IntroductionDiarrheal illness is one of the most common complaintsprompting patients to seek medical care. In developingnations, diarrheal illness accounts for 4,600,000 to 6,000,000childhood deaths per year, and it is the second leading causeof death worldwide [1]. In the United States, an estimated 73million physician consultations and 1.8 million hospitaliza-tions each year result from diarrheal disease [2••].
The etiology of diarrhea in the United States varies withseason and region, but bacteria are the most common cause,with Campylobacter species being the most frequently iso-lated bacteria [3]. Other bacterial causes are listed in Table 1.Accurate epidemiologic data are lacking because most caus-ative organisms are not reportable and most episodes ofdiarrhea are treated in the outpatient setting, frequentlywithout diagnosis.
Diagnosis and management of bacterial diarrhea hasbecome more complex due to the globalization of food pro-duction, burgeoning numbers of immunocompromised andinstitutionalized patients, increased ease of travel to develop-ing nations, and the changing epidemiology of pathogens[1,2••,4]. This article reviews the global and emerging prob-lem of antimicrobial resistance among enteric pathogens anddiscusses present recommendations and coming advances indiagnosis and treatment of bacterial diarrhea.
Emerging Antimicrobial ResistanceThe rapid appearance and spread of antimicrobial resis-tance among diarrheal pathogens has been one of the mostconcerning developments in diarrheal illness. Worseningantimicrobial resistance probably has many causes, butunrestricted use of over-the-counter antibiotics in develop-ing countries and use of antibiotics in animal feed havebeen implicated [5•,6]. Antibiotic resistance among diar-rhea-causing bacteria was initially confined to the develop-ing world but has become more prevalent in developedcountries in recent years.
Emerging resistance in shigellosis provides one of themost dramatic examples of the worldwide problem. Shigella,originally susceptible to a broad spectrum of antibiotics,acquired resistance in the developing world first to sulfona-mides, then to ampicillin and trimethoprim-sulfamethox-azole (TMP-SMX), and finally to nalidixic acid as each drugbecame the first-line therapy of choice [7]. Only the fluoro-quinolones have maintained significant susceptibility indeveloping countries. This is a significant problem for thetreatment of shigellosis in children, in whom quinolonesmay have toxic effects on cartilage [6].
Previous studies in the United States have yielded rela-tively low levels of resistance among Shigella isolates (espe-cially to TMP-SMX,) but dependable susceptibility may berapidly waning [8]. Replogle et al. [9] recently investigatedShigella isolates in Oregon and found resistance to tetracy-cline, ampicillin, and TMP-SMZ in 85%, 63%, and 59% ofisolates respectively. No isolates were resistant to ciproflox-acin. Studies from Canada and Europe have shown simi-larly high rates of resistance [9].
Antimicrobial resistance among Salmonella typhi (thecause of typhoid fever) is a growing worldwide problem [10].Although typhoid fever is a distinct entity outside the realm ofthis review, nontyphoidal Salmonella organisms are a com-mon cause of diarrheal illness, and resistance to ampicillin,TMP-SMX, and chloramphenicol has been increasinglyreported [11]. S. enterica serotype Typhimurium definitivephage type 104 (DT104) is one particular nontyphoidal strainthat carries inherent resistance to ampicillin, chlorampheni-col, streptomycin, sulfonamides, and tetracycline. It has madea dramatic appearance in Europe and is now infiltrating theUnited States [12].
Although third-generation cephalosporins and fluoroqui-nolones are generally effective against salmonellae, reports ofresistance are on the rise. Of particular concern is the confir-
Diarrheal illness caused by bacterial pathogens is a global health problem and remains one of the most common complaints prompting patients to seek medical care. Strategies to increase the yield of stool culture and new rapid diagnostic tests can improve diagnostic ability. Emerging antimicrobial resistance among the common bacterial causes of diarrhea has made treatment more challenging. Emerging fluoroquinolone resistance is a particular concern. Recent studies of rifaximin, a nonabsorbed antibiotic for the treatment of bacterial diarrhea, have shown favorable results. Rifaximin may represent a much-needed addition to the armamentarium against bacterial agents.
288 Gastrointestinal Infections
mation of Typhimurium DT104 isolates with nalidixic acid (aquinolone antibiotic) resistance in enteritis acquired fromfood animals [13•]. Nalidixic acid resistance may be a har-binger of emerging quinolone (such as ciprofloxacin) resis-tance, a development that would have significant clinicalimplications [14].
The recommended treatment of Campylobacter enteritisis generally a quinolone or macrolide, but quinolone resis-tance has been rising rapidly around the world [10]. Qui-nolone-resistant strains from diarrhea cases in Thailandincreased from 0% to 84% between 1990 and 1995 [15].The most recent data indicate that resistance in Thailand isover 95% (Tribble D, Personal communication). Quinoloneresistance has emerged in Europe and North America aswell. Resistance rates in Minnesota rose from 1.3% to 10.2%between 1993 and 1998, and resistance rates in isolatesfrom Ireland have risen from 17.4% to 23% in recent years[5•,16]. One recent study from Barcelona found that 12.5%of Campylobacter isolates from travelers (mostly to India,Africa, and Latin America) were resistant to ciprofloxacin,but a stunning 88% of isolates from Spanish nontravelerspossessed ciprofloxacin resistance [17]. The Minnesotastudy also found that 20% of retail chicken products werecontaminated with ciprofloxacin-resistant Campylobacterorganisms, strengthening the link between animal foodsources and spread of resistant diarrheal pathogens [5•].
Diagnostic ApproachDiagnosis and specific therapy in diarrheal illness shouldbe directed at certain goals: alleviation of symptoms, pre-vention of secondary transmission, reduction of morbid-ity and mortality, and detection and control of outbreaks[2••]. The diagnosis of bacterial diarrhea is relatively laborintensive, with low yield and return of results only after 24to 72 hours. Because most cases of diarrhea are self-lim-
iting and require no specific therapy, diagnostic effortshould be focused on patients who have symptomatic,physical, or epidemiologic findings suggesting that spe-cific diagnosis and treatment are warranted.
The diagnosis of infectious diarrhea begins with a thor-ough history and physical examination, the importance ofwhich cannot be underestimated. Historical and physicalfindings can target patients who are likely to benefit fromfurther laboratory investigation or empiric therapy, such asthose with inflammatory diarrhea or a history of immuno-compromising disease. Excellent reviews of importantdiagnostic clues are available in the guidelines of the Infec-tious Diseases Society of America and the American Col-lege of Gastroenterology [2••,18].
The need for stool culture can often be established usingsimple and rapid laboratory tests. Visual identification ofgross blood or a positive test for occult blood suggests aninflammatory diarrhea (especially enterohemorrhagic Escheri-chia coli [EHEC]) and is an indication for culture [2••]. In onestudy, gross blood increased the yield of culture from 5.6% to20.1% [19]. Microscopic examination of fresh stool withmethylene blue staining can be used to look for polymorpho-nuclear lymphocytes (PMNs), a relatively sensitive test forinflammatory diarrhea [19–21]. Stool may also be examinedby commercial latex agglutination assay for lactoferrin, asurrogate marker for PMNs. A study of this type of assay forlactoferrin found excellent correlation with microscopicexamination for fecal leukocytes, a sensitivity of greater than95% for confirmed Clostridium difficile or Shigella infection,and specificity of 94% and 100%, respectively [21].
Stool culture for infectious diarrhea has changed very lit-tle in the past several decades and remains the gold standardfor diagnosis of bacterial enteritis. However, it is a relativelyexpensive test with a low yield. Studies of stool culture yieldshave typically resulted in positive rates below 10% and as lowas 1.5% [22,23]. The cost per positive culture from these stud-
Table 1. Common bacterial causes of diarrheal illness
Organism Comment
Campylobacter species Most common bacterial cause of diarrhea in United StatesSalmonella (nontyphoidal) species Most common bacteria associated with foodborne outbreaks in United StatesShigella species More prevalent in daycare setting or homosexual malesClostridium difficile Common cause of antibiotic-associated diarrheaEscherichia coli
Enterohemorrhagic (EHEC) Common cause of infectious hemorrhagic colitis in United States, associated with hemolytic-uremic syndrome
Enterotoxigenic (ETEC) Common causes of traveler’s diarrhea and diarrhea of developing countriesEnteropathogenic (EPEC)Enteroinvasive (EIEC) Causes dysentery-like illness
Yersinia enterocolitica May cause mesenteric adenitis that can be confused with appendicitisVibrio species V. cholerae mostly in developing countries; non-cholera species associated with
seafood consumption in United StatesAeromonas Recent increased recognition as cause of diarrheal illnessTreponema pallidum Can cause colitis and proctitis in persons engaging in receptive anal intercourseNeisseria gonorrheaeChlamydia trachomatis
Diagnosis and Treatment of Bacterial Diarrhea • Lawler and Wallace 289
ies ranges from $136 to $1200. Reserving stool culture forpatients with evidence of inflammatory diarrhea or withother special indications can significantly improve the yield ofthe culture. In one prospective study, stool culture performedonly on patients with the presence of fecal leukocytes resultedin an improved recovery rate of 76.7% [22]. Avoiding routinestool culture in patients developing diarrhea more than 72hours after hospital admission (the “3-day rule”) can improvethe yield as well. Rohner et al. [24] studied the results ofalmost 14,000 stool cultures at a university hospital in Swit-zerland and found positive cultures in 12.6% versus 1.4%(P<0.001) before and after 3 hospital days.
Culture should be performed on fresh stool. Rectal swabsare generally inferior. If stool cannot be plated within 2 hours,it should be refrigerated or placed in a transport medium[20,23]. Routine stool culture in most US laboratories con-sists of selective and differential agar plates capable of isolat-ing Salmonella, Shigella, and, if all non–E. coli gram negativesare routinely identified, Aeromonas and Plesiomonas. Mostlaboratories also include a Campylobacter-selective mediumincubated in microaerophilic conditions to detect Campylo-bacter species [20,23]. Other organisms require special mediafor culture diagnosis. Suspicion for EHEC, Yersinia, and Vibrioshould prompt culture in sorbitol-MacConkey (SMAC),cefsulodin-ingrasan-novobiocin (CIN), and thiosulfate-cit-rate-bile-sucrose (TCBS) agars respectively to isolate theseorganisms. Turnaround time for stool culture is at least 24hours, and frequently 48 hours for organisms such as Campy-lobacter species.
Advances in rapid stool diagnosticsRapid detection methods, such as the enzyme immunoassay(EIA), are routinely used for several bacterial pathogens, andtests for others are in development. Commercially availableassays for C. difficile toxin have become a standard tool inmost microbiology laboratories. Most kits detect only C. diffi-cile toxin A, but kits to test against toxins A and B are available[25]. Although a small proportion of C. difficile organismsproduce only toxin B, significant C. difficile–associated diseasemissed by assay for toxin A has been reported [26]. Measuredsensitivities and specificities of these EIAs vary widely depend-ing on the study and the kit. Most studies have found excel-lent specificity but sensitivity that is somewhat less than thatof the cell culture assay [25].
Rapid EIA tests can reduce the diagnostic delay withCampylobacter organisms from 48 hours to less than 3 hours.Studies with a commercially available kit found a sensitivityof 80% to 96% and specificity of 99% to 100% [27,28,29•].In the proper clinical setting, this type of test results in excel-lent positive and negative predictive values. Some laboratorieshave replaced culture with EIA for the diagnosis of Campylo-bacter enteritis.
Rapid tests are also available for diagnosis of EHECinfection. Commercial latex agglutination kits for detec-tion of the O157 or H7 antigens are reliable, but they failto identify shiga-like toxin production [30]. Although less
sensitive than cytotoxicity assays, EIAs are commerciallyavailable for detection of shiga-like toxins produced byShigella and EHEC [30,31]. Such tests can be performeddirectly on stool, but sensitivity increases (to 100% in onestudy) if stool is incubated in broth culture overnightbefore the EIA is performed [32]. The advantage of thistype of test is the detection of all shiga toxin–producing E.coli organisms, regardless of sorbitol fermentation.
Methods for rapid detection of Salmonella and Shigellaorganisms are also being developed. Many immunologicallybased commercial kits are already used in food products, andsome have been tested in human stool specimens. A study ofmultiple kits for the detection of various Shigella and Salmo-nella species in Thailand reported sensitivities and specificitiesbetween 94% and 100% [33]. A kit available in Europe fordetection of serum IgM against Salmonella typhi was recentlytested for the diagnosis of Salmonella serotype enteritidis inPolish children with diarrhea [34•]. The sensitivity and speci-ficity of this assay were 92.6% and 94.8%, respectively, withpositive and negative predictive values of 94.7% and 92.9%when patients were compared with control subjects. Suchimmunoassays are likely to appear in diagnostic microbio-logic laboratories in the United States in the near future.
Rapid molecular diagnostic techniques such as poly-merase chain reaction (PCR) have made their way into sev-eral areas of clinical microbiology. PCR assays have beenused to detect C. difficile toxin genes, Shigella, enteroinva-sive E. coli (EIEC), Campylobacter, and Vibrio organisms instool with impressive accuracy [35–38]. Amplified DNAdetection is likely to be useful in the future. However, a sig-nificant amount of fine tuning may be required before it isavailable for commercial use because the presence of DNApolymerase inhibitors in human feces often interferes withthese tests [33].
TreatmentMost diarrheal illness is self-limited and requires no specificintervention other than hydration [10]. Loperamide is recom-mended for symptomatic treatment as long as the illness isnot severe or dysenteric [18]. The appropriate use of antimi-crobial agents is a challenging aspect of treatment becauseantibiotics have the potential for serious deleterious effects.Antibiotic therapy may prolong carriage of enteric Salmonellaorganisms, probably through alteration of normal flora [14].Antibiotic treatment of EHEC may induce toxin productionand exacerbate hemolytic-uremic syndrome (HUS) [31]. Anti-biotic use is the major predisposing factor for C. difficile infec-tion [25]. Finally, unnecessary use of antibiotics worsens theproblem of rapidly emerging antibiotic resistance among bac-teria that cause enteric infection [6].
Despite these drawbacks, antimicrobial therapy has adefinite role in the management of diarrhea caused by certainpathogens. The benefit of standard antibiotic therapy fordiarrhea caused by Shigella, Vibrio, C. difficile, and enterotoxicE. coli (ETEC) infection is firmly established [1,2••,10,11].
290 Gastrointestinal Infections
Although ETEC is not routinely diagnosed in clinical microbi-ology laboratories, it can be suspected with history of travel toareas of high prevalence, or it can be diagnosed in researchlaboratories. Treatment of ETEC is generally TMP-SMX orciprofloxacin for 5 days [31]. A 3-day course of TMP-SMX alsoappears to be effective, showing even better outcomes withthe addition of loperamide [39]. Although mild to moderateVibrio infections do not usually require antibiotic therapy,antibiotics used in severe cases (as with V. cholerae) can reduceduration of illness, stool frequency, and fecal shedding [10].Tetracycline has long been the drug of choice for such infec-tions, but fluctuating geographic patterns of resistance havebeen seen [6]. Furazolidone and erythromycin have beenused successfully in lieu of tetracycline [6,40]. More recently,single-dose quinolones have been shown to be at least aseffective as the more traditional regimens, and quinoloneresistance among Vibrio species is rare [10,41].
Cessation of antibiotics and re-establishment of normalfecal flora remains the most effective treatment for C. difficile–associated diarrhea. This strategy leads to resolution inapproximately 20% of patients [42]. Ten-day courses of oralvancomycin and metronidazole are equivalent when anti-microbial treatment is warranted [43]. The recommendeddosages are vancomycin, 125 mg four times daily, and met-ronidazole, 500 mg three to four times daily [42]. Many alter-native therapies have been examined, but they are generallyless effective and are beyond the scope of this review.
Antibiotic resistance, especially among S. dysenteriae typeI, has made treatment of shigellosis increasingly difficult. Asmentioned previously, quinolones are the only drugs withproven efficacy in the developing world, and although TMP-SMX sometimes works in developing countries, resistancerates are rapidly increasing. Concerns remain regarding theadministration of quinolones to children and pregnantwomen because of cartilage toxicity in animal models, butarthropathy has not been seen in clinical trials of quinolo-nes in children [44]. Third-generation cephalosporins areactive against Shigella organisms in vitro, but results of clini-cal trials have not been convincing [10]. An important recentdevelopment in the treatment of bacillary dysentery hasbeen the use of short-course therapy (1–3 days). Table 2 out-lines the results of two studies of short-course treatment inchildren with cholera [44,45]. Clinical outcome was similarin the two studies. The microbiologic cure rate was 100% inboth groups in the ZIMBASA study, whereas the study byVinh et al. [45] found a significant reduction in the durationof shedding in the short-course group. Thus, a shortenedcourse of quinolones appears to be effective for treatment ofdysenteric illness from Shigella infection.
Many experts recommend antibiotic treatment for cul-ture-proven Campylobacter enteritis [2••,18], although thisopinion is not universal. Several well-constructed studies haveshown statistically significant clinical improvement with qui-nolone therapy. These studies also suggest that therapy mayreduce the duration of fecal shedding [46–49]. Some of thestudies that did not show statistically significant improve-
ment may have been handicapped because early therapy forCampylobacter infection appears to be most efficacious [50].Quinolones and macrolides can be used to treat Campylo-bacter infection, but emerging quinolone resistance is a grow-ing problem. In areas with high levels of endemic resistance,such as Southeast Asia, a macrolide may be more appropriate;azithromycin (500 mg/d for 3 days) has proven efficacy [51].Rifaximin may be very useful in such cases and is discussedlater in this review.
Antimicrobial therapy in uncomplicated nontyphoidalSalmonella enteritis is somewhat controversial. Trials ofmost antibiotics have shown no clinical benefit, and in facthave sometimes shown prolonged fecal shedding of theoffending bacteria [10]. Some studies have shown thatquinolones may shorten the duration of illness with non-typhoidal Salmonella, although carriage is probably notshortened [14]. Despite the lack of evidence of efficacy inuncomplicated diarrhea, patients at risk for disseminateddisease should probably be treated, because extraintestinalSalmonella infection is associated with significant morbid-ity and mortality [2••]. The recommended empiric anti-biotics for Salmonella infection are quinolones or third-generation cephalosporins because of increased resistanceto other traditional agents [14].
Empiric antimicrobial therapyBecause rapid diagnostic capability for bacterial diarrhea islimited, almost all antimicrobial treatment is initiallyempiric. Suspected cases of severe C. difficile colitis may war-rant empiric therapy with metronidazole if a toxin assay can-not be performed in a timely manner, especially if fecalleukocytes are present. In the absence of risk factors for C.difficile infection, inflammatory diarrhea may be caused byorganisms that respond well to treatment, such as Campylo-bacter, Shigella, and EIEC. Bloody diarrhea in the absence offever or in a child should raise a clinical suspicion of EHEC,and empiric antibiotics should not be used in these patientsto avoid potentially precipitating HUS [30]. Patients withinflammatory diarrhea who have a predisposing risk forsevere or disseminated infection, including those with animmunocompromising condition, diabetes, cirrhosis,advanced age, intestinal hypomotility, or hypochlorhydria,are candidates for empiric treatment. On a case-by-case basis,empiric treatment may be prudent for a variety of reasons, forexample in a patient who is at risk of spreading disease to oth-ers (eg, health-care worker or food handler) or when a specificpathogen is suspected (eg, raw seafood consumption or con-tact with a known case). Finally, empiric treatment of trav-eler’s diarrhea is generally appropriate because treatment inthis instance has been shown to reduce the duration of illnessfrom 3 to 5 days to less than 1 to 2 days [2••].
Quinolones have become the drug of choice for empirictreatment of acute bacterial diarrhea in adults. They remainhighly active against almost all of the usual pathogens,achieve high fecal concentrations, and are generally toleratedwell [52]. A number of randomized, placebo-controlled stud-
Diagnosis and Treatment of Bacterial Diarrhea • Lawler and Wallace 291
ies from Europe and the United States have demonstratedsuccessful treatment of acute diarrhea with ciprofloxacin andnorfloxacin. Pichler et al. [48,53] published two reports ontreatment with ciprofloxacin (500 mg twice daily for 5 days)in 50 and 85 patients, respectively. In the first study, ciproflox-acin reduced the duration of diarrhea from 2.6 to 1.4 days(P<0.01) and decreased the number of positive cultures after48 hours of therapy from 24 to 25 to 0 to 24 (P<0.001). Sim-ilar results were found in the second study, and the meanduration of fever was also reduced in a statistically significantmanner from 3.1 to 1.3 days. Studies by Goodman et al. [49],Wistrom et al. [54], and Dryden et al. [46] found a 1- to 2.4-day reduction in days with diarrhea, compared with results inthe placebo group, along with significantly reduced dailysymptoms and total duration of illness. These studies repre-sented varied populations. Campylobacter or Salmonella werethe predominant organisms isolated, but a large proportionof patients (49% and 71% in two of the studies) had nopositive culture, perhaps reflecting a high incidence of patho-genic E. coli. Three of these studies mention travel history inpatients, with incidence rates of 1%, 25%, and 70% [46,49,54]. Studies that specifically examined quinolones for thetreatment of traveler’s diarrhea have demonstrated similarreductions in days of diarrhea and illness [52]. These findingsappear to be independent of the predominant organismsisolated; the same effect is present with a predominance ofpathogenic E. coli, Salmonella, or Campylobacter [47,55].
Alternatives to quinolones for empiric treatment may beappropriate for children and patients with sensitivity toquinolones or in areas where quinolone-resistant organismsare prevalent. TMP-SMX is a reasonable alternative that iscommonly used in children with traveler’s diarrhea [2••].Among travelers in Thailand, where quinolone-resistantCampylobacter predominates, azithromycin or another mac-rolide is an appropriate choice for empiric therapy [51].Finally, local epidemiology of diarrheal illness and resis-tance patterns should always be considered in choosing anempiric antibiotic, and a thorough knowledge of these datamay prevent future complications.
RifaximinIncreasing antimicrobial resistance, combined with theside effects and potential toxicity of absorbed antibiotics,have renewed interest in nonabsorbed antibiotics for thetreatment of diarrhea. Prior studies with oral aztreonamand bicozamycin have proven the efficacy of this approach,although neither of these drugs was pursued for marketing[56]. Studies of rifaximin, a nonabsorbed rifamycin deriva-tive, in the treatment of traveler’s diarrhea are a new andexciting development.
Rifaximin is a semisynthetic relative of the rifamycinswith activity against a broad spectrum of gram-positive andgram-negative organisms. It is currently licensed in severalEuropean, Latin-American, and Asian countries. Less than1% of oral rifaximin is absorbed systemically, but stoolconcentrations reach levels several hundred times the min-imal inhibitory concentration for 90% (MIC90) of mostenteric pathogens [56,57]. As would be expected with anonabsorbed drug, studies to date have revealed an excel-lent safety profile with a 1% incidence of gastrointestinalside effects and very rare episodes of urticaria [57].
To date, two randomized clinical trials examining theuse of rifaximin in traveler’s diarrhea have been published.The first trial compared rifaximin (200, 400, and 600 mgthree times a day) to a standard dose of TMP-SMX in 72adult US students studying abroad in Mexico [58]. Overall,the mean duration of diarrhea after treatment in all rifaxi-min groups was 43.1 hours, compared with 55.7 hours forTMP-SMX (a nonsignificant difference). These results were astatistically significant improvement over historical placebocontrols from a similar population. Although sample sizeprevented statistical significance, the 200-mg dose of rifaxi-min appeared to be as effective as the higher doses. In fact,all of the microbiologic failures (four of 20 isolated patho-gens from the combined rifaximin groups) occurred in the400- and 600-mg groups (Table 3). The second study com-pared rifamixin (400 mg twice a day) with ciprofloxacin in asimilar population in Mexico (n=163) and in tourists inJamaica (n=24) [59••]. Results in the two groups were simi-lar, with a time to last unformed stool of 25.7 versus 25.0hours in the rifaximin and ciprofloxacin groups, respec-tively. These results were similar for patients with and with-out specific microbiologic diagnosis. Differences in sideeffects appear to be clinically insignificant. A third random-ized, controlled study comparing rifaximin with placebowas presented at a recent scientific meeting [56]. In thisstudy rifaximin (200 and 400 mg three times a day) cut thetime to last unformed stool in half, compared with placebo.
ConclusionsDiarrheal illness from bacterial pathogens continues to bea disease of global significance. Rapidly evolving organ-isms and rapid emergence of antimicrobial resistance areexpanding threats to the treatment advances of the past fewdecades. To counter these threats, new tools have recentlybeen added to the diagnostic and therapeutic armamentar-ium, and promising additions are on the horizon. The nextdecade should bring interesting changes in the manage-ment of this important disease.
292 Gastrointestinal Infections
Tab
le 2
. S
tudi
es o
f sho
rt-c
our
se t
hera
py fo
r sh
igel
losi
s in
chi
ldre
n
Reg
imen
Tre
atm
ent
succ
ess,
%
Stud
yLo
cati
onP
atie
nts,
nSh
ort
cour
seC
ontr
olSh
ort
cour
seC
ontr
olP-
valu
e
Vinh
et a
l. [4
5]Vi
etna
m66
Oflo
xaci
n, 7
.5 m
g/kg
ev
ery
12 h
ours
for
2 do
ses
Nal
idix
ic a
cid,
13.
8 m
g/kg
4
times
a d
ay fo
r 5
days
9075
Not
sig
nific
ant
ZIM
BASA
gro
up [4
4]Z
imba
bwe,
Ban
glad
esh,
So
uth
Afr
ica
128
Cip
roflo
xaci
n, 1
5 m
g/kg
ev
ery
12 h
ours
for
3 da
ysC
ipro
floxa
cin
(sam
e do
se)
for
5 da
ys65
69N
ot s
igni
fican
t
Tab
le 3
.M
icro
bio
logi
c cu
re in
tra
vele
r's
diar
rhea
wit
h id
enti
fied
org
anis
m
Mic
robi
olog
ic c
ure,
n (
%)*
Stud
yLo
cati
onP
atie
nts,
nC
ontr
ol d
rug
Rifa
xim
inC
ontr
ol
DuP
ont e
t al.
[58]
Mex
ico
72TM
P-SM
X16
of 2
0 (8
0)7
of 7
(100
)D
uPon
t et a
l. [5
9••]
Mex
ico
and
Jam
aica
187
Cip
roflo
xaci
n29
of 3
0 (7
4)38
of 4
3 (8
8)
*Diff
eren
ces
are
not
stat
istic
ally
sig
nific
ant.
TM
P-SM
X—
trim
etho
prim
-sul
fam
etho
xazo
le.
Diagnosis and Treatment of Bacterial Diarrhea • Lawler and Wallace 293
References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance
1. Guerrant RL, Bobak DA: Bacterial and protozoal gastroenteritis. N Engl J Med 1991, 325:327–340.
2.•• Guerrant RL, Van Gilder T, Steiner TS, et al.: Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001, 32:331–351.
These guidelines are a consensus of experts from the Infectious Diseases Society of America. They provide an in-depth look at the evidence supporting particular management strategies and are an invaluable resource.
3. Centers for Disease Control and Prevention: Campylobacter Infections. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/campylobacter_g.htm. Accessed March 3, 2003.
4. Castelli F, Pezzoli C, Tomasoni L: Epidemiology of travelers' diarrhea. J Travel Med 2001, 8(Suppl 2): S26–S30.
5.• Smith, KE, Besesr JM, Hedberg CW, et al.: Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. N Engl J Med 1999, 340:1525–1532.
This important study documented a 10-fold rise in quinolone-resistant Campylobacter species in Minnesota. The investigators also found that 14% of retail market chicken products were contaminated with quinolone-resistant Campylobacter organisms. Molecular subtyping of isolates was able to link chicken as a source of human infection.
6. Sack, RB, Raman M, et al.: Antimicrobial resistance in organisms causing diarrheal disease. Clin Infect Dis 1997, 24(Suppl 1):S102–S105.
7. Bennish ML, Salam MA, Hossain MA, et al.: Antimicrobial resistance of Shigella isolates in Bangladesh, 1983-1990: increasing frequency of strains multiply resistant to ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid. Clin Infect Dis 1992, 14:1055–1060.
8. Tauxe RV, Puhr ND, Wells JG, et al.: Antimicrobial resistance of Shigella isolates in the USA: the importance of international travelers. J Infect Dis 1990, 162:1107–111.
9. Replogle ML, Fleming DW, Cieslak PR: Emergence of antimicrobial-resistant shigellosis in Oregon. Clin Infect Dis 2000, 30:515–519.
10. Oldfield, EC, Wallace MR: The role of antibiotics in the treatment of infectious diarrhea. Gastroenterol Clin North Am 2001, 30:817–836.
12. Glynn, MK, Bopp C, Dewitt W, et al.: Emergence of multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States. N Engl J Med 1998, 338:1333–1338.
This study examined the rates of quinolone resistance among S. enter-ica enteritidis isolates and found a 10-fold increase (up to 8.5%) between 1995 and 2000. Phage typing showed that eggs from layer hens were the most common cause of human infection.14. Hohmann, EL: Nontyphoidal salmonellosis. Clin Infect Dis
2001, 32:263–269.15. Hoge CW, Gambel JM, Srijan A, et al.: Trends in antibiotic
resistance among diarrheal pathogens isolated in Thailand over 15 years. Clin Infect Dis 1998, 26:341–345.
16. Moore JE, Crowe M, Heaney N, et al.: Antibiotic resistance in Campylobacter sp isolated from human faeces (1980-2000) and foods (1997-2000) in Northern Ireland: an update. J Antimicrob Chemother 2001, 48:455–457.
17. Gallardo F, Gascon J, Ruiz J, et al.: Campylobacter jejuni as a cause of traveler's diarrhea: clinical features and antimicro-bial susceptibility. J Travel Med 1998, 5:23–26.
18. DuPont HL: Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1997, 92:1962–1975.
19. Slutsker L, Ries AA, Greene KD, et al.: Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemi-ologic features. Ann Intern Med 1997, 126:505–513.
20. Turgeon DK, Fritsche TR: Laboratory approaches to infectious diarrhea. Gastroenterol Clin North Am 2001, 30:693–707.
21. Guerrant RL, Araujo V, Soares E, et al.: Measurement of fecal lactoferrin as a marker of fecal leukocytes. J Clin Microbiol 1992, 30:1238–1242.
22. Guerrant RL, Shields DS, Thorson SM, et al.: Evaluation and diag-nosis of acute infectious diarrhea. Am J Med 1985, 78:91–98.
23. Hoshiko M: Laboratory diagnosis of infectious diarrhea. Pedi-atr Ann 1994, 23:570–574.
24. Rohner P, Pittet D, Pepey B, et al.: Etiological agents of infec-tious diarrhea: implications for requests for microbial cul-ture. J Clin Microbiol 1997, 35:1427–1432.
26. Johnson S, Kent SA, O’Leary KJ, et al.: Fatal pseudomembra-nous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay. Ann Intern Med 2001, 135:434–438.
27. Endtz HP, Ang CW, van den Braak N, et al.: Evaluation of a new commercial immunoassay for rapid detection of Campylo-bacter jejuni in stool samples. Eur J Clin Microbiol Infect Dis 2000, 19:794–797.
28. Hindiyeh M, Jense S, Hohmann S, et al.: Rapid detection of Campylobacter jejuni in stool specimens by an enzyme immunoassay and surveillance for Campylobacter upsalien-sis in the greater Salt Lake City area. J Clin Microbiol 2000, 38:3076–3079.
29.• Tolcin R, LaSalvia MM, Kirkley BA, et al.: Evaluation of the Alexon-trend ProSpecT Campylobacter microplate assay. J Clin Microbiol 2000, 38:3853–3855.
This blinded study compared a commercially available EIA for the detec-tion of Campylobacter organisms with stool culture. The EIA demon-strated 96% sensitivity and 99% specificity, proving that it is a rapid and accurate technique for diagnosing Campylobacter organisms in stool.30. Paton JC, Paton AW: Pathogenesis and diagnosis of Shiga
32. Stapp JR, Jelacic S, Yea YL, et al.: Comparison of Escherichia coli O157:H7 antigen detection in stool and broth cultures to that in sorbitol-MacConkey agar stool cultures. J Clin Microbiol 2000, 38:3404–3406.
33. Sonjai K, Soisangwan R, Sakolvaree Y, et al.: Validation of salmo-nellosis and shigellosis diagnostic test kits at a provincial hos-pital in Thailand. Asian Pac J Allergy Immunol 2001, 19:115–127.
This study found that a commercially available 2-minute serologic test perfomed well in clinical specimens from children with Salmo-nella enteritidis infection compared with negative control subjects. The high sensitivity (92.6%) and specificity (94.8%) rates make this rapid test a powerful tool in the diagnosis of salmonellosis.35. Lawson AJ, Shafi MS, Pathak K, Stanley J, et al.: Detection of
campylobacter in gastroenteritis: comparison of direct PCR assay of faecal samples with selective culture. Epidemiol Infect 1998, 121:547–553.
36. Albert MJ, Islam D, Nahar S, et al.: Rapid detection of Vibrio cholerae O139 Bengal from stool specimens by PCR. J Clin Microbiol 1997, 35:1633–1635.
37. Ye LY, Lan FH, Zhu ZY, et al.: Detection of Shigella and entero-invasive Escherichia coli using polymerase chain reaction. J Diarrhoeal Dis Res 1993, 11:38–40.
294 Gastrointestinal Infections
38. Guilbault C, Labbe AC, Poirier L, et al.: Development and eval-uation of a PCR method for detection of the Clostridium dif-ficile toxin B gene in stool specimens. J Clin Microbiol 2002, 40:2288–2290.
39. Ericsson CD, DuPont HL, Mathewson JJ, et al.: Treatment of traveler's diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA 1990, 263:257–261.
40. Morris JG Jr, Black RE: Cholera and other vibrioses in the United States. N Engl J Med 1985, 312:343–350.
41. Kam KM, Luey KY, Cheung TL, et al.: Ofloxacin-resistant Vibrio cholerae O139 in Hong Kong. Emerg Infect Dis 1999, 5:595–597.
43. Teasley DG, Gerding DN, Olson MM, et al.: Prospective ran-domised trial of metronidazole versus vancomycin for Clostridium-difficile-associated diarrhoea and colitis. Lancet 1983, 2:1043–1046.
44. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatr Infect Dis J 2002, 21:1136–1141.
45. Vinh H, Wain J, Chinh MT, et al.: Treatment of bacillary dysentery in Vietnamese children: two doses of ofloxacin versus 5-days nalidixic acid. Trans R Soc Trop Med Hyg 2000, 94:323–326.
46. Dryden MS, Gabb RJ, Wright SK: Empirical treatment of severe acute community-acquired gastroenteritis with ciprofloxacin. Clin Infect Dis 1996, 22:1019–1025.
47. Mattila L, Peltola H, Siitonen A, et al.: Short-term treatment of traveler's diarrhea with norfloxacin: a double-blind, placebo-controlled study during two seasons. Clin Infect Dis 1993, 17:779–782.
48. Pichler HE, Diridl G, Stickler K, Wolf D: Clinical efficacy of ciprofloxacin compared with placebo in bacterial diarrhea. Am J Med 1987, 82:329–332.
49. Goodman LJ, Trenholme GM, Kaplan RL, et al.: Empiric anti-microbial therapy of domestically acquired acute diarrhea in urban adults. Arch Intern Med 1990, 150:541–546.
50. Salazar-Lindo E, Sack RB, Chea-Woo E, et al. Early treatment with erythromycin of Campylobacter jejuni-associated dysen-tery in children. J Pediatr 1986, 109:355–360.
51. Kuschner RA, Trofa AF, Thomas RJ, et al.: Use of azithromycin for the treatment of Campylobacter enteritis in travelers to Thailand, an area where ciprofloxacin resistance is prevalent. Clin Infect Dis 1995, 21:536–541.
52. Akalin HE: Quinolones in the treatment of acute bacterial diarrhoeal diseases. Drugs 1993, 45(Suppl 3):114–118.
53. Pichler H, Diridl G, Wolf D: Ciprofloxacin in the treatment of acute bacterial diarrhea: a double blind study. Eur J Clin Microbiol 1986, 5:241–243.
54. Wistrom J, Jertborn M, Ekwall E, et al.: Empiric treatment of acute diarrheal disease with norfloxacin: a randomized, pla-cebo-controlled study. Swedish Study Group. Ann Intern Med 1992, 117:202–208.
55. Ericsson CD, Johnson PC, DuPont HL, et al.: Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travel-ers' diarrhea: a placebo-controlled, randomized trial. Ann Intern Med 1987, 106:216–220.
56. Steffen R: Rifaximin: a nonabsorbed antimicrobial as a new tool for treatment of travelers' diarrhea. J Travel Med 2001, 8(Suppl 2):S34–S39.
57. Ericsson CD: Rifaximin: a new approach to the treatment of trav-elers' diarrhea: conclusion. J Travel Med 2001, 8(Suppl 2): S40.
58. DuPont HL, Ericsson CD, Mathewson JJ, et al.: Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers' diar-rhea. Digestion 1998, 59:708–714.
59.•• DuPont HL, Jiang ZD, Ericsson CD, et al.: Rifaximin versus ciprofloxacin for the treatment of traveler's diarrhea: a randomized, double-blind clinical trial. Clin Infect Dis 2001, 33:1807–1815.
This randomized, double-blind, placebo-controlled study compared rifaximin with the standard antibiotic, ciprofloxacin, for the treat-ment of traveler's diarrhea. Rifaximin was shown to have equivalent efficacy and no significant side effects.
