1035

STATE-OF-THE-ART CLINICAL ARTICLE

Peritonitis: Update on Pathophysiology, Clinical Manifestations, and
Management
Caroline C. Johnson, James Baldessarre, From the Division of Infectious Diseases,
Allegheny University of the
and Matthew E. Levison Health Sciences, and Veterans Affairs Medical Center,
Philadelphia,
Pennsylvania; and R. W. Johnson Pharmaceutical Research Institute,
Raritan, New Jersey
Peritonitis results from any local trigger of inflammation. titis, congestive heart
failure, metastatic malignant disease, sysUsually
infection is the trigger, although infection may not temic lupus erythematosus, and
lymphedema and, rarely, in
necessarily be present at the earliest stage. For example, sterile adults with no
underlying disease [3]. The presence of ascites
peritonitis may occur in the localized peritoneal space sur- appears to be the
common link among these various conditions.
rounding an infected but resectable intraabdominal organ, such The route of
infection in primary peritonitis is usually not
as the appendix or gallbladder. In contrast, there may be con- apparent but is
thought to be hematogenous, lymphogenous,
tamination of the peritoneum from a defect in the intestinal via transmural
migration through an intact gut wall from the
wall, before establishment of infection or onset of an inflam- intestinal lumen,
or, in women, from the vagina via the fallomatory
response, e.g., immediately following penetrating ab- pian tubes. In cirrhotic
patients the hematogenous route is most
dominal trauma. Peritonitis has been categorized as primary, likely. Organisms
removed from circulation by the liver may
secondary, or (more recently) tertiary. Peritonitis complicating contaminate
hepatic lymph and pass through the permeable
peritoneal dialysis can be considered as an additional category. lymphatic walls
into the ascitic fluid. In addition, portosystemic
Each of these categories is reviewed herein, with an emphasis shunting greatly
diminishes hepatic clearance of bacteremia,
on recent developments in pathogenesis, evaluation, and man- which would tend to
perpetuate bacteremia and increase the
agement. opportunity to cause metastatic infection at susceptible sites
such as the ascitic collection.
Primary Peritonitis The infrequency of primary peritonitis in forms of ascites
other than that due to liver disease emphasizes the importance
Pathogenesis. Primary peritonitis is an infection of the peri- of intrahepatic
shunting in the pathogenesis of this disease.
toneal cavity not directly related to other intraabdominal abnor- The hepatic
reticuloendothelial system is known to be a major
malities. The vast majority of cases are due to bacterial infec- site for removal
of bacteria from blood, and animal studies
tion; it is also commonly known as spontaneous bacterial have suggested that
destruction of blood-borne bacteria by the
peritonitis. Usually it occurs in the presence of ascites from reticuloendothelial
system is impaired in experimental cirrhosis
any of a variety of underlying conditions [1]. In the preanti- and in alcoholic
liver disease. The decrease in phagocytic activbiotic
era, primary peritonitis accounted for .10% of all pedi- ity seen in alcoholic
cirrhosis is proportional to the severity of
atric abdominal emergencies; it now accounts for .1�2% [2]. the liver disease.
The decline has been attributed to widespread use of antibiotics Enteric bacteria
may also gain access to the peritoneal cavity
for minor upper respiratory tract illness. by directly traversing the intact
intestinal wall. In an animal
Although primary peritonitis may occur in children without model, Escherichia coli
passes from the bowel into the peritopredisposing
disease, it is especially associated with post- neal cavity after the introduction
of hypertonic solutions into
necrotic cirrhosis and nephrotic syndrome. In adults, primary the peritoneum. The
infrequent occurrence of bacteremia and
peritonitis develops in up to 25% of patients with alcoholic the multiplicity of
species in peritoneal fluid when anaerobic
cirrhosis but has also been reported to occur in adults with bacteria are involved
suggest that transmural migration of bacpostnecrotic
cirrhosis, chronic active hepatitis, acute viral hepa- teria is the probable route
of infection of ascitic fluid in most
of these patients.
In prepubertal girls, the pathogenesis of primary peritonitis
is likely related to an ascending infection of genital origin, as Received 21
January 1997; revised 10 February 1997.
Reprints or correspondence: Dr. Matthew E. Levison, Division of Infectious
suggested by the simultaneous presence of pneumococci in
Diseases, Allegheny University�MCP, 3300 Henry Avenue, Philadelphia, vaginal
secretions and peritoneal fluid. Alkaline vaginal secre-
Pennsylvania 19129. tions that occur in this age group may be less inhibitory to
Clinical Infectious Diseases 1997;24:1035�47 bacterial growth than the acidic
secretions of postpubertal feq
1997 by The University of Chicago. All rights reserved.
1058�4838/97/2406�0001$02.00 males.
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1036 Johnson, Baldessarre, and Levison CID 1997;24 (June)
Transfallopian spread is also suggested by the development ings of peritoneal
irritation. Fever (temperature of .1007F) is
of primary peritonitis in women with intrauterine devices. The the most common
presenting sign, occurring in 50%�80% of
route of spread in women with gonococcal or chlamydial peri- cases and even in the
absence of abdominal signs or symptoms.
hepatitis (Fitz-Hugh�Curtis syndrome) is presumably via the Primary peritonitis
should always be considered in the differenfallopian
tubes and paracolic gutters to the subphrenic space, tial diagnosis of
decompensation of previously stable chronic
but it may also be hematogenous. liver disease, especially hepatic encephalopathy.
Although tuberculous peritonitis may result from direct entry Primary tuberculous
peritonitis usually is gradual in onset,
into the peritoneal cavity of tubercle bacilli (from the lymph causing fever,
weight loss, malaise, night sweats, and abdominodes,
intestine, or genital tract in patients with active disease nal distension. The
abdomen may not be rigid and is often
of these organs), it is more likely to be disseminated hematoge- characterized as
being ��doughy�� on palpation. The findings
nously from remote foci of tuberculosis, most commonly in at surgery or laparoscopy
consist of multiple nodules scattered
the lung. Tuberculous peritonitis may become clinically evident over the peritoneal
surface and omentum. Adhesions and a
after the initial focus has completely healed. variable amount of peritoneal fluid
are usually present. SimiMicrobiology.
Several decades ago, the organisms reported larly, C. immitis can cause a
granulomatous peritonitis with
to cause primary peritonitis in children were Streptococcus variable clinical
manifestations.
pneumoniae and group A streptococci. More recently, the num- Although the diagnosis
of primary peritonitis can be estabber
of nephrotic children with streptococcal peritonitis has de- lished with certainty
only after thorough laparotomy to exclude
clined, and the relative frequency of peritonitis due to gram- a primary
intraabdominal site of infection, it can usually be
negative enteric bacilli and staphylococci has increased. In surmised from
examination of the peritoneal fluid. Fluid obcirrhotic
patients, microorganisms of enteric origin account for tained at paracentesis
should be analyzed for cell count, differ-
.70% of the pathogens. ential count, and protein concentration, and a gram stain
and
E. coli is the most frequently recovered pathogen, followed culture should be
performed. Specimens for culture should be
by Klebsiella pneumoniae, S. pneumoniae, and other strepto- sent in an airless,
capped syringe or injected directly into aerococcal
species, including enterococci. Staphylococcus aureus bic and anaerobic broth
culture media; volumes of �10 mL
is an unusual cause of primary peritonitis, accounting for only will increase the
yield of cultures [6].
2%�4% of cases in most series, but has been noted especially A gram stain of the
sediment is diagnostic when positive
in patients with erosion of an umbilical hernia. Anaerobes and but is more commonly
negative. Bacteremia occurs in up to
microaerophilic organisms are infrequently reported [4]. Possi- 75% of patients
with primary peritonitis due to aerobic bacteria,
ble explanations include the intrinsic bacteriostatic activity of but it is rare in
those with peritonitis due to anaerobes. Usually
ascites against Bacteroides species, the relatively high pO2 of the same organisms
isolated from the peritoneal fluid are recovascitic
fluid, and the lack of optimal anaerobic bacteriologic ered from the blood.
techniques used to study patients in the past. The presence The ascitic fluid
protein concentration may be low in primary
of anaerobes correlates strongly with polymicrobial infection. peritonitis (.3.5
g/L) because of hypoalbuminemia and diluOccasionally,
primary peritonitis may also be caused by Neisse- tion of ascitic fluid with
transudate from the portal system.
ria gonorrhoeae, Chlamydia trachomatis, Mycobacterium tu- The leukocyte count in
peritoneal fluid usually is .300/mm3
berculosis, or Coccidioides immitis. (.1,000/mm3 in 85%), with granulocytes
predominating in
Patients who have positive cultures of ascitic fluid with few .80% of cases.
However, the total leukocyte count of some
leukocytes and no clinical signs of peritonitis are considered patients with
ascites uncomplicated by infection may be simito
have bacterascites. This may represent early colonization larly elevated. Indeed,
an increase in ascitic leukocyte counts
before a host response. Mortality among patients with a low has been noted during
diuresis in patients with chronic liver
leukocyte response is the same as among those with a greater disease.
response. Conversely, several series have identified cases of Other parameters of
ascitic fluid that may help in diagnosing
primary peritonitis with negative ascitic fluid cultures, termed primary bacterial
peritonitis are pH and lactate concentration
culture-negative neutrocytic ascites [5]. Blood cultures are pos- [7]. An ascitic
fluid pH of .7.35 and a lactate concentration of
itive for one-third of these patients. The frequency of negative .25 mg/dL are more
specific but less sensitive than a leukocyte
results of ascitic fluid cultures may be decreased by inoculating count of .500/mm3
for diagnostic purposes; using all three
blood culture bottles with ascitic fluid at the bedside. parameters together
increases the diagnostic accuracy.
Clinical presentation and evaluation. In children, primary In patients with
negative ascitic fluid cultures, endoscopic
peritonitis is an acute febrile illness often confused with acute or laparoscopic
peritoneal examination and biopsy may be necappendicitis.
Fever, abdominal pain, nausea, vomiting, and di- essary. Peritonitis secondary to
other intraabdominal causes
arrhea usually occur, with diffuse abdominal tenderness, re- should be excluded,
and specimens appropriate for fungal and
bound tenderness, and hypoactive or absent bowel sounds. In mycobacteriologic
cultures should be obtained. In children, if
cirrhotic patients with primary peritonitis, the clinical manifes- gram-negative
organisms, a mixed flora, or no organisms are
tations may be atypical. Onset may be insidious, with no find- obtained from
peritoneal fluid, full exploratory laparotomy is
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CID 1997;24 (June) Peritonitis Update 1037
generally indicated to rule out possible intraabdominal sources examination for
additional pathological conditions. Antimicroof
continuing peritoneal contamination. However, in end-stage bial therapy is usually
continued for 10�14 days if improvecirrhotic
patients, exploratory laparotomy may be life-threaten- ment is noted, but short-
course therapy for 5 days has been
ing, and the likelihood of finding a primary intraabdominal shown to be as
efficacious as the longer course in some patients.
focus may be small. Administration of intraperitoneal antimicrobials is not
necesSurgery
for these patients can be deferred while the response sary.
to antimicrobial therapy is awaited. Patients with primary peri- Treatment of
primary peritonitis is successful in more than
tonitis usually respond within 48 hours to appropriate antimi- one-half of
cirrhotic patients, but because of the underlying
crobial therapy. The observation of an exponential rate of de- liver condition, the
overall mortality has been reported as high
cline in the number of ascitic fluid leukocytes after initiation as 95% in some
series. Those patients with the poorest prognoof
antimicrobial therapy for primary peritonitis has been found sis were found to have
renal insufficiency, hypothermia, hyperto
help differentiate primary from secondary bacterial peritoni- bilirubinemia, and
hypoalbuminemia [9].
tis [8]. Treatment of peritonitis caused by gram-positive organisms,
In patients with a subacute or chronic course of primary as well as of early
infections, has been more frequently successperitonitis,
other pathogens must be considered, including ful than treatment of gram-negative
or late infections. In neM.
tuberculosis or C. immitis. The diagnosis of tuberculous phrotic patients with
gram-positive infections or in patients
peritonitis can usually be made at operation or laparoscopy and who do not have a
preterminal underlying illness, the survival
confirmed by the histologic characteristics of the peritoneal rate is .90%.
biopsy specimen and bacteriologic examination of the perito- Given the common
occurrence and high mortality of primary
neal biopsy specimen and fluid. The diagnosis of C. immitis peritonitis in the
setting of cirrhosis with ascites, prevention is
peritonitis can be made with a wet mount of ascitic fluid, by a desirable strategy.
This is particularly true for patients who
finding the organism in culture, or on histologic examination. are awaiting liver
transplantation. Selective decontamination
Management and prevention. Because the gram stain is fre- of the gut with oral
norfloxacin (400 mg daily) has been shown
quently negative in primary bacterial peritonitis, the initial to reduce the
incidence of spontaneous bacterial peritonitis.
choice of antimicrobial drug is often empirical, based on the Norfloxacin has the
disadvantage of selecting for gram-positive
most likely pathogens. Some of the third-generation cephalo- organisms, including
S. aureus, and quinolone-resistant gramsporin
antibiotics have been demonstrated to be as efficacious negative organisms. More
recently, trimethoprim-sulfamethoxas
the combination of ampicillin plus an aminoglycoside in azole (double-strength,
given once daily for 5 days each week)
primary bacterial peritonitis. They also eliminate the risk of has been shown to
reduce the incidence of peritonitis and be
nephrotoxicity, which is sufficiently frequent in this group of well tolerated
[10]. A survival-rate advantage has not been
patients to warrant avoidance of aminoglycosides if an equally demonstrated for any
of these preventive regimens.
effective alternative antimicrobial regimen can be used.
Other antimicrobial agents such as the broad-spectrum penicil-
Secondary and Tertiary Peritonitis
lins (e.g., mezlocillin, ticarcillin, and piperacillin), carbapenems
(e.g., imipenem), and b-lactam antibiotic/b-lactamase-inhibitor Pathogenesis.
Secondary intraabdominal infection usually is
combinations (e.g., ticarcillin-clavulanate and ampicillin-sulbac- due to spillage
of gastrointestinal or genitourinary microorgantam)
are potential alternatives. If peritonitis develops during isms into the peritoneal
space as a result of loss of integrity of
hospitalization, the therapeutic regimen, such as administration the mucosal
barrier. Examples include appendicitis, diverticuliof
an aminoglycoside antibiotic and an antipseudomonal penicil- tis, cholecystitis,
penetrating wound of the bowel, and perforalin
or cephalosporin in combination, should also be active against tion of a gastric or
duodenal ulcer. Secondary infection is rela-
Pseudomonas aeruginosa. tively common, taking the form of either generalized
peritonitis
For those situations in which the gram stain is suggestive of or localized
abscesses. Abscesses may be restricted to the ima
Bacteroides species or polymicrobial peritonitis is evident, mediate peritoneal
space around a diseased intraabdominal orantimicrobials
with activity against the Bacteroides fragilis gan, such as pericholecystic,
periappendiceal, or peridiverticugroup
and other anaerobic organisms should be added (e.g., lar abscesses, or to certain
peritoneal recesses, such as
metronidazole, clindamycin). The antimicrobial regimen can interloop,
subdiaphragmatic, subhepatic, lesser sac, or pelvic
be modified once the results of the culture and susceptibility abscesses.
tests are available. Peritoneal signs suggestive of appendicitis in immunocom-
In those cases where there is a strong clinical suspicion of promised patients,
e.g., patients with AIDS, organ transplant
primary bacterial peritonitis but all cultures are sterile, anti- recipients, and
those receiving chemotherapy or corticosteroids
microbial therapy should be continued. Clinical improvement, for neoplasms
(especially myelosuppressive drugs), may be due
together with a significant decline in the ascitic fluid leukocyte to typhlitis, an
inflammation of the cecum [11]. Cecal ulceration
count, should occur after 24�48 hours of antimicrobial therapy in these patients
may progress to perforation and secondary
if the diagnosis is correct; failure to respond should prompt an peritonitis with
colonic flora. Perforation complicating penetrat-
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1038 Johnson, Baldessarre, and Levison CID 1997;24 (June)
ing cytomegalovirus enterocolitis has been described as a com- can undergo
alteration as a result of the primary disease process
mon cause of acute abdomen in patients with AIDS [12]. or previous antimicrobial
therapy. For example, diseases of the
Tertiary peritonitis has been conceived as a later stage in stomach that result in
obstruction, the loss of gastric acidity
the disease, when clinical peritonitis and systemic signs of (e.g., bleeding,
gastric ulcer, or carcinoma), or use of acidsepsis
(e.g., fever, tachycardia, tachypnea, hypotension, reducing drugs may cause gastric
colonization with oral anaerelevated
cardiac index, low systemic vascular resistance, leuko- obes, such as non-fragilis
Bacteroides and Fusobacterium
penia or leukocytosis, and multiorgan failure) persist after treat- species and
other oropharyngeal organisms, e.g., viridans strepment
for secondary peritonitis and either no organisms or low- tococci, microaerophilic
streptococci, Candida species, and
virulence pathogens, such as enterococci and fungi, are isolated lactobacilli.
from the peritoneal exudate. These organisms may gain access Gastric perforation is
associated with either sterile chemical
to the peritoneal cavity by contamination during operative in- peritonitis or
peritonitis due to the above-mentioned pathogens,
terventions, by selection from the initial polymicrobial perito- depending on the
underlying gastric condition. Similarly, the
neal inoculum by antibiotic therapy, or by translocation of normal sparse flora of
the small bowel may be altered by gastric
bowel flora. Translocation may be promoted by intestinal isch- disease or small-
bowel ileus.
emia, endotoxemia, malnutrition, or proliferation of resistant With perforation of
the colon, initially enormous numbers
bowel flora by antibiotic pressure. (a total of .1012/mL) of the hundreds of
different species
The cytokine response in peritonitis has been the subject of that constitute the
normal colonic microflora spill into the
a recent excellent review [13]. Undoubtedly, many of the sys- peritoneal cavity. A
simplification of the numerous species
temic as well as abdominal manifestations of peritonitis are then occurs, so that
once peritoneal infection is established,
mediated by cytokines, such as TNF, IL-1, IL-6, IFN-g, and only about five
pathogens on average remain, usually three
others. Cytokines appear in the systemic circulation of patients anaerobic and two
aerobic species. In patients with gangrewith
peritonitis and to a much greater extent in the peritoneal nous or perforated
appendicitis, the average number of organexudate
[14]. These cytokines are produced by macrophages isms recovered from clinical
specimens has been reported to
and other host cells in response to bacteria or bacterial products, be as high as
9.8 and 12.7, respectively, with 75% of the flora
such as endotoxin [15], or by tissues traumatized during the consisting of
anaerobes [30].
operative procedure [16]. Another potential source is direct The obligate anaerobes
isolated have been found to be more
translocation of cytokines through the intestinal barrier. oxygen-tolerant and have
identifiable virulence factors, as comCytokine
responses have been studied in the peritoneal exu- pared with the rest of the
obligate anaerobic microflora.
date in experimental animal models of peritonitis [17�20], in B. fragilis is the
most frequently isolated anaerobe following
patients with spontaneous bacterial peritonitis [21, 22], in pa- colonic
perforation, and E. coli is the most frequently isolated
tients undergoing continuous ambulatory peritoneal dialysis facultative anaerobe.
(CAPD) [23�25], and in patients with severe secondary bacte- In a now-classic
series of experiments in rodents, Weinstein
rial peritonitis who were undergoing planned relaparotomy and co-workers clarified
the sequence of events that occurs
[14]. Antibodies to TNF have been found to fail to protect following contamination
of the peritoneum with fecal flora
against death [26] and failed to reduce serum levels of IL-1 [31]. In this model,
E. coli is responsible for sepsis and mortaland
IL-6 in an experimental model of peritonitis [17, 20, 27]. ity with early
peritonitis, and B. fragilis, in concert with
In contrast, antibodies to endotoxin were found to prevent death E. coli and
possibly other microorganisms such as enterococci,
in this model, as well as to reduce bacterial numbers in the is responsible for
late peritoneal abscess formation. Such synperitoneal
exudate [28]. Antibodies to IFN-g also afforded a ergy between anaerobes and
facultative microorganisms has
protective effect both in this model of experimental peritonitis long been
recognized in mixed infections [32].
and following intravenous injection of endotoxin [29]. Some of the microorganisms
isolated apparently owe their surMicrobiology.
With gastrointestinal perforation as the pre- vival largely to the presence of
other bacteria in the polycipitating
event, the number and types of microorganisms iso- microbial infection, such as B.
fragilis and E. coli, which if elimilated
from the peritoneal cavity depend on the level of the nated by specific
antimicrobial therapy will result in coincident
perforation. The stomach in the fasting state contains a sparse disappearance of
these other microorganisms. The lower intestinal
microflora of a few relatively more acid-resistant species, e.g., flora can be
altered in the severely ill, hospitalized patient under
lactobacilli or Candida species. Similarly, the duodenum and the pressure of
antibiotic usage that allows proliferation of multiproximal
small bowel contain a sparse microflora in the fasting ple-drug-resistant
microorganisms, such as P. aeruginosa, Enterostate,
whereas the colon contains a high microbial density, i.e., bacter species,
multiple-drug-resistant enterococci, and Candida
about 1012/g, of which .99.9% are obligate anaerobes, mainly species. These
microorganisms can then contribute to peritoneal
of the B. fragilis group. infection that may follow colonic perforation.
E. coli, the predominant colonic facultative anaerobe, is The same microorganisms
may also be isolated from patients
found at counts of 106�8/g, while enterococci are less numerous with so-called
tertiary peritonitis, i.e., persistent peritonitis in
at counts of 104�6/g. The characteristic microflora, however, patients with
impaired host defenses and multiple organ dys-
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CID 1997;24 (June) Peritonitis Update 1039
function who are unresponsive to initial management [33]. therapeutic attempts
[46]. This has led to investigation of endoHowever,
monomicrobial infection with microorganisms that toxin and cytokine levels in
circulation to predict outcome.
have low pathogenicity, such as Candida species, enterococci, However, the
magnitude of levels of endotoxin, TNF, and
and coagulase-negative staphylococci, has been noted even in IL-6, in circulation
in patients with peritonitis, has not been
acute peritonitis in patients with severely impaired defenses invariably related to
prognosis [14, 47�51]. It has been sug[
34]. P. aeruginosa usually is thought of as a nosocomial patho- gested that
cytokine levels in the peritoneal exudate, rather than
gen that emerges under the selective pressure of broad- the blood, better reflect
the severity of the compartmentalized
spectrum antimicrobial agents. In several studies, however, this peritoneal
infection and predict outcome [14].
organism has been isolated in up to 24% of patients with acute Management and
prevention. A skeptical attitude is necescommunity-
acquired perforating appendicitis [35, 36]. sary when reviewing reports on clinical
trials of antimicrobial
Although enterococci are found in 20% of intraabdominal therapy for intraabdominal
sepsis. Surgical therapy alone may
infections, their exact role in polymicrobial infection and the be sufficient to
cure many otherwise healthy, young patients
need for specific antimicrobial therapy remain controversial. with intraabdominal
infection who have no signs of severe
Selective therapy against E. coli and B. fragilis, which has sepsis; even
antimicrobial agents to which the pathogens are
minimal in vitro activity against enterococci, has been found resistant may be
associated with a good outcome for these
to be sufficient to reduce enterococcal counts [37]. Neverthe- patients.
less, in animal models of experimental polymicrobial intra- To establish a specific
role for antimicrobial regimens reabdominal
infection, enterococci have been found to be a sig- quires clinical trials with
sufficient numbers of high-risk panificant
component of the inoculum, which enhances abscess tients whose severity of illness
has been stratified by APACHE
formation, weight loss, bacteremia with B. fragilis and E. coli, II scoring.
Clinical trials are frequently diluted by low-risk
and mortality [37, 38]. patients, since the sickest patients who would test the
efficacy
Similarly, clinical reports have indicated the emergence of of the antimicrobial
agent are often excluded by strict enrollenterococcal
abscesses and bacteremia after treatment of ment requirements.
intraabdominal sepsis with antimicrobial agents that lack sig- Medical management
of secondary peritonitis includes use
nificant in vitro enterococcal activity [39�41]. In addition, a of antimicrobial
therapy and supportive measures to maintain
recent multicenter study of intraabdominal infection has found vital functions,
e.g., to improve or maintain circulation, nutrithat
the presence of enterococci in the initial culture, in addition tion, and
oxygenation to vital organs. Antimicrobial agents
to APACHE II score, independently predicted treatment failure must penetrate to the
site of infection in concentrations that
with broad-spectrum antimicrobial regimens that lacked spe- are sufficient to
overcome the effects of high bacterial density,
cific enterococcal activity [42]. APACHE II score, age, length metabolic inactivity
and slow growth rate of the bacterial
of preinfection hospital stay, and postoperative infections pre- inoculum, low pH,
low redox potential, necrotic tissue, and
dicted the presence of enterococci. It is unknown if initial bacterial products
that may lower the drugs� activity. For
inclusion of antienterococcal therapy will improve outcome for example,
aminoglycosides and clindamycin are less active at
these high-risk patients. acid pH values, aminoglycosides are less active at low
redox
Clinical presentation and evaluation. CT has become invalu- potentials, and b-
lactam drugs are less active against high
able in evaluating patients suspected of having an intraabdomi- bacterial
densities.
nal infection. CT- or ultrasonography-guided aspiration of sus- The animal model of
intraabdominal sepsis demonstrated the
pected intraabdominal abscesses has also become standard in necessity of treating
both the facultative enteric gram-negative
evaluating and managing selected patients. Intraabdominal in- bacilli, namely E.
coli, and the anaerobic gram-negative bacilli,
fection encompasses many different pathological and clinical namely B. fragilis.
Empirical use of an antimicrobial regimen
entities that are associated with widely varying mortality rates active against
these organisms has been well established. Inthat
range from zero to 60%. deed, the need for intraoperative cultures to document
etiologi-
The ability to predict outcome and stratify severity of disease cal microbes and
their antimicrobial susceptibilities has been
is important for clinical decision-making as well as ensuring questioned, because
the results are rarely available to influence
comparability in trials that evaluate different management strat- clinical
decisions [52].
egies with surgical protocols or antimicrobial agents [43]. Out- Early clinical
trials have established the therapeutic regimen
come has been found to be related mainly to host factors (e.g., of clindamycin plus
aminoglycoside as the ��gold standard��
preoperative nutritional status, organ impairment, the severity [53, 54].
Aminoglycosides are frequently underdosed because
of the patient�s systemic response, and the premorbid physio- of fear of
nephrotoxicity or because of underestimation of the
logical reserves, as predicted by the APACHE II scoring sys- expanded volume of
distribution in critically ill patients with
tem) rather than to type and source of the infection [44, 45]. intraabdominal
sepsis. Once-daily aminoglycoside therapy�
Death from intraabdominal infection, especially when the in which the total daily
dose is given to patients with normal
tertiary phase is reached, is thought to result from an exagger- renal function as
a single dose every 24 hours rather than as
ated uncontrolled cytokine release that is unresponsive to all multiple smaller,
divided doses�obviates these dosing prob-
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1040 Johnson, Baldessarre, and Levison CID 1997;24 (June)
lems, because both the bactericidal activity and postantibiotic as the appendix or
gallbladder, after resection of the organ.
effect of aminoglycosides are concentration-dependent, while Similarly,
contamination of the peritoneum from a defect in
their nephrotoxicity is time-dependent. However, too few se- the intestinal wall,
such as immediately following penetrating
verely ill patients with intraabdominal sepsis have been studied abdominal trauma,
may also require only operative intervention
to allow recommendation of the general use of single daily to remove the diseased
organ and a brief course of antimicrobial
doses of these drugs. therapy [53]. Persistent signs of sepsis suggest formation of

Regimens in which a third-generation cephalosporin is substi- an intraabdominal

abscess that requires drainage, continued
tuted for the aminoglycoside or metronidazole is substituted for contamination of
the peritoneum from an inadequately conclindamycin
compare favorably to the ��gold standard.�� Resis- trolled source, superimposed
nosocomial infection with a resistance,
however, emerges readily under selective pressure of anti- tant pathogen, or
tertiary peritonitis.
microbial therapy with third-generation cephalosporins among Treatment against
Enterococcus or Candida species incertain
gram-negative bacilli that produce inducible b-lacta- volved in polymicrobial
infections is controversial. Identifimases,
such as Enterobacter, Serratia, Citrobacter, Morganella, cation of either
microorganism in blood cultures, as the sole
and Acinetobacter species and P. aeruginosa. These organisms organism within
residual or recurrent intraabdominal infechave
a high spontaneous mutation rate for constitutive produc- tion, or as the
predominant pathogen on a gram stain of
tion of large amounts of these b-lactamases that confer resistance peritoneal
exudate is an indication for specific antimicrobial
to all b-lactam drugs, except the carbapenems (imipenem and therapy plus adequate
surgical debridement. Enterococci
meropenem) and cefepime, and are poorly antagonized by sul- have emerged as leading
nosocomial pathogens, undoubtedly
bactam, clavulanic acid, and tazobactam. as a result of their inherent resistance
to many commonly
Patients likely to be infected with these organisms�e.g., used antimicrobial agents
and the recent acquisition of resisthose
having prolonged hospital stays, prior antibiotic treat- tance to previous standard
therapy, i.e., with ampicillin,
ment, postoperative peritonitis, or tertiary peritonitis�are best aminoglycosides,
and vancomycin. Only clinically unproven
treated with a regimen that includes imipenem, meropenem, agents to which the
strains are susceptible in vitro, such
cefepime, a fluoroquinolone, or an aminoglycoside. Resistance as doxycycline,
novobiocin, or quinupristin/dalfopristin, are
among isolates of B. fragilis to metronidazole is rare, while available as
potential therapeutic agents for infection caused
resistance to clindamycin is now unacceptably high in many by these multiresistant
strains of enterococci.
centers. Furthermore, the relative incidence of Clostridium dif- Administration of
amphotericin B is standard therapy for
ficile�associated diarrhea and colonization was found to be invasive candidal
infection, although amphotericin lipid comless
following use of metronidazole than that following use of plex is an equally
efficacious, less nephrotoxic, but more expenclindamycin
in a retrospective study [55]. sive alternative. Azoles such as fluconazole and
itraconozole
Microaerophilic gram-positive cocci, which are frequent co- are also less toxic,
although no comparative trials for candidal
pathogens in polymicrobial anaerobic infection, are resistant peritonitis have been
performed. Candida krusei, Candida tropto
metronidazole, unlike clindamycin, so if metronidazole is icalis, and Torulopsis
glabrata are inherently more resistant to
used it should be combined with an agent active against these azoles, and
resistance to azoles among previously susceptible
pathogens, such as a b-lactam antibiotic other than aztreonam. Candida species is
increasing.
Aztreonam, fluoroquinolones, and aminoglycosides also lack Although a comprehensive
discussion of surgical manageactivity
against microaerophilic gram-positive cocci and theo- ment of secondary peritonitis
is beyond the scope of this reretically
may not be optimal agents to combine with metronida- view, certain recent trends
will be mentioned [59, 60]. Optimal
zole, although clinical trials of these combinations have been management includes
the following: (1) bowel decompression,
found to be efficacious in intraabdominal infection [56]. e.g., by proximal
colostomy for perforation, diverticulitis, or
Monotherapy with agents that have activity against both colonic carcinoma; (2)
closing of traumatic perforations and
aerobes and anaerobes includes the carbapenems imipenem and resection of a
diseased, perforated viscus to stop continued
meropenem and the b-lactam/b-lactamase combinations, such peritoneal contamination;
and (3) drainage of any purulent colas
ampicillin/sulbactam, ticarcillin/clavulanate, and piperacil- lections to reduce
the bacterial inoculum and to remove exceslin/
tazobactam. Unacceptably high B. fragilis resistance to cef- sive levels of
proinflammatory cytokines and other adjuvants,
oxitin has been found in many centers; cefotetan, another sec- such as fecal
matter, food, blood, bile, bullets, or barium.
ond-generation cephalosporin, is less active than cefoxitin In the absence of
perforation, when the disease process, e.g.,
against certain species in the B. fragilis group. acute appendicitis or necrotic
bowel, is anticipated to progress,
The duration of antimicrobial therapy after adequate surgery the involved organ is
resected. Laparoscopic appendectomy
is usually 5�7 days but depends on severity of infection, clini- has been
recommended for acute appendicitis, with conversion
cal response, and normalization of the WBC count [53, 57, to open appendectomy for
perforated appendix or an inflamma58].
Only a short course of antimicrobial therapy (24 hours) is tory mass, as well as
laparoscopic cholecystectomy for acute
required for sterile peritonitis that occurs in the peritoneal space cholecystitis
(with conversion to an open procedure when techaround
an infected but resectable intraabdominal organ, such nical difficulties are
encountered).
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CID 1997;24 (June) Peritonitis Update 1041
Abscesses that present as localized peritonitis may be drained nias, and tertiary
peritonitis with organisms such as enterococci
percutaneously with the aid of ultrasonography or CT, followed or Candida species
[63�65]. Indeed, repeated entry into the
by definitive surgery, if necessary. Percutaneous drainage of inflamed peritoneum
may further escalate the cytokine cascade.
a peridiverticular abscess may permit a subsequent one-stage A review concluded
that in the absence of randomized conprocedure
of primary resection and immediate anastomosis. trolled prospective trials with
appropriate stratification of paPeritonitis
caused by colonic perforation due to diverticuli- tients by severity of illness,
there is insufficient evidence to
tis or colon cancer has been treated with one of three proce- determine if these
procedures improve outcome of severe difdures,
depending on the particular clinical situation: (1) a fuse peritonitis [66].
three-stage procedure, which involves an initial proximal colostomy
to decompress the bowel and divert the fecal stream,
Peritonitis Complicating Peritoneal Dialysis
followed by resection of the diseased bowel, and finally anastomosis
to restore bowel continuity several months later; (2) Pathogenesis. Since its
development in the late 1970s,
a two-stage procedure, which involves initial resection and CAPD has provided a
safe, cost-effective treatment for endtemporary
proximal colostomy, with either a mucous fistula stage renal disease.
Unfortunately, the technique is often abanor
a blind pouch (Hartmann�s procedure), followed by anasto- doned because of its most
common complication, peritonitis
mosis; or (3) a one-stage procedure of primary resection and [67]. The incidence of
peritonitis complicating CAPD varies
immediate anastomosis. considerably between individual patients and centers. Rates
The three-stage procedure has traditionally been reserved for tend to reflect the
experience of the center, the specific technolcritically
ill, high-risk patients; however, the two-stage proce- ogy used, and the users�
susceptibility to infection and ability
dure may be preferred for these patients because it eliminates to comply with
procedures [68]. Overall, the average incidence
the source of peritoneal contamination early [61]. The one- of peritonitis is
1.3�1.4 episodes per patient per year [69].
stage procedure in the patient with colonic perforation has been More than half of
these episodes are experienced by only 25%
questioned because the lumen of the bowel is not cleansed of patients.
preoperatively and because of the assumed risk of breakdown The two most important
routes for development of peritonitis
of the anastomosis in the presence of peritonitis. However, in CAPD patients are
(1) transluminal, resulting from a break in
the one-stage primary resection and immediate anastomosis sterile technique during
dialysate exchange, and (2) contiguous
eliminate need for further hospitalization and shorten disability spread, in which
microorganisms access the peritoneum along
due to a colostomy. Indeed, the one-stage procedure has been the tract of the
dialysis catheter. Less common portals of entry
shown to be efficacious for the moderate-risk patient with co- are hematogenous
spread from a distant site of infection and
lonic perforation (APACHE II score of �15), even in the direct contamination from
the gastrointestinal tract. Diverticcase
of emergency when the bowel has not been cleansed or ular disease of the nonsigmoid
colon appears to be a risk factor
peritonitis is present [61]. for acquisition of infection of intestinal origin,
presumably
Intraoperative peritoneal lavage with saline, following through occult
microperforations; however, isolation of multidrainage
of purulent peritoneal exudates, fecal matter, food, ple enteric pathogens from
peritoneal fluid, especially anaeroand
other foreign debris, is standard procedure during laparo- bic bacteria, suggests
fecal contamination from gross colonic
tomy for peritonitis. However, radical peritoneal debridement perforations [68].
of all fibrinous deposits on peritoneal surfaces is no longer Microbial factors
that may contribute to pathogenesis of
thought to be effective [62]. Continuous peritoneal lavage for peritonitis include
ability to grow in dialysis fluids and pro48�
72 hours postoperatively or until the fluid is clear has duction of extracellular
slime (biofilm). Once organisms gain
been studied, but at present the evidence is insufficient to access to the
peritoneal cavity, further growth may depend on
recommend this procedure. Addition of antibiotics or anti- their survival in the
presence of dialysis fluid. Fresh dialysate
septics to intraperitoneal lavage fluid has also been shown to solutions are
capable of supporting growth of E. coli but
have no added benefit [53]. not that of staphylococci. However, after instillation
into the
Similarly, there has been interest in the role of planned relap- peritoneal cavity,
dialysis effluent supports growth of both
arotomies to treat patients with severe peritonitis. Here, the organisms [69].
commitment is made at the first operation to perform laparo- Other studies have
shown that the growth of P. aeruginosa
tomies at frequent intervals until the abdomen is macroscopi- and E. coli is
enhanced 1,000-fold in dialysis fluids from pacally
��clean,�� with additional surgical procedures, such as tients with peritonitis,
compared with that in such fluids from
resections, performed as necessary [63]. The abdominal fascia uninfected controls
[70]. Both staphylococci and Candida albiis
left open between laparotomies and the defect bridged by cans grow as microcolonies
on polymeric surfaces [71]. Sursaline-
soaked gauze or by a temporary abdominal closure de- rounding biofilm serves to
anchor the organisms and protect
vice, such as mesh. them from host defenses and antibiotic activity [72].
These demanding and costly procedures have been compli- The clinical observation
that some patients remain free of
cated by multiple fistulas, wound contamination, incisional her- CAPD-related
peritonitis for years suggests that host defense
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1042 Johnson, Baldessarre, and Levison CID 1997;24 (June)
factors may also be important in the pathogenesis of this infec- Clinical
presentation and evaluation. Criteria for the diagnotion
[73]. Microbial pathogens that reach the dialyzed perito- sis of CAPD-associated
peritonitis are (1) signs and symptoms
neal cavity are removed by three major lines of defense. First, of peritoneal
irritation, (2) cloudy dialysate effluent with a
despite the dilution of fibrinogen and coagulation proteins, fi- leukocyte count of
.100/mm3, and (3) a positive culture of
brin trapping and sequestration of microorganisms operate ef- dialysate fluid. Any
two of these criteria may be adequate to
ficiently in the dialyzed peritoneum. Second, removal of the establish the
diagnosis [82]. Clinical manifestations of peritonidialysate
serves to eliminate or decrease the inoculum of con- tis vary from mild to severe,
depending largely on the virulence
taminating organisms. Finally, a complex interplay of opsoni- of the pathogen and
the time course of the infection [67].
zation, phagocytosis, and intracellular killing by peritoneal Generally, turbid
dialysate is the first and most common sympmacrophages,
mesothelial cells, and neutrophils serves to com- tom to appear, followed shortly
thereafter by abdominal pain
bat bacterial invasion and prevent infection. and tenderness.
Unfortunately, the dialyzed peritoneal cavity is not a support- Laboratory
evaluation of dialysate effluent is critical to estabive
milieu for operation of these cellular and immunologic lishing the diagnosis of
CAPD-associated peritonitis. A dialydefense
mechanisms because of its low pH (5.5�6.0), high sate leukocyte count of .100/mm3
is the traditional diagnostic
osmolarity (300�400 mOsmol/kg), and decreased levels of IgG value but is not
specific. The differential cell count of dialysate
and complement (1% of their normal levels). A correlation may have a better
predictive value. In one study, polymorphobetween
deficiencies in these host defenses and patient risk for nuclear leukocytes
comprised .50% of the total cell count
peritonitis has not been conclusively identified [73]. (mean, 85%) in infected
patients, while in uninfected patients
Microbiology. In patients undergoing CAPD, peritonitis is the proportion was .40%
(mean, 12%) [82]. A preponderance
usually caused by a single pathogen that originates from the of eosinophils in the
fluid is seen in the self-limited condition
normal flora of the skin or upper respiratory tract. Approxi- ��eosinophilic
peritonitis,�� which often follows placement of
mately 60%�70% of cases are caused by gram-positive cocci, the Tenckhoff catheter
and may represent allergy to the tubing
20%�30% by gram-negative bacilli, and the remainder by vari- [83, 84].
ous other bacteria, fungi, and mycobacteria [74]. Coagulase- Peritoneal
eosinophilia also occurs with fungal peritonitis
negative Staphylococcus is the single most common pathogen, or recent
intraperitoneal administration of antibiotics. Gram
followed by S. aureus and species of Streptococcus. Among staining of dialysis
fluid detects only 20%�30% of peritonitis
the gram-negative organisms, most Enterobacteriaceae species episodes. Gram-
positive organisms, especially S. aureus, are
have been associated with CAPD peritonitis, but no single more likely to be
detected than are gram-negative ones [85].
species predominates in all reported series. Although a rare Cultures offer a
greater yield than gram stains but require
pathogen in other types of peritonitis, P. aeruginosa occurs concentration of the
dialysate by centrifugation, filtration, or
with relative frequency in CAPD peritonitis (5%�10% of lysis-centrifugation [86].
cases). It warrants special note because of its association with Even with these
specialized methods, 3%�30% of CAPDsignificant
morbidity and late complications [75, 76]. related peritonitis episodes are
culture-negative. Presumably,
Fungi have become an important cause of CAPD-related most are due to fastidious,
low-virulence organisms or coaguperitonitis
in recent years because of their increasing frequency lase-negative staphylococci
that survive less well in dialysis
and problematic management. Although many different fungi fluid [70]. Cases of
culture-negative peritonitis that do not
have been isolated, including Aspergillus, Mucor, Rhizopus, respond to empirical
antibiotic treatment should be further inAlternaria,
Fusarium, Penicillium, and Drechslera species, vestigated by performance of
dialysate fluid cultures for myco-
C. albicans accounts for 80%�90% of cases [74, 76]. Risk bacteria and fungi. Blood
cultures are usually negative, regardfactors
for acquisition of fungal peritonitis are bacterial perito- less of the etiologic
agent.
nitis within the preceding month, recent hospitalization, pres- Management and
prevention. The increased use of intraperitoence
of extraperitoneal infection, use of immunosuppressive neal antibiotics as therapy
for peritonitis has allowed most paagents,
and concomitant HIV infection, but diabetes mellitus tients to be treated on an
ambulatory basis. Hospitalization is
does not pose a special risk [77, 78]. indicated for those who are severely ill or
who are unable to
Mycobacteria have been described as pathogens in fewer than manage administration
of intraperitoneal antibiotics at home. A
3% of cases of CAPD-related peritonitis, but they may also variety of antimicrobial
agents have been used successfully for
account for a portion of cases labeled as ��culture-negative�� [79]. treatment,
including penicillins, cephalosporins, aztreonam, imiOverall,
86% of mycobacterial isolates reported in the literature penem, aminoglycosides,
fluoroquinolones, and macrolide and
have been of group IV (rapid growers), such as M. fortuitum and glycopeptide
antibiotics. Initial therapy may be guided by results
M. chelonae [80]. One particularly large outbreak involved 17 of the dialysis fluid
gram staining, but since these are uncompatients
who developed infection with M. chelonae following monly positive, empirical
treatment with a cephalosporin or vantreatment
with contaminated intermittent peritoneal dialysis ma- comycin plus aminoglycoside
is typically initiated.
chines [81]. Other rare causes of peritonitis in patients undergoing In relatively
mild episodes of peritonitis, a single agent with
CAPD are viruses, algae, and M. tuberculosis. antistaphylococcal activity may also
be suitable. Antibiotic se-
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CID 1997;24 (June) Peritonitis Update 1043
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of fungal peritonitis is controversial because of the rial peritonitis: a review of
28 cases with emphasis on improved survival
and factors influencing prognosis. Am J Med 1978;64:592�8.
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Gayowski T, Yu VL, Wagener MM. Trimethoprim-sulfamethoxat
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