A disulfiram-like reaction can occur when alcohol or alcohol-containing medications

are taken concurrently with metronidazole.

164 Because metronidazole is a carcinogen

and, in some animal species, a mutagen, it should be used in pregnancy only if clearly

needed. Similarly, metronidazole’s safety in children has not been proved, and many

prefer not to use it in this population if other options exist.

154

Oral vancomycin produces fecal concentrations that are several 100 times the

concentration needed to inhibit toxin-producing strains of C. difficile.

161 A 10 to 14-

day course of oral vancomycin (125–500 mg orally 4 times daily) is recommended

for the treatment of CDI, with all dosing regimens equally effective in the patients

studied.

154

,

161

,

165

,

166 Because of equal efficacy and high concentrations in the colon

with all doses, vancomycin 125 mg is the most commonly prescribed dose. Although

oral vancomycin is not well absorbed, measurable serum concentrations have been

found in patients with both normal and compromised renal function, though higher

and longer dose regimens, severe infection, and renal dysfunction were more

associated with serum concentrations.

167

Fidaxomicin is the newest antimicrobial indicated for the treatment of CDI.

168

,

169

Fidaxomicin is a macrocyclic antibiotic active against C. difficile that is poorly

absorbed and achieves high colonic concentrations.

170

It has limited antimicrobial

spectrum and largely preserves colonic flora. In the primary clinical trial, patient

outcomes on initial infection were similar when compared with vancomycin.

169 This

finding, along with a significantly higher cost of therapy, has led many clinicians to

suggest fidaxomicin be reserved as second-line therapy.

150

,

171 However, one potential

advantage for fidaxomicin was in recurrence rates, which were found to be

significantly lower with fidaxomicin compared to vancomycin (15.4% vs. 25.3%, P

= 0.005). While recurrence is a concern in CDI treatment, it is not yet clear if it is

possible to identify patients for whom the higher cost would provide an additional

benefit from this effect.

Table 69-5

Clostridium difficile Infection Severity of Disease

Published guidelines

Severity Am J Gastroenterology 2013 SHEA/ISDA 2010

Mild-to-moderate Diarrhea plus signs and symptoms

that do not meet severe or

complicated criteria

White blood count ≤15,000 cells/mL

AND

Serum creatinine <1.5× baseline

Severe Serum albumin <3 g/dL

PLUS

either white blood count ≥15,000

cells/mL

or

Abdominal tenderness

White blood count >15,000 cells/mL

OR

Serum creatinine ≥1.5× baseline

Severe-to-complicated Admission to intensive care unit

Hypotension

Fever ≥38.5°C

Ileus or significant distension

Mentalstatus changes

White blood count ≥35,000 or

<2,000 cells/mL

Serum lactate >2.2 mmol/L

End organ failure

Hypotension or shock, ileus,

megacolon

Source: Cohen SH et al. Society for Healthcare Epidemiology of America; Infectious Diseases Society of

America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 Update by the Society for

Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect

Control Hosp Epidemiol. 2010;31:431; Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of

Clostridium difficile infections. Am J Gastroenterol. 2013;108:478.

p. 1465

p. 1466

Because B.W. is not critically ill, metronidazole (500 mg orally 3 times daily) for

10 to 14 days is recommended as first-line treatment.

157–159 Oral metronidazole and

oral vancomycin are generally considered equally efficacious in mild-to-moderate

disease,

158 but vancomycin use should be limited to prevent emergence of

vancomycin-resistant organisms.

172

In addition, oral vancomycin capsules are

significantly more expensive than a course of oral metronidazole. Some of this cost

differential can be offset by using the IV vancomycin preparation to prepare an oral

solution which can be flavored and prepared as directed in the package insert.

Once therapy directed against C. difficile is initiated, diarrhea or cramping should

subside within 2 to 4 days. If B.W.’s symptoms have not resolved, vancomycin can

be tried.

152

ALTERNATIVE THERAPIES

Toxin Binders

Traditional anion-binding resins (e.g., cholestyramine, colestipol) are not as reliable

or as rapidly effective as oral metronidazole or vancomycin and are not

recommended as routine therapy.

173

Probiotics

Using probiotics introduces probiotic microorganisms into the normal flora to

counteract disturbances and reduce the colonization with pathogenic species.

174

Although orally administered, Lactobacillus species and the yeast Saccharomyces

boulardii have been used to treat CDI, no data support the use of probiotics alone.

Adjunctive use has been suggested to prevent CDI and its recurrences. A hospital

trial looking at prevention of all ADD with Lactobacillus reported positive results

for the prevention of CDI.

175 The results of that study, however, are tempered by the

methodological exclusion of patients receiving antibiotics with a high risk of causing

CDI, making generalization to other patient groups difficult. The exact role of

probiotics in treatment or prevention of CDI is not yet known.

150

,

171 Adding further

caution to the widespread use of probiotics, reports of isolated adverse effects,

including fungemia, with ingestion of viable S. boulardii have been reported.

158

,

176

Antidiarrheals

CASE 69-17, QUESTION 7: Should B.W. be given any antidiarrheal agent to relieve her symptoms?

Opiates and other antiperistaltic agents should be avoided in patients with CDI.

Although these types of drugs may relieve diarrheal symptoms, they may also delay

toxin removal from the GI tract. Evidence supporting these negative effects is

minimal as data are scarce,

9 but caution would suggest avoiding any antimotilty agent

in B.W.

CASE 69-17, QUESTION 8: Following resolution of B.W.’s CDI, is it necessary to send a follow-up stool

sample to determine whether it is negative for C. difficile toxin?

After resolution of diarrhea, obtaining a follow-up stool sample to determine

whether it is negative for C. difficile toxin is not recommended as part of routine

practice because most patients with positive tests will not develop a recurrence of

their diarrhea.

158

In addition, up to 3% of healthy adults carry small numbers of C.

difficile in their feces, whereas colonization rates are much higher (31%–37%) in

hospitalized patients and infants under 1 month.

177

,

178

Transmission

CASE 69-18

QUESTION 1: H.T., a 76-year-old man with multiple medical conditions, is admitted to the same 10-bed

hospital ward as B.W. H.T.’s medical history is significant for a stroke that has left him bedridden in a nursing

home. His only medications are those used to manage his hypertension. On day 4 of his hospitalization, H.T.

complained of severe abdominal pain and watery, loose stools with blood. Physical examination revealed an illappearing man with a temperature of 101°F and hypotension. His WBC is 21,000 cells/mL. A stool specimen is

positive for C. difficile toxin, and colonoscopy reveals pseudomembranes and colitis. A surgical consultant is

considering an emergent colectomy because of possible bowel perforation secondary to the CDI. What are

H.T.’s risk factors for acquiring C. difficile–associated pseudomembranous colitis during his hospitalization?

H.T.’s risk factors for acquiring CDI include his advanced age, bedridden

status,

179 underlying diseases,

180 and admission to the hospital. CDI is spread when

hospital personnel or equipment contaminated with C. difficile spores come into

contact with susceptible patients. Physical proximity to an infected patient has been

associated with an increased risk of CDI.

181 Therefore, measures to prevent the

spread of CDI include hand disinfection before and after contact with infected

patients; the use of gloves and gowns; enteric isolation precautions; and proper hand

washing with soap and water (to remove any potential spores) after contact with

infected patients with CDI. Contaminated equipment should be properly

disinfected.

182

Although C. difficile is often thought of as a nosocomial pathogen, it is being

increasingly isolated in outpatient settings.

141

,

183 This changing epidemiology has led

to a standard definition of community-associated CDI in patients without any

healthcare facility exposure within the last 12 weeks.

162 While many communityassociated CDI infections appear in patients without antimicrobial exposure,

antimicrobial use remains the highest risk factor.

184 Although proton-pump therapy

and other acid suppression has been increasingly suspected as a cause of these

infections, a meta-analysis of community-associated CDI did not find acid

suppression to be a significant risk; however, corticosteroid use was associated with

the disease.

184

CASE 69-18, QUESTION 2: Over the next few days, all 10 patients on the ward with B.W. and H.T. are

found to have C. difficile toxin in their stools. Five patients have diarrhea and the other five are asymptomatic.

What is the role of antibiotic therapy directed at C. difficile in controlling this outbreak?

Neither oral metronidazole nor vancomycin is reliably effective in eradicating the

carrier state (i.e., asymptomatic fecal excretion), and neither is recommended for use

in this situation.

185 The lack of efficacy of these drugs is probably because of the fact

that, unlike the vegetative forms of C. difficile, the spores of C. difficile are resistant

to the action of antibiotics.

182 Furthermore, compared with placebo, vancomycin

administration is associated with a significantly higher rate of C. difficile carriage 2

months after treatment.

185

Controlling overall antibiotic use in the hospital can be a useful strategy.

Antimicrobial stewardship is increasingly seen as a major control mechanism for

CDI.

150 Restricting the use of single agents like clindamycin can be an effective

component in efforts to control nosocomial epidemics of CDI.

179 With the emergence

of the BI/NAP1 strain, control of all antibiotic use, especially fluoroquinolones, may

be important in outbreak control.

186

p. 1466

p. 1467

Finally, the overuse of acid suppressive therapy in the hospital setting, particularly

proton-pump inhibitors, has been linked with increases in CDI.

187 Efforts to control

use of these drugs have been increasingly recommended.

188

CASE 69-18, QUESTION 3: What effect will the current CDI outbreak have on the outcomes of the

infected patients and on health care costs?

In a prospective study, hospitalized patients who developed CDI had a 3.6-day

increase in length of stay.

189 A large retrospective cohort study in the Veterans

Affairs Administration reported a 2.3-day increase in hospitalization, with an

increase of 4.4 days with severe disease.

190 A review of available economic data

suggests additional hospital costs of $8900 to $30,000 for each case of CDI.

191 The

current outbreak on the hospital ward is likely to increase both hospital costs and

individual lengths of stay.

Severe C. difficile Infection

CASE 69-18, QUESTION 4: What treatment is recommended for H.T. who is critically ill from a CDI?

What criteria should be used to characterize patients as “critically ill”?

Up to 57% of patients with antibiotic-associated pseudomembranous colitis who

require surgical intervention (colectomy) die.

192 Although the precise definition of

“critically ill” is not clear, it has variably included patients with pseudomembranes,

age over 60, serum albumin <2.5 mg/dL, fever >38.3°C, severe abdominal pain, and

marked leukocytosis (greater than 15,000–20,000 cells/mL).

146

,

193 Recent guidelines

from the Society for Healthcare Epidemiology of America and the Infectious Disease

Society of America have suggested the definition of severity as presence of any of

either of the following two parameters: white blood cell count ≥15,000 cells/mL or

serum creatinine 1.5 times baseline

158

(See Table 69-5). Growing evidence suggests

that vancomycin 125 mg orally 4 times daily may be more effective than

metronidazole in patients with predefined severe disease.

158

,

193 An additional

definition of “severe, complicated” disease has been suggested for patients like H.T.,

who have hypotension, shock, ileus, or megacolon. The recommended therapy for

H.T. would be a combination of vancomycin 500 mg orally 4 times daily and

metronidazole 500 mg intravenously every 8 hours.

158 This combination therapy was

shown to reduce mortality from 36.4% to 15.9% when compared with monotherapy

in a small observational study.

194 The combination of high-dose therapies is theorized

to overcome the difficulties for either medication to get to the site of action in the

colon.

NON-ORAL TREATMENT

CASE 69-18, QUESTION 5: Three days after oral vancomycin and intravenous metronidazole is initiated,

H.T. develops an ileus and cannot take anything by mouth. What therapeutic options are available to treat

H.T.’s pseudomembranous colitis?

Adequate antibiotic levels in the colon are necessary to treat C. difficile–

associated pseudomembranous colitis. If the oral route is not feasible (e.g., patients

with an ileus or bowel obstruction), the clinician must choose an agent that is either

secreted or excreted into the GI tract in its active form. IV vancomycin is not a

desirable agent in this situation because it is not secreted into the GI tract. In contrast,

intravenous metronidazole is eliminated by both renal and hepatic routes, and

bactericidal concentrations are achieved in both serum and bile.

195

The literature contains few reports of successful attempts to treat CDI or

pseudomembranous colitis with IV metronidazole (500 mg q6–8h) alone.

196–198

Likewise, unsuccessful attempts to treat CDI with IV metronidazole have been

reported.

196

,

199 The clinical response of CDI to PO vancomycin in a patient who did

not survive was difficult to ascertain.

161

In adults, enteral vancomycin 500 mg 4 times daily can be given through an

ileostomy or colostomy (if present). Several reports of successful outcomes using

intracolonic vancomycin (as an adjunct to oral or IV antibiotics) in patients with CDI

have been documented. Rectal doses of vancomycin have varied from 500 mg q4–8h

to 1,000 mg/L q8h.

200 Rectal vancomycin administration volumes of 500 mL are

suggested to better ensure delivery to the transverse and distal colon.

150 Saline can be

used as a carrier, but electrolytes should be monitored because absorption can occur.

Lactated Ringer’s solution may be preferred if hyperchloremia is present.

150

Because patients with CDI are at risk for colonic perforation, enteral vancomycin

should be administered cautiously.

Relapse

CASE 69-19

QUESTION 1: P.V. is a 57-year-old male who acquired CDI on the same ward as the other infected patients.

P.V. was treated with metronidazole 500 mg orally 3 times daily for 10 days while in the hospital. One week

after discharge from the hospital, P.V. once again developed abdominal pain and diarrhea. His clinic physician

assumed these symptoms could not be related to a relapse of his CDI because he had responded so well to

metronidazole. What is the likelihood that CDI has recurred?

Regardless of the antibiotic regimen prescribed for CDI, symptomatic relapse

occurs in 5% to 30% of patients who respond to their initial treatment regimen.

155

,

182

Relapses occur 2 weeks to 2 months (median of 7 days) after treatment has been

discontinued.

201

In most instances, relapses are caused by germination of dormant

spores that are intrinsically resistant to antibiotics. Reinfection with C. difficile from

external sources, however, may account for up to half of all second episodes.

202

In

rare instances, either vancomycin

203 or metronidazole

204 may have caused CDI.

Risk factors for recurrent CDI include increasing age (≥65 years), use of protonpump inhibitors, renal insufficiency, continued use of antimicrobials during CDI

treatment, and glucocorticoid use.

205

,

206

Data suggest that patients with a poor immune response to C. difficile toxin A are

more likely to have a relapse of CDI.

207

It is not clinically helpful in the case of P.V.,

because no standard tests are currently available for this immune response. The

influence of the immune system, however, has led to the usage of IV immune globulin

in refractory or severe cases of CDI.

208

,

209 The utility of the usage of immune

globulins has been debated in small single institution reviews. Immune globulins

would not be the considered the next line of therapy for P.V.

CASE 69-19, QUESTION 2: How should P.V.’s CDI relapse be treated?

Most infections resulting from relapse are not related to bacterial resistance and

they respond to retreatment with the same antibiotic used for initial treatment of the

CDI.

155

,

210 Thus, an appropriate approach for P.V. is to administer another 10 to 14-

day course of oral metronidazole.

For patients with multiple recurrences of CDI, the optimal management plan is

unresolved.

182 Different approaches have been tried, including (a) high-dose oral

vancomycin

p. 1467

p. 1468

(2,000 mg/day)

211

; (b) a 4- to 6-week course with vancomycin, after which the

dose is tapered over a 1- to 2-month period

211

,

212

; (c) exchange resins

213

,

214 with or

without antibacterials; (d) “pulse” dosing of vancomycin every 2 to 3 days

211

; or (e) a

combination of vancomycin and rifampin (600 mg orally twice daily).

215 Tapered and

pulse therapy with vancomycin were shown to be most effective in a clinical trial

comparing multiple strategies.

211 When combined with standard antibiotic therapy, a

clinical trial with the probiotic S. boulardii for cases of relapsing CDI noted a 65%

response rate versus a 36% response rate for combination therapy with placebo.

216

The relapse rate was reduced to 17% when S. boulardii was combined with highdose vancomycin.

217

Following treatment with vancomycin, a “chaser” course of rifaximin, a poorly

absorbed rifamycin derivative, was successful in separate case series for patients

with multiple relapses.

218

,

219 Concern must be raised that the single failure occurred

in concert with emerging rifaximin resistance.

218

Because of its more minimal impact on fecal flora, fidaxomicin may be

recommended for recurrent infections, although there is less evidence for its use in

recurrence compared to other recommended agents.

171 Fidaxomicin’s inherent

advantage in limiting recurrence with initial treatment and treatment of first

recurrences may lie in cost savings.

220

,

221

Finally, fecal microbiota transplant (FMT) therapy has been more widely

investigated in second and third relapses and has shown significant promise.

222

Healthy fecal donors, often family members, are the usual source for fecal

microbiota, though frozen “banks” of FMT samples have been increasing.

223

Administration of FMT can be provided through nasogastric or nasojejeunal tubes,

colonoscopy, or colonic enemas. Although published data overall remain small, a

systematic review of the literature supports the efficacy (85% cure rates) and limited

adverse effects of this therapy.

222 Long-term follow-up from a multi-center study of

17 patients found 88% to 94% success rates.

224 A single cost-effectiveness model,

using literature-based data, found FMT to be more cost-effective compared to

treatment of recurrences with vancomycin.

224

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thePoint.lww.com/AT11e. Below are the key references for this chapter, with

the corresponding reference number in this chapter found in parentheses after the

reference.

Key References

Cohen SH et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the

Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America

(IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431–455. (162)

Crump JA et al. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial

management of invasive salmonella infections. Clin Microbiol Rev. 2015;28(4):901–937. (31)

DuPont HL. Acute infectious diarrhea in immunocompetent adults. N EnglJ Med. 2014;370(16):1532–1540. (3)

Goldstein EJ et al. Pathway to prevention of nosocomial Clostridium difficile infection. Clin Infect Dis.

2015;60(Suppl 2):S148–S158. (188)

Harris JB et al. Cholera. Lancet. 2012;379(9835):2466–2476. (5)

Navaneethan U, Giannella RA. Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol.

2008;5(11):637–647. (2)

Meltzer E, Schwartz E. Enteric fever: a travel medicine oriented view. Curr Opin Infect Dis. 2010;23(5):432–437.

(55)

Pawlowski SW et al. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology. 2009;136(6):1874–

1886. (7)

Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J

Gastroenterol. 2013;108:478–498. (150)

COMPLETE REFERENCES CHAPTER 69 INFECTIOUS

DIARRHEA

Barr W, Smith A. Acute diarrhea. Am Fam Physician. 2014;89(3):180–189.

Navaneethan U, Giannella RA. Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol.

2008;5(11):637–647.

DuPont HL. Acute infectious diarrhea in immunocompetent adults. N EnglJ Med. 2014;370(16):1532–1540.

Dickinson B, Surawicz CM. Infectious diarrhea: an overview. Curr Gastroenterol Rep. 2014;16(8):399.

Harris JB et al. Cholera. Lancet. 2012;379(9835):2466–2476.

Corinaldesi R et al. Clinical approach to diarrhea. Intern Emerg Med. 2012;7(Suppl 3):S255–S262.

Pawlowski SW et al. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology. 2009;136(6):1874–

1886.

DuPont HL. Clinical practice. Bacterial diarrhea. N EnglJ Med. 2009;361(16):1560–1569.

Murphy GS. Ciprofloxacin and Loperamide in the Treatment of Bacillary Dysentery. Ann Intern Med.

1993;118(8):582.

Bierer DW. Bismuth subsalicylate: history, chemistry, and safety. Rev Infect Dis. 1990;12(Suppl 1):S3.

Cottreau J et al. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol.

2012;6(1):17–23.

Dylag K et al. Probiotics in the mechanism of protection against gut inflammation and therapy of gastrointestinal

disorders. Curr Pharm Des. 2014;20(7):1149–1155.

Guandalini S. Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol. 2011;45(Suppl):S149–

S153.

Steffen R et al. JAMA patient page. Traveler’s diarrhea. JAMA. 2015;313(1):108.

Dolecek C et al. A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment

of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One. 2008;3(5):e2188.

Swerdlow DL, Ries AA. Cholera in the Americas. Guidelines for the clinician. JAMA. 1992;267(11):1495–1499.

King CK et al. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional

therapy. MMWR Recomm Rep. 2003;52(RR-16):1–16.

Sirinavin S et al. Norfloxacin and azithromycin for treatment of nontyphoidalsalmonella carriers. Clin Infect Dis.

2003;37:685.

Robilotti E et al. Norovirus. Clin Microbiol Rev. 2015;28(1):134–164.

Tate JE, Parashar UD. Rotavirus vaccines in routine use. Clin Infect Dis. 2014;59(9):1291–1301.

Morris JG, Jr. Cholera and other types of vibriosis: a story of human pandemics and oysters on the half shell. Clin

Infect Dis. 2003;37(2):272–280.

Fillion K, Mileno MD. Cholera in travelers: shifting tides in epidemiology, management, and prevention. Curr

Infect Dis Rep. 2015;17(1):455.

Nelson EJ et al. Antibiotics for both moderate and severe cholera. N EnglJ Med. 2011;364(1):5–7.

Khan WA et al. Comparison of single-dose azithromycin and 12-dose, 3-day erythromycin for childhood cholera:

a randomised, double-blind trial. Lancet. 2002;360(9347):1722–1727.

Ryan ET et al. Case records of the Massachusetts General Hospital. Case 20-2011. A 30-year-old man with

diarrhea after a trip to the Dominican Republic. N EnglJ Med. 2011;364(26):2536–2541.

McMullan R et al. Food-poisoning and commercial air travel. Travel Med Infect Dis. 2007;5(5):276–286.

Chen XM et al. Cryptosporidiosis. N EnglJ Med. 2002;346(22):1723–1731.

Cabada MM, White AC. Treatment of cryptosporidiosis: do we know what we think we know? Curr Opin Infect

Dis. 2010;23(5):494–499.

RossignolJFrançois A et al. Treatment of diarrhea caused by cryptosporidium parvum: a prospective randomized,

double blind, placebo controlled study of nitazoxanide. J Infect Dis. 2001;184(1):103–106.

Abubakar I et al. Treatment of cryptosporidiosis in immunocompromised individuals:systematic review and metaanalysis. Br J Clin Pharmacol. 2007;63(4):387–393.

Crump JA et al. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and

antimicrobial management of invasive salmonella infections. Clin Microbiol Rev. 2015;28(4):901–937.

Chimalizeni Y et al. The epidemiology and management of non typhoidal salmonella infections. Adv Exp Med

Biol. 2010;659:33–46.

Gordon MA. Salmonella infections in immunocompromised adults. J Infect. 2008;56(6):413–422.

Humphries RM et al. In vitro susceptibility testing of fluoroquinolone activity against Salmonella: recent changes

to CLSI standards. Clin Infect Dis. 2012;55(8):1107–1113.

Kariuki S et al. Antimicrobial resistance and management of invasive Salmonella disease. Vaccine. 2015;33(Suppl

3):C21–C29.

Ko WC et al. A new therapeutic challenge for old pathogens: community-acquired invasive infections caused by

ceftriaxone- and ciprofloxacin-resistant salmonella enterica serotype choleraesuis. Clin Infect Dis. 2005;40:315.

Gunell M et al. In vitro activity of azithromycin against nontyphoidal Salmonella enterica. Antimicrob Agents

Chemother. 2010;54(8):3498–3501.

Onwuezobe IA et al. Antimicrobials for treating symptomatic non-typhoidal Salmonella infection. Cochrane

Database Syst Rev. 2012;11:CD001167.

Hohmann EL. Nontyphoidalsalmonellosis. Clin Infect Dis. 2001;32(2):263–269.

Pegues DA. Salmonella species. In: Bennett JE, Blaser MJ, ed. Mandell, Douglas, and Bennett’s Principles and

Practice of Infectious Diseases. Vol 2. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:2559–2568.

Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and

treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the

Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine

Association of the Infectious Diseases Society of America 2015;

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed August 28, 2015.

Sanchez-Vargas FM et al. Salmonella infections: an update on epidemiology, management, and prevention. Travel

Med Infect Dis. 2011;9(6):263–277.

Butler T. Treatment of typhoid fever in the 21st century: promises and shortcomings. Clin Microbiol Infect.

2011;17(7):959–963.

Harris JB. Enteric fever and other causes of fever and abdominal symptoms. In: Bennett JE, Blaser MJ, ed.

Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Vol 1. 8th ed. Philadelphia,

PA: Elsevier Saunders; 2015:1270–1282.

Parry CM. The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam. Trans R

Soc Trop Med Hyg. 2004;98(7):413–422.

Parry CM et al. Typhoid fever. N EnglJ Med. 2002;347(22):1770–1782.

Crump JA et al. Clinical response and outcome of infection with Salmonella enterica Serotype Typhi with

decreased susceptibility to fluoroquinolones: a United States FoodNet Multicenter Retrospective Cohort Study.

Antimicrob Agents Chemother. 2008;52(4):1278–1284.

Parry CM et al. The management of antimicrobial-resistant enteric fever. Expert Rev Anti Infect Ther.

2013;11(12):1259–1261.

Parry CM et al. Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin

combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents

Chemother. 2007;51(3):819–825.

Mahmud AK et al. Typhoid fever. Mymensingh Med J. 2008;17(2):236–244.

Rai S et al. Rationale of azithromycin prescribing practices for enteric fever in India. Indian J Med Microbiol.

2012;30(1):30–33.

Pandit A et al. An open randomized comparison of Gatifloxacin versus Cefixime for the treatment of

uncomplicated enteric fever. PLoS One. 2007;2(6):e542.

Frenck RW et al. Azithromycin versus Ceftriaxone for the treatment of uncomplicated typhoid fever in children.

Clin Infect Dis. 2000;31(5):1134–1138.

Bhutta ZA et al. Failure of short-course ceftriaxone chemotherapy for multidrug-resistant typhoid fever in

children: a randomized controlled trial in Pakistan. Antimicrob Agents Chemother. 2000;44(2):450–452.

Meltzer E, Schwartz E. Enteric fever: a travel medicine oriented view. Curr Opin Infect Dis. 2010;23(5):432–437.

Sjolund-Karlsson M et al. Salmonella isolates with decreased susceptibility to extended-spectrum cephalosporins

in the United States. Foodborne Pathog Dis. 2010;7(12):1503–1509.

Dave J et al. Trends in antibiotic susceptibility of enteric fever isolates in East London. Travel Med Infect Dis.

2015;13(3):230–234.

Chisti MJ et al. High-dose intravenous dexamethasone in the management of diarrheal patients with enteric fever

and encephalopathy. Southeast Asian J Trop Med Public Health. 2009;40(5):1065–1073.

Kaye D et al. Treatment of chronic enteric carriers of Salmonella typhosa with ampicillin. Ann N Y Acad Sci.

1967;145:429.

Phillips WE. Treatment of chronic typhoid carriers with ampicillin. JAMA. 1971;217(7):913.

Nolan CM, White PC, Jr. Treatment of typhoid carriers with amoxicillin. Correlates of successful therapy.

JAMA. 1978;239(22):2352–2354.

Pichler H et al. Treatment of chronic carriers of Salmonella typhi and Salmonella paratyphi B with trimethoprimsulfamethoxazole. J Infect Dis. 1973;128:(Suppl):743–744.

Ferreccio C et al. Efficacy of ciprofloxacin in the treatment of chronic typhoid carriers. J Infect Dis.

1988;157(6):1235–1239.

Kaye D et al. Comparison of parenteral ampicillin and parenteral chloramphenicol in the treatment of typhoid

fever. Ann N Y Acad Sci. 1967;145(2):423–428.

Ferreccio C et al. Efficacy of ciprofloxacin in the treatment of chronic typhoid carriers. J Infect Dis.

1988;157:1235.

Diridl G et al. Treatment of chronic salmonella carriers with ciprofloxacin. Eur J Clin Microbiol. 1986;5(2):260–

261.

Sammalkorpi K et al. Treatment of chronic Salmonella carriers with ciprofloxacin. Lancet. 1987;2(8551):164–165.

Gotuzzo E et al. Use of norfloxacin to treat chronic typhoid carriers. J Infect Dis. 1988;157:1221.

Jackson BR et al. Updated recommendations for the use of typhoid vaccine—Advisory Committee on

Immunization Practices, United States, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(11):305–308.

Crump John A, Mintz Eric D. Global trends in typhoid and paratyphoid fever. Clin Infect Dis. 2010;50(2):241–

246.

Zaidi MB, Estrada-Garcia T. Shigella: a highly virulent and elusive pathogen. Curr Trop Med Rep. 2014;1(2):81–

87.

Niyogi SK. Shigellosis. J Microbiol. 2005;43(2):133–143.

DuPont AW. Postinfectious irritable bowelsyndrome. Clin Infect Dis. 2008;46(4):594–599.

Carter JD, Hudson AP. Reactive arthritis: clinical aspects and medical management. Rheum Dis Clin North Am.

2009;35(1):21–44.

Bennish ML et al. Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella

dysenteriae Type 1 infection in Bangladesh. Clin Infect Dis. 2006;42(3):356–362.

Klontz KC, Singh N. Treatment of drug-resistant Shigella infections. Expert Rev Anti Infect Ther. 2015;13(1):69–

80.

Gu B et al. Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Shigella

between Europe-America and Asia-Africa from 1998 to 2009. Int J Antimicrob Agents. 2012;40(1):9–17.

Bowen A et al. Importation and domestic transmission of Shigella sonnei resistant to ciprofloxacin—United

States, May 2014–February 2015. MMWR Morb Mortal Wkly Rep. 2015;64(12):318–320.

Kantele A et al. Antimicrobials increase travelers’ risk of colonization by extended-spectrum betalactamaseproducing Enterobacteriaceae. Clin Infect Dis. 2015;60(6):837–846.

Shanks GD et al. Single dose of azithromycin or three-day course of ciprofloxacin as therapy for epidemic

dysentery in Kenya. Acute Dysentery Study Group. Clin Infect Dis. 1999;29(4):942–943.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

Khan WA et al. Treatment of shigellosis: V. Comparison of azithromycin and ciprofloxacin. A double-blind,

randomized, controlled trial. Ann Intern Med. 1997;126(9):697–703.

Baker KS et al. Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a

cross-sectionalstudy. Lancet Infect Dis. 2015;15(8):913–921.

Sjolund Karlsson M et al. Outbreak of infections caused by Shigella sonnei with reduced susceptibility to

azithromycin in the United States. Antimicrob Agents Chemother. 2013;57(3):1559–1560.

Hassing RJ et al. Case of Shigella flexneri infection with treatment failure due to azithromycin resistance in an

HIV-positive patient. Infection. 2014;42(4):789–790.

Jain SK et al. Antimicrobial-resistant Shigella sonnei: limited antimicrobial treatment options for children and

challenges of interpreting in vitro azithromycin susceptibility. Pediatr Infect Dis J. 2005;24(6):494–497.

Shiferaw B et al. Antimicrobial susceptibility patterns of Shigella isolates in Foodborne Diseases Active

Surveillance Network (FoodNet) sites, 2000–2010. Clin Infect Dis. 2012;54(Suppl 5):S458–S463.

Bennett JE et al. Bacillary dysentery:shigella and enteroinvasive escherichia coli. Vol 2. 8th ed. Philadelphia, PA:

Elsevier Saunders; 2015.

Heiman KE et al. Notes from the field: Shigella with decreased susceptibility to azithromycin among men who

have sex with men—United States, 2002–2013. MMWR Morb Mortal Wkly Rep. 2014;63(6):132–133.

Kirkpatrick BD, Tribble DR. Update on human Campylobacter jejuni infections. Curr Opin Gastroenterol.

2011;27(1):1–7.

Ternhag A et al. A meta-analysis on the effects of antibiotic treatment on duration of symptoms caused by

infection with campylobacter species. Clin Infect Dis. 2007;44(5):696–700.

Epps SV et al. Foodborne Campylobacter: infections, metabolism, pathogenesis and reservoirs. Int J Environ Res

Public Health. 2013;10(12):6292–6304.

Acheson D, Allos BM. Campylobacter jejuni Infections: update on emerging issues and trends. Clin Infect Dis.

2001;32(8):1201–1206.

Ricotta EE et al. Epidemiology and antimicrobial resistance of international travel-associated Campylobacter

infections in the United States, 2005–2011. Am J Public Health. 2014;104(7):e108–e114.

Platts-Mills JA et al. Detection of Campylobacter in stool and determination of significance by culture, enzyme

immunoassay, and PCR in developing countries. J Clin Microbiol. 2014;52(4):1074–1080.

Ge B et al. Antimicrobial resistance in campylobacter: susceptibility testing methods and resistance trends. J

Microbiol Methods. 2013;95(1):57–67.

Allos BM. Campylobacter jejuni infections: update on emerging issues and trends. Clin Infect Dis. 2001;32:1201.

Kendall ME et al. Travel-associated enteric infections diagnosed after return to the United States, Foodborne

Diseases Active Surveillance Network (FoodNet), 2004–2009. Clin Infect Dis. 2012;54(Suppl 5):S480–S487.

Bomsztyk M, Arnold RW. Infections in travelers. Med Clin North Am. 2013;97(4):697–720, xi.

Dupont HL. Systematic review: the epidemiology and clinical features of travellers’ diarrhoea. Aliment

Pharmacol Ther. 2009;30(3):187–196.

Caeiro Juan P et al. Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of

Traveler’s diarrhea. Clin Infect Dis. 1999;28(6):1286–1289.

Advice for travelers. Med Lett Drugs Ther. 2015;57(1466):52–58.

Paredes-Paredes M et al. Advances in the treatment of Travelers’ diarrhea. Curr Gastroenterol Rep.

2011;13(5):402–407.

Riddle Mark S et al. Effect of adjunctive loperamide in combination with antibiotics on treatment outcomes in

Traveler’s diarrhea: a systematic review and meta analysis. Clin Infect Dis. 2008;47(8):1007–1014.

DuPont HL et al. Expert review of the evidence base for prevention of Travelers’ diarrhea. J Travel Med.

2009;16(3):149–160.

Infante RM et al. Enteroaggregative Escherichia coli diarrhea in travelers: response to rifaximin therapy. Clin

Gastroenterol Hepatol. 2004;2(2):135–138.

Steffen R et al. Therapy of travelers’ diarrhea with rifaximin on various continents. Am J Gastroenterol.

2003;98(5):1073–1078.

Adachi JA et al. Azithromycin found to be comparable to levofloxacin for the treatment of US Travelers with

acute diarrhea acquired in Mexico. Clin Infect Dis. 2003;37(9):1165–1171.

Taylor DN et al. A randomized, double-blind, multicenter study of rifaximin compared with placebo and with

ciprofloxacin in the treatment of travelers’ diarrhea. Am J Trop Med Hyg. 2006;74(6):1060–1066.

Dupont HL et al. Treatment of Travelers’ diarrhea: randomized trial comparing rifaximin, rifaximin plus

loperamide, and loperamide alone. Clin Gastroenterol Hepatol. 2007;5(4):451–456.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

Sanders JW et al. Azithromycin and loperamide are comparable to levofloxacin and loperamide for the

treatment of Traveler’s diarrhea in United States Military Personnel in Turkey. Clin Infect Dis. 2007;45(3):294–

301.