Bacterial Enteric Infections

Actualizado Reviewed

Epidemiology

HIV-associated alterations in mucosal immunity or intestinal integrity and treatment with acid-suppressive agents may increase the risk of enteric bacterial infections. Rates of Gram-negative bacterial enteric infections are at least 10 times higher among adults with HIV than in the general population, but these rates are lower among people with HIV who are treated with antiretroviral therapy (ART).1 The risk of bacterial diarrhea varies according to CD4 T lymphocyte (CD4) cell count and is greatest in individuals with clinical AIDS or CD4 counts <200 cells/mm3.

The bacteria most frequently isolated by culture from adults with HIV in the United States are Shigella, Campylobacter, and nontyphoidal Salmonella spp. (particularly Salmonella enterica serotypes Typhimurium and Enteritidis).1-6 Diarrheagenic Escherichia coli, particularly enteroaggregative E. coli, may contribute to the burden of diarrheal disease,7 but their role is understood poorly because reporting to public health systems is not required. Data on Helicobacter pylori infection in HIV infection are limited and do not suggest excess risk in people with HIV.8

Clostridioides difficile–associated infection (CDI) is common in people with HIV9; in addition to traditional risk factors, such as exposure to a health care facility or to antibiotics, data10 suggest that low CD4 count (<50 cells/mm3) is an independent risk factor. Incidence of community-onset CDI is increasing, and clinicians also should consider CDI in the evaluation of outpatient diarrheal illnesses in people with HIV.

Other enteric infections that may cause diarrhea—such as Mycobacterium avium complex (MAC), cytomegalovirus, and various protozoa—are discussed elsewhere in these guidelines.

As with bacterial enteric infections in people without HIV, the probable source for most bacterial enteric infections in people with HIV is ingestion of contaminated food or water.11 Sexual activity with the potential for direct or indirect fecal-oral exposure also increases risk of infections, especially with Shigella12 and Campylobacter.3,13-16

Clinical Manifestations

Three major clinical syndromes of infection are associated with Gram-negative enteric bacteria among people with HIV:

  • Self-limited gastroenteritis;
  • Severe and prolonged diarrheal disease, potentially associated with fever, bloody diarrhea, and weight loss; and
  • Bacteremia associated with extra-intestinal involvement, with or without concurrent or preceding gastrointestinal (GI) illness.6,17,18

Severe community-associated diarrhea often is defined as six or more loose stools (loose stool is defined as defecated material that takes the shape of a container) per day with or without other signs of systemic illness, such as fecal blood, orthostatic hypotension, or fever. In people with HIV, the risk of more profound illness increases with the degree of immunosuppression but risk diminishes with ART therapy.1,4,5,11,18,19 Relapses in infection with Salmonella and other Gram-negative bacterial enteric pathogens after appropriate treatment have been well documented in people with HIV.11,20,21 As in other populations, CDI can cause a variety of syndromes, from watery diarrhea to toxic megacolon.10

Although enteric pathogens can be associated with clinical proctitis (e.g., pain with defecation, tenesmus, bloody discharge),22 other infections that may be transmitted during intimate contact (e.g., Chlamydia trachomatis including lymphogranuloma venereum, Neisseria gonorrhoeae, herpes simplex virus, Treponema pallidum, and mpox) more commonly cause this syndrome, especially in those with relevant exposures (e.g., condomless receptive anal intercourse).23 Proctocolitis with diarrhea caused by STIs is less common but may occur; relevant exposures should be queried.24

Diagnosis

Assessment of patients with diarrhea should include a complete exposure history (i.e., ingestion of contaminated food or water, including through recreational exposure to water, sexual history or other fecal-oral exposures, animal/pet exposures, travel-related exposures, exposure to antibiotics or chemotherapies, use of acid-suppressing medications, recent hospitalization); a medication review, because diarrhea is a common side effect of some ART and antibiotics; quantification of the diarrheal illness by stool frequency, consistency, volume, duration, and presence of blood; and associated signs and symptoms, such as presence and duration of fever. Physical examination should include measurement of temperature and assessment of intravascular volume and nutritional status.

The diagnosis of Gram-negative bacterial enteric infection is established through cultures of stool and blood or stool molecular methods (i.e., culture-independent diagnostic tests [CIDTs]), ideally before antibiotics are given. Although stool molecular methods rapidly diagnose enteric infections, stool cultures are required to obtain phenotypic antibiotic sensitivity testing for isolated enteric pathogens and may also be helpful during outbreak investigations to identify the source. Thus, the Centers for Disease Control and Prevention (CDC) recommends reflex stool cultures and antibiotic sensitivity testing for specimens with positive CIDT reports given increasing resistance detected in enteric bacterial infections.25 Because incidence of bacteremia associated with Salmonella gastroenteritis is high in people with HIV—particularly those with advanced disease—blood cultures should be obtained from any patient who has diarrhea and fever. For shigellosis, blood cultures may be helpful but are less likely to be positive than in salmonellosis.18

Other infections for which people with HIV are at risk, albeit at a lower rate, are non-jejuni, non-coli Campylobacter spp.—such as C. fetus, C. upsaliensis, and C. lari—and the enterohepatic Helicobacter spp. (H. cineadi and H. fennelliae), which were described originally as Campylobacter spp. Blood culture systems typically will grow these bacteria, but they are unlikely to be identified on routine stool cultures performed by most laboratories because growing these fastidious organisms requires special stool culture conditions.

The diagnosis of CDI can be made only through careful selection of the correct population for testing and a correlation of clinical and laboratory findings. Populations at risk for C. difficile diarrhea include individuals who recently received or currently are receiving antibiotics (including antimicrobial prophylaxis) or cancer chemotherapy; those who have been hospitalized in the past 4 to 6 weeks (or currently are hospitalized); those who reside in a long-term care facility; those with CD4 counts <200 cells/mm3; those taking acid-suppressive medications; and those with moderate-to-severe community-acquired diarrhea.26 Only people with diarrhea (defined as three or more loose stools in 24 hours) should be tested for CDI to limit detection of asymptomatic colonization, and only stool samples that take the shape of the container (i.e., diarrheal) should be tested.27 Detection of either the C. difficile toxin B gene (using nucleic acid amplification testing [NAAT]) or the C. difficile toxin B protein (using an enzyme immunoassay [EIA]) is required for diagnosis. Current EIAs suffer from low sensitivity, whereas polymerase chain reaction (or PCR) assays have high sensitivity and can detect asymptomatic carriers. Glutamate dehydrogenase (GDH) antigen enzyme immunoassays, which detect an antigen common to C. difficile strains, whether or not toxigenic, must be combined with a second confirmatory test for stool C. difficile toxin B.28,29 Based on the criteria above (i.e., person meets the definition of diarrhea and the stool sample is diarrhea, taking the shape of the container), Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (or SHEA) guidelines for CDI support using an NAAT alone or a multiple-step algorithm (e.g., GDH plus toxin B assay) versus an EIA alone for C. difficile testing.29 

Endoscopy generally should be reserved for patients in whom stool culture, microscopy, C. difficile toxin B assay, and blood culture fail to reveal an etiology or in whom treatment for an established diagnosis fails. Endoscopy with biopsy may be required for diagnosing etiologies other than bacterial enteric infections—including cryptosporidiosis, microsporidiosis, cytomegalovirus, or MAC gastroenteritis—and noninfectious causes of GI symptoms.

Clinicians should remain alert to the possibility of sexually transmitted infections (STIs). In patients with relevant exposures and symptoms of proctitis or proctocolitis, diagnostic evaluation and treatment for STIs should are recommended.30

Preventing Exposure

Multiple epidemiologic exposures can place people at risk for enteric illnesses. The most common are ingestion of contaminated food or water and fecal-oral exposures. Providing advice and education about such exposures is the responsibility of the health care provider. The clinical condition and CD4 count of a person with HIV can help the provider determine what prevention recommendations are most appropriate. People with HIV with CD4 counts <200 cells/mm3 or a history of AIDS-defining illness31 are at the greatest risk of enteric illnesses; however, excess risk of undetermined magnitude or duration may persist in those with lesser degrees of immune impairment, including individuals treated with ART.

Individuals in the community should be advised to wash their hands regularly with soap and water or alcohol-based cleansers to reduce the risk of enteric infection (AIII). To prevent enteric infections, soap and water are preferred over alcohol-based cleansers, which do not kill C. difficile spores and are active only partially against norovirus and Cryptosporidium (AIII). People with HIV should be advised to wash their hands with soap and water after potential contact with human feces (e.g., through defecation, sexual exposures, cleaning feces from infants, contact with a person who has diarrhea), after handling pets or other animals, after gardening or other contact with soil, and before preparing food and eating (AIII). In addition to handwashing, use of barriers (e.g., condoms, dental dams, and gloves) can reduce exposure to feces when engaging in sex practices such as anal sex and oral-anal contact (AIII).22,30,32 Avoiding sex while any partner has diarrhea may further reduce risk of transmission. Travelers to relevant locations may be counseled on food and water hygiene (see the CDC Travelers’ Health webpage).33

Preventing Disease

Antimicrobial prophylaxis to prevent bacterial enteric illness is not routinely recommended, including for travelers (AIII). Prophylactic antimicrobial treatment can elicit adverse reactions, promote the emergence of resistant organisms, and increase the risk of CDI. In rare cases, however, antimicrobial prophylaxis (e.g., with rifaximin or azithromycin) should be considered—such as for immunosuppressed travelers, depending on their level of immunosuppression, the region of travel, and the trip’s duration (CIII).34,35 In addition, immunizations, (e.g., against Salmonella serotype Typhi), should be recommended in advance of travel to relevant locations (see Immunizations for Travel in the Immunizations section of the Adult and Adolescent Opportunistic Infection Guidelines) (AIII).

For people with HIV already taking trimethoprim-sulfamethoxazole (TMP-SMX) (e.g., for Pneumocystis jirovecii pneumonia prophylaxis), TMP-SMX may offer limited protection against traveler’s diarrhea.36 For pregnant people, azithromycin would be the preferred agent for prophylaxis (BIII). Clinicians should be aware of concerns about fluoroquinolone safety. Given increased recognition of fluoroquinolone toxicities, as well as increasing rates of antimicrobial resistance among enteric bacterial pathogens outside the United States, routine use of fluoroquinolones for prophylaxis is discouraged (AIII).37

Treating Disease

Empiric Therapy

In most situations, treatment of diarrheal disease in people with HIV does not differ significantly from that in immunocompetent individuals. Decisions on therapy are based on an assessment of diarrhea severity and hydration status. Patients should be informed of the importance of maintaining hydration and be given oral or intravenous (IV) rehydration, if indicated (AIII). Because diarrheal disease can produce temporary malabsorption or lactose intolerance, consuming a bland diet and avoiding fat, dairy, and complex carbohydrates are likely to be useful and are therefore recommended (BIII). The effectiveness and safety of probiotics or antimotility agents have not been studied adequately in people with HIV who have diarrheal illnesses.38 Antimotility agents should be avoided if concern about inflammatory diarrhea, including CDI, exists (BIII).

After obtaining stool samples for diagnostic evaluation, the initiation and duration of empiric antimicrobial therapy depend on the patient’s CD4 count and clinical appearance. If stool samples are obtained, antibiotic susceptibility testing should be performed to confirm and inform antibiotic choice. For example, in patients with CD4 counts >500 cells/mm3 who have had 1 to 2 days of loose stools without fever or blood, no further work-up and no treatment other than oral rehydration may be required. However, a short course of antibiotics (e.g., ciprofloxacin for 5 days [BIII]) may be indicated in people with HIV and CD4 counts of 200 to 500 cells/mm3 who have diarrhea severe enough to compromise quality of life or ability to work. Patients with severe disease (advanced HIV disease [i.e., CD4 counts <200 cells/mm3 or concomitant AIDS-defining illness] and clinically severe diarrhea [i.e., ≥6 liquid stools per day or bloody stools or a lower number of liquid stools per day but accompanied by fever or chills concerning for invasive bacterial disease]) should undergo inpatient diagnostic evaluation to determine the etiology of the diarrheal illness and receive parenteral antimicrobial treatment (AIII). In stable patients, empiric therapy with oral ciprofloxacin (BIII) or azithromycin (BIII) is recommended, particularly if the infection is not associated with international travel. However, even in the United States, all patients should have careful follow-up since rates of resistance to ciprofloxacin and (to a lesser extent) azithromycin in common enteric pathogens are substantial, and therefore treatment failure may occur. In patients with severe disease, treatment with empiric IV ceftriaxone is recommended until antimicrobial susceptibility results are available (BIII). Given the rise of antimicrobial resistance in enteric pathogens, however, updated outbreak information, local susceptibility patterns and travel history always should be considered. For example, if Campylobacter or Shigella bacteremia is suspected, a carbapenem is preferred for empiric therapy (BIII).

Therapy should be adjusted based on the results of the diagnostic work-up. For diarrhea that is persistent (i.e., lasting >14 days) in the absence of other clinical signs of severity—such as bloody stool or dehydration—antibiotic therapy can be withheld and directed therapy initiated once a diagnosis is confirmed. Noninfectious etiologies of persistent diarrhea (e.g., inflammatory bowel disease) also should be considered in the differential diagnosis (BIII).

International travel: Diarrhea is one of the most common illnesses affecting international travelers. Antimicrobial resistance among enteric bacterial pathogens outside the United States is an important public health problem. For example, traveler’s diarrhea caused by fluoroquinolone-resistant C. jejuni in South and Southeast Asia or Africa is common.39,40 Clinicians should consider the possibility of a resistant infection when prescribing empiric therapy for travelers with HIV who experience diarrhea or a syndrome consistent with a systemic infection while traveling or upon returning to the United States, given reports of multidrug-resistant Enterobacteriaceae acquisition during travel.41-45

Pathogen-Specific Therapy

Nontyphoidal Salmonella Species

Immunocompetent hosts who do not have HIV often do not require antibiotic treatment for Salmonella gastroenteritis (typically caused by nontyphoidal Salmonella spp.) because the condition is usually self-limited, and treatment may prolong the carrier state. In contrast, all people with HIV and salmonellosis should be treated (AIII), even though no clinical trials have compared antimicrobial therapy with placebo. Notably, HIV infection increases the risk of Salmonella bacteremia 20 to 100 times and mortality as much as seven times compared to people who do not have HIV.19,46

The treatment of choice for susceptible nontyphoidal Salmonella spp. infection is a fluoroquinolone (AIII). Ciprofloxacin is the preferred agent (AIII).47 Other fluoroquinolones—such as levofloxacin and moxifloxacin are recommended as alternatives to ciprofloxacin (BIII). Although they have not been well evaluated in clinical trials, they likely would be effective in treating salmonellosis in people with HIV. Depending on antibiotic susceptibility, alternatives to the fluoroquinolones include TMP-SMX or expanded-spectrum cephalosporins, such as ceftriaxone (BIII). Fluoroquinolone resistance in nontyphoidal Salmonella spp. appears to be increasing, with preliminary CDC data showing genetic markers of fluoroquinolone resistance among 19% of 20,831 nontyphoidal Salmonella spp. isolates tested in the United States in 2023.48 In agreement with IDSA guidelines, the Panel recommends ceftriaxone over ciprofloxacin if invasive disease is suspected or confirmed, at least until susceptibilities return (BIII).47,48

The optimal duration of therapy for HIV-related nontyphoidal Salmonella infection has not been defined. For patients with CD4 counts ≥200 cells/mm3 who have mild gastroenteritis without bacteremia, 7 to 14 days of treatment is recommended (BIII). For the same patients with bacteremia, 14 days is appropriate provided clearance of bacteremia is documented. Longer treatment is recommended if bacteremia persists or if the infection is complicated (i.e., if metastatic foci are present) (BIII). For any patients with advanced HIV disease (CD4 count <200 cells/mm3) and Salmonella infection, a minimum of 2 weeks with extension up to 6 weeks of antibiotics in severe disease or bacteremia is often recommended (BIII).49

People with HIV and Salmonella bacteremia, which typically occurs in those with advanced HIV disease, should be monitored clinically for recurrence after treatment (BIII). As people with HIV age, it is also important to remember that rates of invasive Salmonella infections increase with age in each age group beyond infancy.50,51 Recurrence may present as bacteremia or as an anatomically localized infection, including intraabdominal, endothelial, urinary tract, soft tissue, bone and joint, lung, or meningeal foci. Secondary prophylaxis should be considered for patients with recurrent Salmonella bacteremia (BIII), and it also might be considered for patients with recurrent gastroenteritis (with or without bacteremia), and in those with CD4 counts <200 cells/mm3 with severe diarrhea (BIII). The value of this secondary prophylaxis has not been established and must be weighed against the risks of long-term antibiotic exposure. Recurrent Salmonella bacteremia constitutes an AIDS-defining illness,31 and HIV suppression with ART appears to decrease the risk of recurrent illnesses.

In patients whose Salmonella infection is resolved and who have responded to ART with sustained viral suppression and CD4 counts >200 cells/mm3, secondary prophylaxis for salmonellosis likely can be discontinued (CII). Clinicians also should be aware that recurrence may indicate development of antimicrobial resistance during therapy.

Shigella Species

Therapy for Shigella infections should be considered because it may slightly shorten the duration of illness and help prevent transmission to others (AIII); however, because antimicrobial resistance of Shigella spp. is increasing and limited data demonstrate that antibiotic therapy limits transmission, antibiotic treatment may be withheld in people with HIV and CD4 >500 cells/mm3 with mild symptoms or whose diarrhea is resolving before culture confirmation of Shigella infection (CIII). When treatment is offered, antibiotic selection should be guided by the results of antibiotic susceptibility testing.43,52-55

Preferred treatment for susceptible shigellosis is a fluoroquinolone, preferably ciprofloxacin, for 5 to 10 days (AIII) with levofloxacin serving as an alternative (BIII). Importantly, preliminary CDC data estimate 60% of Shigella spp. isolated among the general U.S. population in 2023 harbored genetic markers of resistance to ciprofloxacin, and 55% of such isolates tested in 2022 had a ciprofloxacin minimum inhibitory concentration (MIC) of ≥0.12 µg/mL.48 Although current Clinical and Laboratory Standards Institute criteria categorize Shigella isolates with a ciprofloxacin MIC of 0.12 and 0.25 µg/mL as susceptible and a MIC of 0.5 µg/mL as intermediate, these isolates typically harbor a fluoroquinolone resistance gene or mutation. Until the clinical significance of these findings can be determined, alternative antibiotics should be considered to treat patients whose isolates have ciprofloxacin MICs ≥0.12 µg/mL (BIII).56 In general, automated antimicrobial susceptibility test panels do not have doubling dilutions that span the MIC range to determine susceptibility to ciprofloxacin based on the CDC recommendation of ≤0.06. As such, a clinically validated manual antimicrobial susceptibility testing method such as reference broth microdilution or a gradient diffusion method would be required to confirm susceptibility at the lower MIC range. Ciprofloxacin-resistant S. sonnei and S. flexneri infections in the United States are associated with international travel, homelessness, and men who have sex with men (MSM); ciprofloxacin-resistant shigellosis among MSM appears to be acquired predominantly within the United States, rather than during travel.43

Depending on antibiotic susceptibilities, in stable patients without concern for bacteremia, azithromycin (5 days) or TMP-SMX (5–7 days) may be alternatives (BIII). Azithromycin has not been evaluated in people with HIV and shigellosis, and the therapy suggested is extrapolated from limited data in immunocompetent hosts.56 Azithromycin susceptibility testing is not widely available in clinical laboratories but can be performed by many state public health laboratories. Preliminary CDC data estimate 34% of Shigella spp. isolated among the general U.S. population in 2023 harbored genetic markers of resistance to azithromycin.48 Azithromycin-resistant Shigella spp. infections in MSM with HIV have been reported.57-59

Multidrug resistance is common among shigellae, and clinicians should be aware that rates of infections caused by extensively drug resistant Shigella strains (strains resistant to azithromycin, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and ampicillin) are increasing in the United States.60 Therefore, while IV ceftriaxone is recommended therapy for susceptible Shigella, in severely ill people requiring empiric parenteral therapy, carbapenems can be initiated before antimicrobial susceptibilities are available (BIII).

Treatment for people with Shigella bacteremia is less well defined but extending treatment to at least 14 days is recommended (BIII). Azithromycin is not recommended for treatment of Shigella spp. bacteremia (AIII). Chronic suppressive or maintenance therapy is not recommended for first-time Shigella infections (BIII). Recurrent infections can occur, particularly in individuals with CD4 counts <200 cells/mm3, in which case, extending antimicrobial therapy for up to 6 weeks is recommended (BIII). Because of Shigella’s extremely low infectious dose, patients with shigellosis should be counseled about transmission prevention. As with Salmonella infections, suppression of HIV replication with ART is expected to decrease the risk of recurrent shigellosis.

Campylobacter Species

The optimal treatment of campylobacteriosis in people with HIV is poorly defined and multidrug resistance might occur.61,62 Culture and testing for the antibiotic susceptibility of Campylobacter isolates is recommended (BIII). In the United States in 2018, 29% of C. jejuni isolates were resistant to ciprofloxacin, and 2% were resistant to azithromycin; among C. coli isolates, 41% of isolates were resistant to fluoroquinolones, and 13% were resistant to azithromycin.48

For people with mild disease and CD4 counts >200 cells/mm3, therapy should be withheld unless symptoms persist for more than several days (CIII). For mild-to-moderate campylobacteriosis, initiating therapy with azithromycin for 5 days or a fluoroquinolone—such as ciprofloxacin—for 7 to 10 days (if the organism is sensitive) is recommended (BIII). Azithromycin has not been evaluated in people with HIV and campylobacteriosis, and the therapy suggested is extrapolated from limited data in immunocompetent hosts.39 Azithromycin susceptibility testing, however, is not widely available in clinical laboratories but can be performed by many state public health laboratories. Campylobacter bacteremia should be treated for at least 14 days using a fluoroquinolone if the isolate is sensitive (BIII).63 Adding a second active agent—such as an aminoglycoside—may be prudent in patients with bacteremia to limit the emergence of antibiotic resistance (BIII). Third generation cephalosporins are not reliably active and use of alternative cell-wall active agents such as carbapenems may be necessary in severely ill people requiring empiric parenteral therapy until antimicrobial susceptibilities return. Antibiotic choice should be guided by antibiotic susceptibility tests. Azithromycin is not recommended for treatment of Campylobacter bacteremia (AIII). Chronic suppressive or maintenance therapy is not recommended for first-time Campylobacter infections in people with HIV (BIII). However, recurrent infections can occur, particularly in people with CD4 counts <200 cells/mm3. In recurrent disease, extending the length of antimicrobial therapy for 2 to 6 weeks is reasonable (BIII). As with Salmonella infections, suppression of HIV replication with ART is expected to decrease the risk of recurrent Campylobacter spp. infections.64

Clostridioides difficile

No randomized controlled trials have been conducted for CDI therapy in people with HIV. Available data suggest that people with HIV respond to treatment of CDI similarly to people without HIV.9 Thus, treatment of CDI in people with HIV is the same as in people without HIV. Guidelines and subsequent updates for treatment of CDI have been published29,65 and should be consulted for further information.

Treatment of an Initial Episode of Clostridioides difficile–Associated Infection

Four randomized clinical trials all conducted in the general population (two identical studies with ~60% hospitalized patients; two studies restricted to hospitalized patients)66-69 have revealed that, when compared to oral vancomycin, fidaxomicin increased the likelihood of a sustained clinical response of CDI (at 28 days) in the initial therapy of CDI (relative risk [RR] 1.16; 95% confidence interval [CI], 1.09–1.24).65 Fidaxomicin was equivalent to oral vancomycin in initial clinical cure, serious adverse events and all-cause mortality. Given these data, the 2021 IDSA CDI Clinical Practice Guideline update65 for adults suggests treatment with fidaxomicin rather than oral vancomycin, for initial CDI whether CDI is severe or nonsevere. Fidaxomicin remains very expensive but should be considered in people with HIV and CDI, if available (AI). Oral vancomycin is also an acceptable option for initial CDI (AI). Earlier multicenter, randomized, double-blind studies identified that oral vancomycin is superior to metronidazole for treatment of CDI.70,71 Thus, metronidazole is to be considered as an alternative drug for CDI therapy only if fidaxomicin or vancomycin are unavailable and CDI is nonsevere (white blood cell count <15,000 cells/mL and serum creatinine concentrations <1.5 mg/dL) (CI).29

Treatment of Recurrent Clostridioides difficile–Associated Infection

Treatment of recurrent CDI is complex and, in part, defined by the specific circumstances of the patient with recurrent CDI and the number of prior CDI episodes. Brief guidance is provided here; the 2017 and 2021 IDSA CDI guidelines should be consulted for a full discussion of this topic.29,65 Risk factors for CDI recurrence are age ≥65 years, history of CDI, compromised immunity, severe CDI, and certain virulent strains (ribotypes 027/078/244). Similar to an initial episode of CDI and also based on the randomized clinical trials cited above,66-69 the Panel recommends administering fidaxomicin, instead of oral vancomycin, to adults with recurrent CDI (AI), consistent with the 2021 IDSA CDI Clinical Practice Guideline update.65 Fidaxomicin therapy increased the likelihood of a sustained clinical response for recurrent CDI at 30 days (RR 1.27; 95% CI, 1.05–1.54). For treatment of an initial CDI recurrence, fidaxomicin was equivalent to oral vancomycin in initial clinical cure, serious adverse events, and all-cause mortality. Vancomycin is also an acceptable option for recurrent CDI (see the IDSA Guideline for tapered and pulsed regimens) (AI).

Bezlotoxumab is a humanized monoclonal antibody against C. difficile toxin B approved for prevention of recurrent CDI in high-risk adults when used in conjunction with standard-of-care (SOC) antibiotic therapy. The 2021 IDSA CDI Clinical Practice Guideline update suggests use of bezlotoxumab as a cointervention along with vancomycin as the SOC antibiotic in patients with a history of CDI in the last 6 months or other risk factors for recurrence (i.e., age ≥65 years, compromised immunity, severe CDI, or certain virulent strains (ribotypes 027/078/244).65 However, data on the benefit of bezlotoxumab therapy when fidaxomicin is used as the SOC antibiotic are limited. Limited case reports suggest that fecal microbiota therapy (FMT) (i.e., fecal transplant) may be successful and safe to treat recurrent CDI in people with HIV.72-74 However, it is important to note that complications of FMT, including transmission of enteric pathogens and antibiotic-resistant bacteria with deaths, have been reported.75,76 FMT for treatment of recurrent CDI may be considered after three total CDI episodes (initial and two recurrent CDI episodes) (CIII).29,65 The effect of ART on recurrence of CDI is unknown, but ART initiation should follow standard guidelines, similar to other enteric infections (see the Special Considerations Regarding ART Initiation section below).

Special Considerations Regarding ART Initiation

ART initiation should follow standard guidelines. The presence of an enteric infection should not delay ART initiation (AIII). The presence of a diarrheal illness is relevant only in terms of a patient’s ability to ingest and absorb ART. If recurrent enteric infections are documented or Salmonella bacteremia occurs, prompt initiation of ART should be considered regardless of CD4 count.

Monitoring of Response to Therapy and Adverse Events (Including Immune Reconstitution Inflammatory Syndrome)

Patients should be monitored closely for response to treatment, defined clinically by improvement in systemic signs and symptoms, resolution of diarrhea, and sterilization of infected tissues or body fluids, such as blood. Follow-up stool testing may be required when public health considerations and state policies dictate the need to ensure micro¬biologic cure, such as in health care or food service workers. Follow-up stool culture and antibiotic susceptibility testing should be considered for patients with incomplete clinical response to appropriate antimicrobial therapy. In patients with persistent or recurrent diarrhea despite therapy, clinicians should consider other enteric infections (including STIs; see the Diagnosis section above) in the context of the patient’s immune status and exposures, as well as the possibility of C. difficile or the development of antimicrobial resistance (BIII).

Observational studies suggest that plasma drug concentrations in people with HIV may be decreased as a result of severe diarrhea or malabsorption.77,78 Coadministration of fluoroquinolones with magnesium- or aluminum-containing antacids or with calcium, zinc, or iron should be avoided because these agents interfere with fluoroquinolone absorption (AII).79 Although larger prospective studies are needed to determine the impact of severe diarrhea on antibiotic absorption, it is prudent to use IV antibiotics in clinically unstable patients (AIII).

Immune reconstitution inflammatory syndrome has not been described in association with treatment for typical bacterial enteric pathogens.

Preventing Recurrence

The pharmacologic approach to recurrent enteric infections is covered in the section on directed therapy for each bacterial species. As noted above, secondary prophylaxis should be considered for patients with recurrent Salmonella bacteremia (BIII) and, in some circumstances, for those with recurrent shigellosis (BIII) or campylobacteriosis (BIII).

Special Considerations During Pregnancy

The diagnosis of bacterial enteric infection in pregnant people with HIV is the same as in people who are not pregnant and should be managed the same, with several considerations. Based on their safety profile, expanded-spectrum cephalosporins or azithromycin should be the first-line therapy for bacterial enteric infections during pregnancy if antimicrobials are required, depending on the organism and the results of susceptibility testing (BIII).80 Arthropathy has been noted in the offspring of animals treated with quinolones during pregnancy. However, studies evaluating quinolone use in pregnant people did not find an increased risk of birth defects or musculoskeletal abnormalities.81-83 Thus, quinolones can be used for bacterial enteric infections in pregnant people with HIV if indicated by susceptibility testing or failure of first-line therapy, as listed above with a shared medical decision-making decision model in discussion with the patient (BIII). TMP-SMX use in the first trimester should be avoided, if possible, because of an association with an increased risk of birth defects, specifically neural tube, cardiovascular, and urinary tract defects (BIII).84-86 However, a review of potential risks related to TMP-SMX use cites the low quality of current data and supports the use of TMP-SMX in pregnant people with HIV as clinically indicated.87 Clinicians should consider giving supplemental folic acid 4 mg/day to people who are on TMP-SMX if they are capable of becoming pregnant prior to pregnancy or as soon as possible in their first trimester (BIII).84,85,88 Neonatal care providers should be informed if maternal sulfa therapy was used near delivery because of the theoretical increased risk of hyperbilirubinemia and kernicterus in the newborn. Because oral rifaximin and fidaxomicin are not absorbed systemically, these can be used in pregnancy as in nonpregnant individuals. However, pregnant people should have a shared medical decision with their providers and be made aware about the limited data about Fidaxomicin in pregnancy (BIII).

Vancomycin and metronidazole are two antimicrobials that have been utilized in the perinatal period in the United States. Intravenous vancomycin has been utilized as intrapartum prophylaxis in the penicillin allergic patient colonized with group B streptococcus,89 and minimal absorption is expected with oral therapy. Although vancomycin for enteric disease is recommended for use only in its oral formulation, which is not absorbed in meaningful concentrations from the gastrointestinal tract,90 it should be noted that with intravenous use, vancomycin readily crosses the placenta.91 A study of 10 infants evaluated after the second or third trimester for in utero exposure of maternal intravenous vancomycin therapy for serious staphylococcal infections found no hearing loss or renal toxicity attributed to vancomycin.91 A review of metronidazole use in pregnancy for treatment of trichomoniasis or bacterial vaginosis found no increase in risk of birth defects.92 Studies on the use of metronidazole for CDI in pregnancy were not found.

References

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