setting,
1
the threat
of infection with health care–associated pathogens is
concerning, given the rapid colonization of hospital-
ized patients with resistant bacteria.
Source control (surgical measures to eradicate a
focus of infection, prevent ongoing microbial con-
tamination, and restore functional anatomy) is fun-
damental to the management of patients with com-
plicated intra-abdominal infections. Empiric antimi-
crobial therapy, although adjunctive, is nevertheless
important in the overall management plan, and the
search for the optimal antimicrobial regimen contin-
ues. After beginning with an overview of intra-
abdominal infections, this review focuses on criteria
for choosing empiric antimicrobial therapy for com-
plicated infections and on the available and emerging
therapeutic options for these infections.
■ CAUSES AND CLASSIFICATION
OF INTRA-ABDOMINAL INFECTIONS
More than a century ago, aerobic and anaerobic bac-
teria were each implicated as probable causes for the
development of intra-abdominal infections. With the
availability of advanced anaerobic culture techniques,
it became firmly established by the mid-1970s that
serious intra-abdominal infections involved synergis-
tic mixtures of bacteria.
2
Intra-abdominal infections generally occur because
a normal anatomic barrier is disrupted. The most
common disruptions occur in hollow viscera, allow-
ing intraluminal bacteria to invade and proliferate in
typically sterile regions such as the peritoneal cavity
or the retroperitoneum.
Peritonitis: Wide variations in presentation
Although the term peritonitis is often used synony-
mously for intra-abdominal infections, the degree of
Dr.Weigelt reported that he has received research grant support, consulting/advi-
sory fees, and honoraria for speaking or writing from Pfizer Inc., Wyeth Pharma-
ceuticals, Schering-Plough Corp., and Ortho-McNeil Pharmaceutical.
Upside Endeavors, a medical education company, prepared an initial outline and
reference list for this article, which the author revised, added to, and developed
into the final manuscript.
peritoneal involvement can vary greatly. Clinical
presentation of intra-abdominal infections varies
from localized appendicitis to diffuse inflammation
of the abdominal cavity, characterized as general-
ized peritonitis. Intra-abdominal infections also can
be described as primary, secondary, or tertiary peri-
tonitis (see “Peritonitis at a glance” sidebar).
Whereas primary infections usually do not involve
a hollow viscus, secondary infections are associated
with hollow viscus perforations. Tertiary infections
are associated with immunocompromised patients
and usually involve treatment failures.
3,4
Tertiary
peritonitis is defined as the persistence or recur-
rence of intra-abdominal infection despite what
appears to be have been adequate source control
and appropriate antimicrobial therapy. It also may
be associated with bacteria that are usually consid-
ered to have low virulence, such as enterococci and
Staphylococcus epidermidis.
5
Uncomplicated vs complicated infections
Intra-abdominal infections also can be categorized as
uncomplicated versus complicated, although the dis-
tinction is not always clear. Complicated intra-
abdominal infections are often defined as extending
beyond the hollow viscus of origin into the peritoneal
space with associated abscess formation or peritoni-
tis.
1
These infections are potentially serious medical
conditions that require an invasive procedure for
source control.
1
■ DESPITE PROGRESS, STILL A MAJOR BURDEN
The overall incidence of intra-abdominal infections
is difficult to establish and varies with the underlying
abdominal disease processes. The clinical significance
of complicated intra-abdominal infections is often
measured by the substantial burden they place on
health care resources in terms of the need for emer-
gency room services, hospital admission, imaging and
laboratory diagnostics, and surgery (both initial and
repeat interventions).
6
In addition, ineffective initial
empiric antimicrobial therapy can significantly
increase the cost of treating intra-abdominal infec-
tions, underscoring the need for prompt and appro-
priate interventions.
6
Tremendous progress has been made over the past
century in the management of intra-abdominal infec-
tions, as mortality rates have dropped from approxi-
mately 90% in 1900 to 23% in 2002.
7
However, mor-
tality rates still can vary widely depending on the
source of the infection, ranging from 0.25% for the
appendix
8
to much higher rates for the stomach/duo-
denum (21%), pancreas (33%), small bowel (38%),
large bowel (45%), and biliary tract (50%).
9
Although outcomes have improved, complicated
intra-abdominal infections still are associated with a
high rate of mortality related to organ dysfunction in
critically ill surgical patients. As a result, these infec-
tions require a combination of appropriate and timely
surgical source control and broad-spectrum antimicro-
bial therapy for optimal outcomes. The ultimate treat-
ment goals are to avoid invasive sepsis/bacteremia,
local destructive effects of infection, and death.
■ RISK STRATIFICATION
Many factors can contribute to the severity of an intra-
abdominal infection and to a patient’s risk for a poor
outcome. These include patient age, underlying comor-
bidities (eg, diabetes, cardiovascular disease, cancer),
the extent of infection, where the infection was
acquired (community vs health care setting), the pres-
ence of compromised organ function or sepsis, nutri-
tional status, and the success of initial source control
procedures.
1,10
Dividing patients with intra-abdominal infections
into lower and higher risk categories is not always
straightforward, but attempting to assess a patient’s
risk of treatment failure and/or death is essential to
optimizing a treatment plan. Proper risk stratification
also is important when comparing treatment regimens
and when introducing new antimicrobial agents.
Several types of patients with complicated intra-
COMPLICATED INTRA-ABDOMINAL INFECTIONS
Peritonitis at a glance
Primary bacterial peritonitis refers to spontaneous
bacterial peritonitis that arises without a breach in the
peritoneal cavity. It is most commonly seen in infancy
and early childhood and in patients with cirrhosis or
compromised immune function.
Secondary bacterial peritonitis occurs secondary to
spillage of gut organisms through a hole in the gastro-
intestinal tract. It may be community-acquired or health
care–associated.
Tertiary peritonitis is characterized by persistent or
recurrent infection that typically occurs at least 48 hours
after apparently adequate management of primary or
secondary peritonitis. It is most often seen in patients
with significant comorbidities and in those with compro-
mised immune function.
S30 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007
abdominal infections have been identified as being at
higher risk for a poor outcome, including those with
higher scores on the Acute Physiology and Chronic
Health Evaluation (APACHE II) classification, poor
nutritional status, hypoalbuminemia, significant cardio-
vascular disease, and unsuccessful surgical attempts to
control the local infection.
11–16
Notably, many of these
risk factors are not specifically related to intra-abdomi-
nal infection but more to the patient’s physiologic sta-
tus or underlying medical condition (Table 1).
10
Patients who acquire infection within the hospital
also have a poorer prognosis. Several studies have
demonstrated that the presence of resistant microor-
ganisms is associated with higher rates of treatment
failure.
17–19
Accordingly, the selection of empiric
antimicrobial therapy is likely to influence, at least in
part, clinical outcome. Stratifying patients according
to the probability that they harbor health care–asso-
ciated resistant pathogens is another approach that
can be useful in selecting antimicrobial therapy.
■ BACTERIOLOGY
The bacteria that cause intra-abdominal infections
are derived from the endogenous flora of the gas-
trointestinal tract. An appreciation of the normal
microflora within the gastrointestinal tract is key to
understanding the spectrum of intra-abdominal infec-
tions that may ensue. Figure 1 lists bacteria com-
monly found in various segments of the gastrointesti-
nal tract.
20
Polymicrobial isolates are the hallmark
Polymicrobial isolates remain the hallmark of intra-
abdominal infections.
The most commonly isolated aerobe is Escherichia
coli, and the most commonly isolated anaerobe is Bac-
teroides fragilis.
1,4,10
Other Bacteroides isolates include
Bacteroides distasonis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, and Bacteroides vulgatus.
The role of enterococci in intra-abdominal infec-
tions remains controversial, but treatment failure
attributable to these organisms appears to be common
in high-risk patients.
21–23
When enterococci are iso-
lated, Enterococcus faecalis and Enterococcus faecium
account for 90% and 10% of episodes, respectively.
24
Pseudomonas aeruginosa and other enteric gram-
negative bacteria (eg, Acinetobacter species) are other
potential pathogens of concern because they are
increasingly resistant to many antimicrobials.
Infection with P aeruginosa is typically observed in
high-risk patients such as those with late-onset noso-
comial infection and those who have received previ-
ous antimicrobial therapy, undergone recurrent sur-
geries, or both. In constrast, patients with early-onset
health care–associated or community-acquired infec-
tions have a low prevalence of P aeruginosa.
10
Staphylococcus aureus is also a potential pathogen
with inherent antibiotic resistance issues.
25
Type/site of infection and acquisition mode
indicate likely pathogens
The likely etiology of intra-abdominal infections can
be predicted based on the type of peritonitis, the site
of infection, and the mode of acquisition.
1,4,10
In gen-
eral, primary (spontaneous) bacterial peritonitis is typ-
ically monomicrobial (eg, streptococci, E coli, staphy-
lococci), whereas secondary and tertiary peritonitis are
polymicrobial mixtures of aerobic and anaerobic bac-
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007 S31
WEIGELT
TABLE 1
Independent risk factors for death or treatment
failure in patients with intra-abdominal infections
10
Higher APACHE II score Liver disease
Advanced age Malignancy
Hypoalbuminemia Renal disease
Hypocholesterolemia Corticosteroid therapy
Malnutrition Unsuccessful operation
Preoperative organ
impairment
APACHE II = Acute Physiology and Chronic Health Evaluation II
FIGURE 1. Usual microflora of the gastrointestinal tract.
Stomach
Streptococci,
Lactobacillus
spp
Colon
Bacteroides
spp,
Clostridium
spp,
E coli
,
Enterobacter
spp,
Klebsiella
spp,
peptostreptococci,
enterococci, many
others
Biliary tract
Normally sterile,
but
Escherichia coli
,
Klebsiella
spp,
enterococci found
in some patients
Proximal small bowel
E coli
,
Klebsiella
spp
,
Lactobacillus
spp
,
streptococci
,
diphtheroids,
enterococci
Distal ileum
Bacteroides fragilis
,
Clostridium
spp,
E coli
,
Enterobacter
spp,
Klebsiella
spp,
peptostreptococci,
enterococci
teria (and occasionally fungi in cases of tertiary peri-
tonitis). In community-acquired secondary peritonitis,
gram-positive and gram-negative facultative and aero-
bic organisms often are implicated in infections
derived from the stomach, duodenum, biliary system,
and proximal small bowel.
When bacteria are present with cholecystitis, the
most commonly isolated organisms are E coli, Klebsiella
species, and enterococci. Infections arising from perfo-
rations in the distal small bowel are typically caused by
gram-negative aerobic and facultative bacteria as well
as by anaerobes. For infections beyond the proximal
small bowel, a variety of anaerobes must also be con-
sidered. A wide range of bacteria also may cause
colon-derived intra-abdominal infections, but faculta-
tive and obligate anaerobic organisms outnumber aer-
obic bacteria (eg, streptococci, enterococci, gram-
negative coliforms) by a ratio of 10,000:1.
26
In health care–associated intra-abdominal infec-
tions, which typically encompass tertiary peritonitis,
nosocomial isolates particular to the site of previous
surgery and to the specific hospital and unit may
determine which organisms are responsible.
1
Most
patients with tertiary peritonitis require treatment
with multiple antimicrobials, and fungal infection,
especially with Candida species, must always be con-
sidered. The organisms most commonly associated
with primary, secondary, and tertiary peritonitis are
outlined in Table 2.
■ GENERAL TREATMENT APPROACH
Fluid resuscitation, source control (ie, surgical
debridement, drainage, and repair), and appropriate
systemic antibacterial therapy are paramount to the
successful treatment of complicated intra-abdominal
infections.
1,4,10
While antimicrobial agents should not
be discounted in any treatment regimen for a patient
with peritonitis, source control must be considered
paramount. Without source control, antibiotics will
not successfully treat a patient with secondary or ter-
tiary peritonitis.
Once the diagnosis of complicated intra-abdomi-
nal infection is suspected (ie, due to presence of a sys-
temic and local inflammatory response), it is appro-
priate to plan which methods will be needed for
source control and to begin antimicrobial therapy
immediately. Therapy need not be delayed until an
exact diagnosis is established or the results of appro-
priate cultures are available.
1
Withholding antimicro-
bials or using inadequate empiric antimicrobial ther-
apy can result in increased failure rates and increased
mortality.
27–31
■ ISSUES IN ANTIMICROBIAL SELECTION AND USE
Avoid inappropriate use
Routine use of full-course antimicrobial therapy is not
appropriate for all patients with intra-abdominal
infections. Patients with bowel injuries due to pene-
COMPLICATED INTRA-ABDOMINAL INFECTIONS
TABLE 2
Pathogens associated with peritonitis
Type/site Common Common
of infection aerobes anaerobes
Primary bacterial peritonitis
Children
Streptococcus
⎯
(spontaneous)
pneumoniae,
group A streptococci
Cirrhosis
Escherichia coli,
⎯
Klebsiella
spp,
S pneumoniae
Peritoneal Staphylococci, ⎯
dialysis streptococci
Secondary bacterial peritonitis
Gastroduodenal Streptococci,
E coli
⎯
Biliary tract
E coli, Klebsiella
spp,
Clostridium
spp or
enterococci
Bacteroides
spp
(both infrequent)
Small or
E coli, Klebsiella
spp,
B fragilis
and other
large bowel
Proteus
spp
Bacteroides
spp,
Clostridium
spp
Appendicitis
E coli, Bacteroides
spp
Pseudomonas
spp
Abscesses
E coli, Klebsiella
spp,
B fragilis
and other
enterococci
Bacteroides
spp,
Clostridium
spp,
anaerobic cocci
Liver
E coli, Klebsiella
spp,
Bacteroides
spp
enterococci, (rare)
staphylococci
Spleen Staphylococci, ⎯
streptococci
T
ertiary bacterial peritonitis
All of the above, All of the above
but more likely to
involve resistant
Pseudo-
monas aeruginosa
,
Enterobacter
spp,
enterococci, MRSA,
coagulase-negative
staphylococci, and
Candida
spp
MRSA = methicillin-resistant
Staphylococcus aureus
S32 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007
trating, blunt, or iatrogenic trauma that are repaired
within 12 hours should receive only short-course
(perioperative) antimicrobial therapy, as should
patients with intraoperative contamination of the
operative field by enteric contents under other cir-
cumstances.
1
Likewise, patients with acute perfora-
tions of the stomach, duodenum, or proximal jejunum
in the absence of antacid therapy or malignancy
require only perioperative antimicrobial therapy, as
do patients with acute appendicitis without evidence
of gangrene, perforation, abscess, or peritonitis.
1
Appropriate perioperative antimicrobial therapy in
these cases is no more than 24 hours in duration.
Factors that influence antimicrobial selection
Antimicrobial therapy poses an important clinical
challenge because of the diverse bacteriology of com-
plicated intra-abdominal infections and the emergence
of bacterial resistance. In general, selection of an
empiric agent or combination regimen must be directed
at providing reliable activity against E coli, other gram-
negative facultative bacteria, and B fragilis.
1,4,10
Consideration also must be given to whether the infec-
tion was community-acquired or health care–associated
(Table 3). The continuing emergence of antimicrobial
resistance among some gram-negative enteric
pathogens and B fragilis has become concerning.
32–34
Many other factors influence the selection of an
antimicrobial agent, including its potential to induce
bacterial resistance, its risk of hypersensitivity, its
overall tolerability, its dosing frequency, and its cost.
Accordingly, the search continues for an effective
antimicrobial regimen that has activity against resist-
ant pathogens, a minimal risk of side effects, a con-
venient dosing schedule, and potential cost benefits.
Available antimicrobial options
Several intravenous antibiotics have been investigated,
as monotherapy or as part of a combination regimen,
for the management of patients with intra-abdominal
infections. The old standard of care involved double-
or triple-antimicrobial therapy (eg, aminoglycoside/
beta-lactam/clindamycin) to provide coverage against
an array of potential pathogens. In recent years,
monotherapy with imipenem/cilastatin (Primaxin)
has become the new gold standard because of its broad
spectrum of activity against anticipated pathogens and
its relative safety and ease of use. In addition to
imipenem/cilastatin,
29,35,36
contemporary agents with
documented efficacy include cefoxitin,
37,38
ampi-
cillin/sulbactam,
39
ticarcillin clavulanate (Timentin),
40
and piperacillin/tazobactam (Zosyn).
41–44
More recently,
meropenem (Merrem),
45–47
ertapenem (Invanz),
48
and
tigecycline (Tygacil)
49
have been shown to be effective
as monotherapy.
The use of oral antibiotics (eg, ciprofloxacin, amox-
icillin/clavulanate) as step-down therapy for patients
with intra-abdominal infections is a relatively recent
advance that can be considered in most patients.
■ ANTIMICROBIAL TREATMENT GUIDELINES
Antimicrobial agents and regimens currently recom-
mended by the Infectious Diseases Society of America,
the Surgical Infection Society, the American Society
for Microbiology, and the Society of Infectious Disease
Pharmacists are outlined in Table 4.
1,10
The overall evi-
dence suggests that no regimen has been shown to be
superior to another.
Low-risk patients. The general consensus is that
for low-risk patients with community-acquired intra-
abdominal infections (most cases of secondary peri-
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007 S33
WEIGELT
TABLE 3
Considerations in antimicrobial selection
For patients with community-acquired secondary peritonitis
Choose agents active against enteric gram-negative aerobic
and facultative bacilli and against beta-lactam–susceptible
gram-positive cocci
For distal small bowel and colon-derived infections and more
proximal gastrointestinal perforation with obstruction, choose
agents with activity against anaerobes
Avoid agents used to treat nosocomial infection in the intensive
care unit, except for high-risk patients
Inclusion of agents with enterococcal coverage provides no
benefit in outcomes for patients with community-acquired
infections
For high-risk patients (ie, with high APACHE II score, poor
nutritional status, significant cardiovascular disease, immuno-
suppression, or inability to obtain adequate source control),
use agents with a wider spectrum of antibacterial activity
For patients with tertiary and health care–associated peritonitis
More resistant flora are routinely encountered in this setting
Organisms are similar to those in other nosocomial infections
Treatment is based on local nosocomial flora and their resist-
ance patterns
Agents that offer enterococcal coverage are appropriate for
health care–associated infections
Consider fungal infections based on the patient’s history of
prior antimicrobial use and underlying risk factors
APACHE II = Acute Physiology and Chronic Health Evaluation II
tonitis), narrow-spectrum agents such as antianaero-
bic cephalosporins or ampicillin/sulbactam are prefer-
able to more costly broad-spectrum agents as well as to
those with a greater risk of toxicity. Specific entero-
coccal coverage, although not routinely warranted for
these patients, is a benefit of penicillin derivatives.
High-risk patients. Patients who are at high risk
for failure (ie, with health care–associated secondary
peritonitis or any form of tertiary peritonitis) should
be treated with a broad-spectrum regimen with ade-
quate coverage against gram-negative aerobic/faculta-
tive anaerobic organisms. Addition of empiric cover-
age for enterococci and Candida species should be
considered on a patient-by-patient basis. Both
monotherapy (eg, imipenem/cilastatin, meropenem,
piperacillin/tazobactam) and combination therapy
(eg, an aminoglycoside, aztreonam, ciprofloxacin, or a
third-/fourth-generation cephalosporin plus an
antianaerobe) are appropriate options.
Special considerations. Special consideration is
required for patients with tertiary peritonitis who are
likely to be infected with difficult-to-treat organisms,
such as coagulase-negative staphylococci, enterococci
(including vancomycin-resistant strains), multidrug-
resistant gram-negative bacilli, or yeasts. Empiric ther-
apy in these cases must consider the patient’s history of
previous antimicrobial therapy and local (ie, in the
hospital or unit) patterns of organisms and resistance.
■ NEWER THERAPEUTIC OPTIONS
Tigecycline
Subsequent to the publication of the most recent guide-
lines for treatment of intra-abdominal infections,
1,10
tigecycline was approved by the US Food and Drug
Administration (FDA) for use in patients with compli-
cated intra-abdominal infections. Tigecycline is a gly-
cylcycline antibiotic with expanded broad-spectrum
activity in vitro against bacteria commonly associated
with intra-abdominal infections. Its overall spectrum of
activity includes aerobic and facultative gram-positive
and gram-negative bacteria and anaerobic bacteria.
50–53
While tigecycline exhibits greater activity against
many gram-negative bacteria compared with earlier-
generation tetracycline compounds, it lacks reliable
activity against P aeruginosa.
54,55
It has a distinct mech-
anism of action that is not affected by resistance mech-
anisms that are common in response to beta-lactam,
tetracycline, and aminoglycoside antibiotics.
Direct comparison with imipenem/cilastatin. Tige-
cycline’s efficacy was compared with that of imipen-
em/cilastatin in 1,642 patients with complicated intra-
abdominal infections in two double-blind, randomized
phase 3 trials whose results were reported in a pooled
analysis in 2005.
49
All patients had known or suspected
complicated intra-abdominal infection and underwent
appropriate source control. The most common infec-
tion diagnoses were complicated appendicitis (51%)
and complicated cholecystitis (14%).
Among microbiologically evaluable patients, clinical
cure rates were 86.1% (441/512) with tigecycline and
86.2% (442/513) with imipenem/cilastatin (95% CI for
the difference, –4.5% to 4.4%; P < .0001 for noninferi-
ority).
49
Tigecycline’s efficacy was noninferior to that of
imipenem/cilastatin across a variety of intra-abdominal
infection diagnoses (Figure 2). In both treatment
groups, clinical cure rates varied by the type of infection
and were lower, for instance, in patients with intra-
abdominal abscess and higher in patients with compli-
COMPLICATED INTRA-ABDOMINAL INFECTIONS
TABLE 4
Recommended empiric antimicrobial regimens for treatment of intra-abdominal infections
1,10
Type of infection Monotherapy regimens Combination regimens
Low-risk, community-acquired • Ampicillin/sulbactam (various) • Cefazolin (various) or cefuroxime (various)
secondary peritonitis • Ticarcillin/clavulanate (Timentin) plus clindamycin (various) or metronidazole (various)
• Ertapenem (Invanz) • Ciprofloxacin (various), levofloxacin (Levaquin), or
• Cefotetan (Cefotan) gatifloxacin (Tequin) plus clindamycin or metronidazole
• Cefoxitin (various)
High-risk or health care-associated • Imipenem/cilastatin (Primaxin) • Aminoglycoside,
†
aztreonam (Azactam), ciprofloxacin,
secondary peritonitis and • Meropenem (Merrem) or third/fourth-generation cephalosporin
‡
all tertiary peritonitis* • Piperacillin/tazobactam (Zosyn) plus clindamycin or metronidazole
*Regimen may need to be modified based on need to provide coverage for methicillin-resistant S
taphylococcus aureus
, coagulase-negative staphylococci, enterococci, and
Candida
species.
†
Once-daily administration recommended.
‡
Cefepime (Maxipime), cefotaxime (various), ceftazidime (various), ceftizoxime (Cefizox), ceftriaxone (various)
S34 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007
cated appendicitis. Not unexpectedly, patients in both
treatment groups who had polymicrobial infections had
a lower rate of successful outcomes compared with those
who had monomicrobial infections.
Both tigecycline and imipenem/cilastatin were well
tolerated in these pooled studies, with a similar fre-
quency and distribution of treatment-emergent adverse
events.
49
Gastrointestinal events were the most fre-
quently reported adverse events in both treatment
groups. Overall, the three most commonly reported
adverse events were nausea (24.4% incidence with
tigecycline vs 19.0% with imipenem/cilastatin; P =
.010), vomiting (19.2% and 14.3%, respectively; P =
.008), and diarrhea (13.8% and 13.2%, respectively; P
= .719). Despite the statistically significantly higher
incidence of nausea and vomiting with tigecycline,
rates of premature discontinuation due to an adverse
event did not differ between the two groups.
This large pooled analysis demonstrated that tigecy-
cline was similarly efficacious and well tolerated when
compared with imipenem/cilastatin in patients with
complicated intra-abdominal infections.
49
No economic
analysis of these agents was performed, but for a patient
with normal renal function, the cost of a course of tige-
cycline monotherapy, based on average wholesale
price,
56
is similar to that of imipenem/cilastatin for the
duration of therapy used in these pooled studies (5 to
14 days). Actual drug acquisition costs and patient
variables, however, would influence a formal economic
evaluation.
Role in therapy. Where does tigecycline fit into
clinical practice, given that many good options for
treating patients with complicated intra-abdominal
infections are currently available? There are a number
of situations in which tigecycline might be a reason-
able option, as outlined below.
• The logical patient of choice for tigecycline ther-
apy would be one with a complicated intra-abdominal
infection caused by a known resistant organism.
• Empiric therapy with tigecycline might be
appropriate if local bacterial isolates from intra-
abdominal infections demonstrated a resistance pat-
tern that would make tigecycline a reasonable choice
in a specific patient population based on a risk-strati-
fication system. This would clearly be a local decision
that would need to be based on objective data.
• Empiric therapy with tigecycline for a patient
with tertiary peritonitis would be appropriate as long
as P aeruginosa were not a concern. In such cases, this
empiric therapy should be coupled with antifungal
therapy until culture results can be obtained.
It is doubtful that tigecycline will become a first-
line choice for most patients with complicated intra-
abdominal infections unless an economic advantage
over other regimens can be shown in future studies.
Doripenem and other investigational antimicrobials
New antibiotics for intra-abdominal infection are
hard to come by these days, but a few investigational
agents are on the horizon.
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 74 • SUPPLEMENT 4 AUGUST 2007 S35
WEIGELT
Cu
r
e
r
ate
(%)
0
10
20
30
40
50
60
70
80
90
100
Other
Complicated appendicitis
Complicated cholecystitis
Perforation of the intestines
Intra-abdominal abscess
Complicated diverticulitis
Gastric and duodenal perforations
Peritonitis
Diagnosis
Imipenem/cilastatin
Tigecycline monotherapy
Cure rates by clinical diagnosis in patients with complicated intra-abdominal infections
FIGURE 2. Clinical cure
rates at the test-of-cure
visit after treatment with
imipenem/cilastatin or tige-
cycline in 1,025 microbio-
logically evaluable adults
with complicated intra-
abdominal infections. Data
are from a pooled analysis
of two randomized phase 3
trials.
49
Doripenem is an investigational carbapenem with
broad-spectrum coverage that promises to have activity
against extended-spectrum beta-lactamase (ESBL)-
producing gram-negative organisms.
57
A phase 3 trial
comparing doripenem with an active control in
patients with complicated intra-abdominal infections
was recently completed
58
but has not yet been reported.
A New Drug Application for doripenem was submit-
ted to the FDA in December 2006 for indications
including complicated intra-abdominal infections.
Other investigational antibiotics that do not cur-
rently appear to have a role in the therapy of abdominal
infections include iclaprim, ceftobiprole, ceftaroline,
and garenoxacin. As bacterial resistance rises, we can
hope that the search for new antibiotics will continue.
■ DURATION OF ANTIMICROBIAL THERAPY
A final issue of importance to the use of antibiotics for
any condition is the duration of treatment. Excessive
or prolonged therapy is considered to be one driver of
bacterial resistance.
59
A common problem in clinical
practice is the temptation to provide extended treat-
ment regimens to patients with intra-abdominal infec-
tion. An antimicrobial regimen for intra-abdominal
infection should be continued until all presenting
clinical signs and symptoms are resolved, including
normalization of body temperature and white blood
cell count and return to baseline gastrointestinal func-
tion.
1,4
When source control is adequate, the antimi-
crobial course can be restricted to 5 to 7 days.
■ SUMMARY AND CONCLUSIONS
Source control remains the most important component
in the successful treatment of complicated intra-abdom-
inal infections. Proper selection of empiric antibiotic
therapy is adjunctive but is still important to the over-
all treatment plan. Selection of empiric antimicrobial
therapy for complicated intra-abdominal infections
depends on the severity of the illness and how the infec-
tion was acquired. Knowledge of bacterial resistance in
the hospital and community must be available to
inform selection of the optimal regimen. Patients with
community-acquired intra-abdominal infections pro-
ducing mild to moderate disease should not routinely
receive extended-spectrum antibiotic regimens.
Excessive use of these regimens in this population has
the potential to increase bacterial resistance.
1
A number of antibiotics have demonstrated efficacy
in treating complicated intra-abdominal infections, and
treatment guidelines offer specific recommendations.
1,10
However, rising rates of antibiotic-resistant bacteria in
community and hospital settings highlight the need for
new therapeutic options. Newer agents such as tigecy-
cline and possibly doripenem, when available, have a
potential role in the empiric treatment of complicated
intra-abdominal infections when coverage is needed
against gram-positive (including methicillin-resistant S
aureus and enterococci) and gram-negative bacteria as
well as aerobic and anaerobic bacteria.
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