Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Incidence rates of gram-negative bacterial enteric infections are 20- to 100-fold higher among HIV-infected adults than in the general population (488Celum CL, Chaisson RE, Rutherford GW, et al. Incidence of salmonellosis in patients with AIDS. J Infect Dis 1987;156:998-1002., 489Sorvillo FJ, Lieb L, Waterman SH. Incidence of campylobacteriosis among patients with AIDS in Los Angeles County. J Acquir Immune Defic Syndr 1991;4:598-602., 490Angulo FJ, Swerdlow DL. Bacterial enteric infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21(Suppl 1):S84-93., 491Nelson MR, Shanson DC, Hawkins DA, Gazzard BG. Salmonella, campylobacter and shigella in HIV-seropositive patients. AIDS 1992;6:1495-8., 492Sanchez TH, Brooks JT, Sullivan PS, et al. Bacterial diarrhea in persons with HIV infection, United States, 1992-2002. Clin Infect Dis 2005;41:1621-7.). The most common causes among adults in the United States are Salmonella (particularly Salmonella serotypes Typhimurium and Enteritidis), Shigella, and Campylobacter. As with non-HIV-associated bacterial enteric infections, the probable source for most HIV-infected associated infections is ingestion of contaminated food or water (490Angulo FJ, Swerdlow DL. Bacterial enteric infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21(Suppl 1):S84-93.). Sexual activity with the potential for fecal-oral exposure also increases risk for infections, especially with Shigella (493Aragon TJ, Vugia DJ, Shallow S, et al. Case-control study of shigellosis in San Francisco: the role of sexual transmission and HIV infection. Clin Infect Dis 2007;44:327-34.) and Campylobacter (494Quinn TC, Goodell SE, Fennell C, et al. Infections with Campylobacter jejuni and Campylobacter-like organisms in homosexual men. Ann Intern Med 1984;101:187-92.). Acquisition of enteric bacterial infections might be facilitated by HIV-associated gastric achlorhydria, by treatment with agents that decrease gastric acid secretion, and by HIV-associated alterations in mucosal immunity. Although diarrheagenic Escherichia coli, especially enteroaggregative E. coli, are a frequent cause of diarrhea among HIV-infected persons in resource-limited settings, they do not appear to cause more morbidity in HIV-infected patients than in other persons in more developed regions (495Huang DB, Mohanty A, DuPont HL, Okhuysen PC, Chiang T. A review of an emerging enteric pathogen: enteroaggregative Escherichia coli. J Med Microbiol 2006; 55:1303-11.).

The three major clinical syndromes of infection with gram-negative enteric bacteria among HIV-infected patients include the following:

• Self-limited gastroenteritis;
• A more severe and prolonged diarrheal disease, associated with fever, bloody diarrhea, weight loss, and possible bacteremia (bloody diarrhea is more frequent with Shigella but also can occur with Campylobacter or Salmonella (496Baer JT, Vugia DJ, Reingold AL, et al. HIV infection as a risk factor for shigellosis. Emerg Infect Dis 1999;5:820-3., 497Kristjansson M, Viner B, Maslow JN. Polymicrobial and recurrent bacteremia with Shigella in a patient with AIDS. Scand J Infect Dis 1994;26:411-6.); and
• Septicemia, which can exhibit extra-intestinal involvement with or without concurrent or preceding gastrointestinal illness (498Snijders F, Kuijper EJ, de Wever B, et al. Prevalence of Campylobacter-associated diarrhea among patients infected with human immunodeficiency virus. Clin Infect Dis 1997;24:1107-13., 499Tee W, Mijch A. Campylobacter jejuni bacteremia in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients: comparison of clinical features and review. Clin Infect Dis 1998;26:91-6., 500Tee W, Mijch A, Wright E, Yung A. Emergence of multidrug resistance in Campylobacter jejuni isolates from three patients infected with human immunodeficiency virus. Clin Infect Dis 1995;21:634-8., 501Meier PA, Dooley DP, Jorgensen JH,et al. Development of quinolone-resistant Campylobacter fetus bacteremia in human immunodeficiency virus-infected patients. J Infect Dis 1998;177:951-4.).

The risk for more profound illness increases with the degree of immunosuppression (488Celum CL, Chaisson RE, Rutherford GW, et al. Incidence of salmonellosis in patients with AIDS. J Infect Dis 1987;156:998-1002., 490Angulo FJ, Swerdlow DL. Bacterial enteric infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21(Suppl 1):S84-93., 491Nelson MR, Shanson DC, Hawkins DA, Gazzard BG. Salmonella, campylobacter and shigella in HIV-seropositive patients. AIDS 1992;6:1495-8., 502Casado JL, Valdezate S, Calderon C, et al. Zidovudine therapy protects against Salmonella bacteremia recurrence in human immunodeficiency virus-infected patients. J Infect Dis 1999;179:1553-6.). Relapses in infections with Salmonella and other gram-negative bacterial enteric pathogens after appropriate treatment have been well-documented in HIV-infected patients (497Kristjansson M, Viner B, Maslow JN. Polymicrobial and recurrent bacteremia with Shigella in a patient with AIDS. Scand J Infect Dis 1994;26:411-6., 503Mayer KH, Hanson E. Recurrent Salmonella infection with a single strain in the acquired immunodeficiency syndrome: confirmation by plasmid fingerprinting. Diagn Microbiol Infect Dis 1986;4:71-6., 504Rubino S, Spanu L, Mannazzu M, et al. Molecular typing of non-typhoid Salmonella strains isolated from HIV-infected patients with recurrent salmonellosis. AIDS 1999;13:137-9.). Salmonella is a particularly common cause of septicemia, which is prone to relapse. Recurrent Salmonella septicemia constitutes an AIDS-defining illness and might require chronic suppressive therapy (488Celum CL, Chaisson RE, Rutherford GW, et al. Incidence of salmonellosis in patients with AIDS. J Infect Dis 1987;156:998-1002.). The development of antimicrobial resistance during therapy, often associated with clinical deterioration or relapse, can also occur among HIV-infected persons with gram-negative enteridities (500Tee W, Mijch A, Wright E, Yung A. Emergence of multidrug resistance in Campylobacter jejuni isolates from three patients infected with human immunodeficiency virus. Clin Infect Dis 1995;21:634-8., 501Meier PA, Dooley DP, Jorgensen JH,et al. Development of quinolone-resistant Campylobacter fetus bacteremia in human immunodeficiency virus-infected patients. J Infect Dis 1998;177:951-4.).

The diagnosis of gram-negative bacterial enteric infection is established through cultures of stool and blood. Because of the high rate of bacteremia associated with Salmonella gastroenteritis in HIV-infected patients, in particular patients with advanced disease, blood cultures should be obtained from any patient with diarrhea and fever.

HIV-infected persons are notably at risk for infection with non-jejuni non-coli Campylobacter species, including C. fetus, C. upsaliensis, C. lari, and the enterohepatic Helicobacter species, H. cineadi, and H. fennelliae (originally described as Campylobacter species). Although blood culture systems will typically grow these bacteria, routine stool cultures performed by most laboratories will fail to identify these more fastidious organisms, which require special conditions for stool culture. Clinicians might wish to notify their clinical laboratory service of a patient's HIV status and to consider evaluation of stool specimens for non-jejuni non-coli Campylobacter if initial microbiological evaluation is unrevealing. Endoscopy can be diagnostically useful. If lower endoscopy is performed, ulcerations similar to those seen with CMV colitis might be evident and can only be distinguished through histopathologic examination and culture. Clinicians should notify their microbiology laboratories if they suspect infection with diarrheagenic E. coli so that appropriate molecular diagnostic methods can be used or the specimen can be sent to a reference laboratory.

Scrupulous handwashing can reduce risk for diarrhea in HIV-infected persons, including diarrhea caused by enteric bacteria (242Huang DB, Zhou J. Effect of intensive handwashing in the prevention of diarrhoeal illness among patients with AIDS: a randomized controlled study. J Med Microbiol 2007;56:659-63.). HIV-infected persons should be advised to wash their hands after potential contact with human feces (e.g., defecation, cleaning feces from infants), after handling pets or other animals, after gardening or other contact with soil, before preparing food, before eating, and before and after sex (AIII). HIV-infected persons should avoid unprotected sex practices that might result in oral exposure to feces (e.g., anal sex, oral-anal contact) and in addition to hand-washing they should be advised to use barriers during sex to reduce exposures when possible (e.g., condoms, dental dams) (AIII).

Food

Health-care providers should advise HIV-infected persons, particularly those with a CD4+ count <200 cells/µL, not to eat raw or undercooked eggs, including specific foods that might contain raw eggs (e.g., certain preparations of hollandaise sauce, Caesar and other salad dressings, certain mayonnaises (e.g., homemade), uncooked cookie and cake batter, and eggnog); raw or undercooked poultry, meat, and seafood (raw shellfish in particular); unpasteurized dairy products; unpasteurized fruit juices; and raw seed sprouts (e.g., alfalfa sprouts or mung bean sprouts) (BIII). Poultry and meat are safest when adequate cooking is confirmed by thermometer (i.e., internal temperature of 180° F (82° C) for poultry and 165° F (74° C) for red meats). If a thermometer is not used when cooking meats, the risk for illness is decreased by eating poultry and meat that have no trace of pink color. However, color change of the meat (e.g., absence of pink) does not always correlate with internal temperature. Produce should be washed thoroughly before being eaten (BIII). Health-care providers should advise HIV-infected persons to avoid cross-contamination of foods. Uncooked meats, including hot dogs, and their juices should not come into contact with other foods (BIII). Hands, cutting boards, counters, knives, and other utensils should be washed thoroughly after contact with uncooked foods (BIII). Health-care providers should advise HIV-infected persons that, although the incidence of listeriosis is low, it is a serious disease that occurs with unusually high frequency among severely immunosuppressed HIV-infected persons. Immunosuppressed, HIV-infected persons who wish to reduce the risk for acquiring listeriosis should adhere to the following precautions (CIII): Avoid soft cheeses (e.g., feta, Brie, Camembert, blue-veined, and Mexican-style cheese such as queso fresco); hard cheeses, processed cheeses, cream cheese (including slices and spreads), cottage cheese, or yogurt need not be avoided. Cook leftover foods or ready-to-eat foods (e.g., hot dogs) until steaming hot before eating. Avoid foods from delicatessen counters (e.g., prepared salads, meats, cheeses) or heat/reheat these foods until steaming before eating. Avoid refrigerated pâtés and other meat spreads or heat/reheat these foods until steaming; canned or shelf-stable pâté and meat spreads need not be avoided. Avoid raw or unpasteurized milk (including goat's milk) or milk products or foods that contain unpasteurized milk or milk products.

Pets

HIV-infected persons should avoid direct contact with stool from new pets, dogs or cats aged <6 months, or stray pets (BIII). Gloves should always be worn when handling feces or cleaning areas that might have been contaminated by feces from pets (BIII). Persons should avoid or limit contact with reptiles (e.g., snakes, lizards, iguanas, and turtles) and chicks and ducklings because of the risk for salmonellosis (BIII).

Travel

The risk for foodborne and waterborne infections among immunosuppressed, HIV-infected persons is magnified during travel to economically developing countries. Persons who travel to such countries should avoid foods and beverages that might be contaminated, including raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made with tap water, unpasteurized milk and dairy products, and items sold by street vendors (AII). Foods and beverages that are usually safe include steaming hot foods, fruits that are peeled by the traveler, bottled (including carbonated) beverages, hot coffee and tea, beer, wine, and water that is brought to a rolling boil for 1 minute. Treating water with iodine or chlorine might not be as effective as boiling and will not prevent infection with Cryptosporidium but can be used when boiling is not practical (BIII).

Prophylactic antimicrobial agents are not usually recommended for travelers (DIII). The effectiveness of these agents depends on gastrointestinal pathogens' local antimicrobial resistance patterns, which are seldom known. Moreover, these agents can elicit adverse reactions, promote the emergence of resistant organisms, and increase risk for enteric Clostridium difficile infection. However, for HIV-infected travelers, antimicrobial prophylaxis can be considered, depending on the level of immunosuppression and the region and duration of travel (CIII). Use of fluoroquinolones or rifaximin can be considered when prophylaxis is deemed necessary (CIII). As an alternative (e.g., for pregnant women and persons already taking TMP-SMX for PCP prophylaxis), TMP-SMX might offer limited protection against traveler's diarrhea (BIII). Risk for toxicity should be considered before treatment with TMP-SMX is initiated solely because of travel.

Immunocompetent hosts without HIV infection often do not require treatment for Salmonella gastroenteritis; the condition is self-limited and treatment might prolong the carrier state. However, no treatment trials have examined the strategy of watchful waiting for spontaneous resolution among patients with HIV infection, and the risk for bacteremia is sufficiently high that most specialists recommend treatment of all HIV-associated Salmonella infections (BIII).

The initial treatment of choice for Salmonella infection is a fluoroquinolone (AIII) (505Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331-51.). Ciprofloxacin is the preferred agent (AIII) (505Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331-51.); other fluoroquinolones (levofloxacin and moxifloxacin) also would likely be effective in treatment of salmonellosis among HIV-infected persons, but these agents have not been well-evaluated in clinical studies (BIII). Depending on antibiotic susceptibility, alternatives to the fluoroquinolones might include TMP-SMX or expanded spectrum cephalosporins (e.g., ceftriaxone or cefotaxime) (BIII).

The length of therapy for HIV-related Salmonella infection is poorly defined. For patients with CD4⁺ counts ≥200 cells/µL and mild gastroenteritis, with or without bacteremia, 7-14 days of treatment for salmonellosis is reasonable (BIII); among patients with advanced HIV disease (CD4⁺ count <200 cells/µL), a longer course of antibiotics (e.g., 2-6 weeks) is often recommended (CIII).

Therapy for shigellosis is indicated both to shorten the duration of illness and to prevent spread of the infection to others (AIII) (505Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331-51.). The recommended treatment is with a fluoroquinolone for 3-7 days (AIII). Depending on antibiotic susceptibilities, alternatives to this treatment may include TMP-SMX for 3-7 days or azithromycin for 5 days (BIII). Cases of shigellosis acquired internationally have high rates of TMP-SMX resistance; in addition, HIV-infected persons have higher rates of adverse effects related to this agent. As a result, fluoroquinolones are preferred as first-line treatment. Treating patients who have Shigella bacteremia is less well defined. Depending on the severity of infection, extending treatment to 14 days is reasonable, using the agents described previously (BIII).

As with non-HIV-infected patients, the optimal treatment of campylobacteriosis among persons with HIV infection is poorly defined. Among patients with mild disease, some clinicians might opt to withhold therapy unless symptoms persist for more than several days. Increasing resistance to fluoroquinolones makes the choice of therapy especially problematic. For mild-to-moderate campylobacteriosis, initiating therapy with a fluoroquinolone (e.g., ciprofloxacin) or a macrolide (e.g., azithromycin), pending susceptibility test results, and treating for 7 days is a reasonable approach (BIII). Patients with bacteremia should be treated for ≥2 weeks (BIII), and adding a second active agent (e.g., an aminoglycoside) might be prudent (CIII).

Patients should be monitored closely for response to treatment, as defined clinically by improvement in systemic signs and symptoms and resolution of diarrhea. A follow-up stool culture to demonstrate clearance of the organism is not generally required if a complete clinical response has been demonstrated, but should be considered for those patients who fail to respond clinically to appropriate antimicrobial therapy or when public health considerations dictate the need to ensure microbiologic cure (e.g., health-care or food service workers). If after a diagnosis of gram-negative bacterial enteritis and diarrhea ersists or recurs after intervention, other enteric infections should be considered, particularly Clostridium difficile.

IRIS has not been described in association with treatment for bacterial enteric diarrhea.

Treatment failure is defined by the lack of improvement in clinical signs and symptoms of diarrheal illness and the persistence of organisms in stool, blood, or other relevant body fluids or tissue after completion of appropriate antimicrobial therapy for the recommended duration. Some patients with Salmonella bacteremia might remain febrile for 5-7 days despite effective therapy. Therefore, careful observation is required to determine the adequacy of the response.

Treatment should be guided by drug susceptibility testing of isolates recovered in culture. An evaluation of other factors that might contribute to failure or relapse, such as malabsorption of oral antibiotics, a sequestered focus of infection (e.g., an undrained abscess), adverse drug reactions that interfere with antimicrobial activity, or infection with other agents (e.g., C. difficile) should be undertaken as indicated.

HIV-infected persons with Salmonella septicemia, which typically occurs in those with advanced HIV disease (e.g., CD4⁺ count <200 cells/µL), should be monitored clinically for recurrence after treatment (BIII). For persons with recurrent Salmonella septicemia, 6 months or more of antibiotics treatment of acute disease should be considered as secondary prophylaxis, although the value of this intervention has not been established and must be weighed against the risks of long-term antibiotic exposure (CIII). In patients who have responded to ART, secondary prophylaxis can probably be stopped. Chronic suppressive or maintenance therapy is not recommended for Campylobacter or Shigella infections among persons with HIV infection (EIII). Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person prevented (BIII).

The diagnosis of bacterial enteric infections among pregnant women is the same as among nonpregnant women. Bacterial enteric infections in the pregnant woman should be managed as in the nonpregnant woman, with several considerations. Arthropathy has been noted in immature animals when quinolones are used during pregnancy. However, approximately 400 cases of quinolone use in pregnancy have been reported to various pregnancy registries, and use has not been associated with arthropathy or birth defects after in utero exposure. Thus, quinolones can be used in pregnancy for bacterial enteric infections in HIV-infected pregnant women as indicated (CIII) (395Nahum GG, Uhl K, Kennedy DL. Antibiotic use in pregnancy and lactation: what is and is not known about teratogenic and toxic risks. Obstet Gynecol 2006;107:1120-38.). Alternate agents for use in pregnancy include expanded spectrum cephalosporins, TMP-SMX, or azithromycin, depending on the organism and the results of susceptibility testing (CIII). Neonatal-care providers should be informed if maternal sulfa therapy is used near delivery because of the theoretical increased risk for hyperbilirubinemia and kernicterus to the newborn.