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Bacterial Infections Associated with HIV

HIV InSite Knowledge Base Chapter
April 1998

Lisa Goozé, MD, Stanford University

http://hivinsite.ucsf.edu/InSite?page=kb-05-01-01

Introduction

Infections with opportunistic pathogens have been one of the hallmarks of the acquired immunodeficiency syndrome since the beginning of the epidemic. An abundance of research and literature has been dedicated to these opportunistic fungi, viruses, and parasites. Less attention has been given to the bacterial infections complicating the course of persons infected with HIV. Even before HIV was found to be the causative agent of the syndrome, however, case reports appeared describing fulminant bacterial infections in these immunocompromised patients. It is now recognized that bacterial pneumonia and bacteremia occur at a higher frequency among HIV-infected patients compared to age-matched controls.(1,2) Diseases caused by bacteria are responsible for a significant proportion of the morbidity and mortality seen in this population. Bacterial infections were the leading cause of death in HIV-infected patients in Rhode Island over a two and half year period.(3) One study of 46 autopsy cases found evidence of bacterial infection in 83%.(4)

The course of certain bacterial infections does not differ from that in the immunocompetent host, whereas other bacterial infections are notable for an increased incidence, a more fulminant course, invasive disease, and unusual rates of relapse. It is important to remember that HIV-infected patients may not present with an acute onset of symptoms, fever, or elevated white blood cell count, which are characteristic of bacterial infections in the normal host. Many bacterial pathogens, including Staphylococcus, Streptococcus, Shigella, Campylobacter, Listeria, and Legionella, to name only a few, have been described in persons infected with HIV. Staphylococcus aureus is one of the most common bacterial infections in AIDS patients, followed by Streptococcus pneumoniae. This chapter will describe infections caused by Haemophilus influenzae, Pseudomonas aeruginosa, Rhodococcus equi, and salmonellae to illustrate some of the atypical characteristics of bacterial infections in the HIV-infected host.

Haemophilus influenzae

Epidemiology

Haemophilus influenzae is one of the most common bacterial infections occurring in persons infected with HIV. H. influenzae is a well-known pathogen in children, and is responsible for meningitis, epiglottitis, septic arthritis, cellulitis, and bacteremia. It can also cause pneumonia; upper respiratory tract infections, such as otitis and sinusitis; as well as genital infections. Infections in adults are less common and tend to occur in the elderly with chronic illnesses, or in younger adults with underlying medical conditions associated with impaired immunity.(5,6)

Current reports suggest that HIV infection increases the risk of acquiring invasive H. influenzae infection. A population-based study of invasive H. influenzae infections in adults(7) found an annual incidence of 1.7 cases per 100,000, compared to an annual incidence of 41 cases per 100,000 HIV-infected adults. This latter incidence, however, was based on only two cases. A more recent population-based study conducted in San Francisco(8) found an incidence of invasive H. influenzae of 2.8 per 100,000 in men 20 to 49 years of age. The incidence in HIV-infected men 20 to 49 years of age was 22.7 per 100,000 regardless of AIDS status, 79.2 per 100,000 in those with AIDS, and 14.6 per 100,000 in HIV-infected men without AIDS. In a large multicenter study, H. influenzae was the third most common cause of bacterial pneumonia in HIV-infected persons after Streptococcus pneumoniae and Staphylococcus aureus.(1)

Haemophilus influenzae organisms are classified into encapsulated and nonencapsulated strains. The encapsulated strains are further classified into types a through f, based on six antigenically different polysaccharide capsules. Type b is the most common strain causing serious infection in children, whereas the remaining types a, c, d, e, and f rarely cause disease. Nontypable (ie, unencapsulated) strains occur more often in adults. Although in the past, nontypable strains were believed to be less pathogenic, it is now well recognized that they frequently cause serious invasive disease including pneumonia and sepsis. In Farley's population-based surveillance study, 47.5% of invasive infections were caused by nontypable strains.(7) Musher and colleagues(5) found that 87% of H. influenzae isolates causing pneumonia were nontypable. In one study of H. influenzae pneumonia, three of four blood isolates obtained from HIV-infected patients were non-typable.(9) In a larger series, 58% of invasive infections in HIV-infected men were caused by nontypable strains.(8)

Pathogenesis

Shortly after birth, exposure to H. influenzae occurs and upper respiratory tract carriage is common. It is a normal colonizer of the pharynx and can be spread from person to person by airborne droplets or by direct contact with secretions. Host defenses against H. influenzae include bactericidal and opsonizing antibody, complement, and cells of the mononuclear-phagocytic system. Anticapsular antibody to type b is acquired in childhood and protects most adults from serious infection, whereas immunity to nontypable H. influenzae is less well understood. HIV-infected individuals have defects in humoral immunity as well as cell-mediated immunity, which undoubtedly contributes to the increased rate of invasive disease. Whether this is due to an impaired ability to mount an appropriate immune response or to failure of preexisting immunity is unknown.(10)

Clinical Manifestations

Pneumonia, sepsis, and, less often, meningitis are the clinical syndromes most frequently seen in the HIV-infected adult, and may affect both severely immunocompromised people with AIDS and asymptomatic HIV-positive persons. It is unclear whether the risk of invasive infection is related to the degree of immunocompromise.(8) Mortality from invasive H. influenzae (regardless of HIV status) is 25 to 30%.(7,8)

The clinical presentation of H. influenzae infection does not differ from that in the HIV-negative person. The presenting symptoms of fever and productive cough in the case of pneumonia, or typical findings of meningitis are usually present. One series of 34 cases of H. influenzae pneumonia found fever and productive cough in 100%, chest pain in 53%, and dyspnea in 47%. Most patients had an elevated white blood cell count, with a left shift in 65%.(9) Of note, a separate report of 12 patients with H. influenzae pneumonia found that three patients were afebrile and the majority presented with a subacute course, both atypical presentations for a bacterial pneumonia.(11)

Diagnosis

Because history, physical examination, and radiologic studies do not distinguish H. influenzae pneumonia, bacteremia, or meningitis from that caused by other bacteria, diagnosis requires a positive culture. Cultures of normally sterile sites such as blood, CSF, or joint fluid confirm the diagnosis. A positive sputum culture alone should be interpreted with caution as H. influenzae can colonize the pharynx. A sputum gram stain with polymorphonuclear leukocytes, gram-negative coccobacilli, and few if any epithelial cells is very suggestive in the appropriate clinical setting.

A study of pulmonary H. influenzae in adults found positive blood cultures in 20%.(5) In patients with H. influenzae pneumonia with AIDS, ARC, or AIDS risk factors, bacteremia was documented in 12%.(9,12) Chest radiographs most commonly reveal unilateral or bilateral infiltrates, but diffuse infiltrates mimicking Pneumocystis carinii pneumonia (PCP) as well as pleural effusions can be seen.(9,11,12)

Treatment

Ampicillin had been the drug of choice for Haemophilus influenza infections until resistant strains were first recognized in 1974. The majority of ampicillin resistance is due to the presence of beta lactamase. The rate of ampicillin-resistant H. influenzae in HIV-infected adults is unknown. Interestingly, out of 34 cases of H. influenzae pneumonia in adults with AIDS, ARC, or AIDS risk factors, none produced beta lactamase.(9) In two separate studies of adults with AIDS or AIDS risk factors, each of 10 cases of H. influenzae type b bacteremia and each of 8 cases of H. influenzae pneumonia were beta lactamase negative.(10,12) In contrast, in Farley's(7) surveillance study of invasive H. influenzae in immunocompetent adults, 36% of isolates tested produced beta lactamase. In a more recent study of community-acquired bacterial pneumonia in persons with, or at risk for HIV, found two of four cases of H. influenzae pneumonia were resistant to ampicillin.(13) During empiric treatment of serious infections, a third generation cephalosporin, trimethoprim-sulfamethoxazole, or a second generation cephalosporin are recommended, depending on resistance patterns in the area, until identification and sensitivities of the organism are available. Because chest radiographs can mimic PCP pneumonia, it would be prudent to treat empirically for bacterial pneumonia as well as PCP until a definitive diagnosis is made.

Prevention

Haemophilus influenzae infections occur at an increased rate in HIV-infected adults, and preventive measures including vaccination, prophylactic antibiotics, and intravenous immune globulin have all been considered. Haemophilus influenzae type b conjugate vaccine is effective in HIV-infected adults with an improved antibody response the earlier it is given in the course of HIV disease.(14,15) Given the relatively low incidence of invasive H. influenzae infections and the significant proportion caused by nontypable strains, the overall benefit of the vaccine is questionable. Recent data have demonstrated a transient increase in viral load after pneumococcal and influenza vaccination(16) and after immunization with tetanus toxoid booster.(17) Clearly, the risk versus benefit needs to be carefully considered, because the long-term consequences of the transient increase in immune activation are unknown.

Recent studies have documented a decrease in bacterial pneumonia in patients receiving anti-PCP prophylaxis with TMP-SMX(1) and in those receiving clarithromycin or azithromycin for MAC prophylaxis.(18,19) Specific incidence of H. influenzae pneumonia was described.

Pseudomonas aeruginosa

Epidemiology

Pseudomonas aeruginosa is an important nosocomial pathogen causing significant morbidity and mortality. It is ubiquitous in nature, having been isolated from water, soil, plants, and animals. P. aeruginosa is infrequently found as part of the normal flora but patients inevitably become colonized after hospitalization. The exact mode of transmission is not known but probably includes person to person, reservoir to person, and colonization with subsequent autoinfection. Hospital outbreaks have been traced to nebulizers, endoscopes, contaminated "sterile" fluids, and therapeutic pools. Risk factors for acquiring infection have been well defined and include cystic fibrosis, neutropenia, thermal injuries, severe trauma, chronic peritoneal dialysis, corticosteroids, cytotoxic drug use, and intravascular catheters.(20,21)

It is clear that P. aeruginosa as well as other Pseudomonas species are emerging as important opportunistic pathogens in the HIV-infected host. The main differences from P. aeruginosa infections in the immunocompetent host are the lack of classical risk factors, the predominance of community-acquired infection, and high relapse rates. P. aeruginosa has emerged as one of the most common causes of gram negative bacteremia and pneumonia in HIV-infected hospitalized patients.(22-25) The incidence of P. aeruginosa infections in AIDS patients appears to be on the rise, with many studies demonstrating an annual increase in cases.(26-28)

An attempt has been made to identify risk factors for Pseudomonas infection in HIV-infected persons. Studies differ in their design and sample populations, making overall conclusions difficult. Recent hospitalization; catheters; neutropenia; cytomegalovirus infection and/or therapy; prior PCP; aerosolized pentamidine; recent antimicrobial, antiviral, or immunosuppressive therapy; and steroids have all been implicated.(26-32)

Traditionally, P. aeruginosa has been considered a nosocomial pathogen and community-acquired infection has been unusual. One characteristic of P. aeruginosa infections in the HIV-infected population is the predominance of community-acquired rather than nosocomial cases. Series report that 57 to 88% of cases are community acquired.(26-28,31,32) In many of these studies, a large proportion of patients had recently been hospitalized, raising the question of whether there had been nosocomial colonization with P. aeruginosa that then led to infection.

Pathogenesis

Pseudomonas aeruginosa is an opportunistic pathogen, rarely causing disease in healthy adults. The pathogenesis of Pseudomonas infections is complex because the organism is both invasive and toxigenic. Infection occurs in a setting in which normal defense mechanisms are no longer intact. Severe burns and the use of catheters and endotracheal tubes are examples of situations in which the organism can take advantage of a breach in the normal host barriers. Underlying defects in cell-mediated or humoral immunity occurring in various immunodeficiency disorders as well as AIDS predispose to infection. Pseudomonas has several stages of infection, including adherence, colonization, invasion and dissemination, and systemic effects.(33) The production of virulence factors including exotoxins, phospholipases, proteases, pili, and polysaccharides all play a role in the pathogenesis of disease.(33) The presence of antibodies to the cell surface antigen lipopolysaccharide is correlated with survival and it has been demonstrated that AIDS patients are unable to mount an effective antibody response to lipopolysaccharide at the onset of P. aeruginosa bacteremia.(34)

Clinical Manifestations

Pseudomonas aeruginosa produces a wide spectrum of disease in both the immunocompetent and immunocompromised host. Manifestations of disease are extensive and include pneumonia, sepsis, catheter-associated bacteremia, urinary tract infection, meningitis, malignant otitis externa, endocarditis, corneal and conjunctival ulcers, sinusitis, osteomyelitis, septic arthritis, soft tissue infections, and dermatitis.

The majority of HIV-infected persons with P. aeruginosa infections described in the literature have low CD4 counts (<100) and a previous or concomitant AIDS-defining illness.(26-28,31,32,35) Pneumonia and bacteremia are the most common syndromes in HIV-infected persons. The presentation of P. aeruginosa pneumonia is nonspecific. Fever and productive cough are typically present with dyspnea and pleuritic chest pain seen less frequently.

Unusual manifestations of P. aeruginosa infection have been described, including malignant otitis externa(30,31) which is classically seen in elderly diabetics and aggressive soft tissue infections.(28) Berger and colleagues(36) reported four unusual cases of P. aeruginosa skin infections in AIDS patients. Ecthyma gangrenosum, a rare manifestation of P. aeruginosa bacteremia, occurred in two cases without bacteremia. A third patient developed subcutaneous nodules during clinical improvement from P. aeruginosa sepsis, and a fourth case of hot tub exposure led to folliculitis and cellulitis.

Infections with P. aeruginosa are usually thought of as occurring in acutely ill, hospitalized patients. Baron,(26) however, described 12 individuals with community-acquired P. aeruginosa bronchopulmonary infection who presented with an indolent course. Some had been symptomatic for up to a month, others were afebrile at presentation, and none were bacteremic.

Diagnosis

As with other bacterial infections, the diagnosis of P. aeruginosa relies on isolation of the organism. Bacteremia is seen in 25 to 56% of cases of pneumonia.(28,32,35) Sputum cultures, positive in 54 to 100% of cases of P. aeruginosa pneumonia, can be useful.(26,30,35,37) Chest radiographs usually reveal focal infiltrates without an apparent lobar predilection; cavities have been reported in up to 69% of cases.(28,30-32,35) Interestingly a diffuse interstitial pattern mimicking PCP can be seen as well as pleural effusions.(30-32,35) The presentation and radiographic appearance of Pseudomonas pneumonia can be quite variable and suggestive of other pathogens, therefore empiric therapy should include antipseudomonal agents until the etiology is known.

Treatment and Outcome

For specific treatment regimens and doses, it is best to follow the recommendations of the formulary of the facility in which treatment is provided or those of an infectious disease consultant.

General treatment issues, such as combination therapy versus monotherapy, duration of treatment, and intravenous versus oral regimens, are controversial.(31,37,38) In a study of 200 HIV-uninfected patients with P. aeruginosa bacteremia, combination therapy with antipseudomonal beta lactams and aminoglycosides was superior to monotherapy.(37) Only six patients, however, received an antipseudomonal beta lactam agent alone and the study predated fluoroquinolone use, so the question of efficacy of monotherapy with these agents remains unanswered. Studies of P. aeruginosa infections in HIV-infected patients have not been able to address these treatment issues because of small numbers of patients studied. In a review of 21 patients with P. aeruginosa bacteremia, response rates were better with combination than with monotherapy.(31) Regardless of the number of agents used, the choice of antibiotic(s) should be guided by antimicrobial susceptibility results as soon as they are available.

An unusual feature of Pseudomonas infection in the HIV-infected host is the significant rate of relapse. Relapse rates as high as 43% have been reported with multiple relapses occurring in an individual patient.(26) These relapses may or may not occur at the same site as the initial infection. Mortality rates range from 12.5 to 40%.(26-32) Given the significant mortality and relapse rates, combination therapy with an antipseudomonal beta lactam plus an aminoglycoside or a fluoroquinolone is recommended. The duration of treatment and efficacy of oral regimens remains unknown. Some authors have suggested prophylactic or maintenance regimens with aerosolized aminoglycosides similar to that used in cystic fibrosis patients.(21,26)

Rhodococcus equi

Epidemiology

Rhodococcus equi, a gram-positive aerobic pleomorphic coccobacillus, was first described as a causative agent of pneumonia in foals in 1923.(39) Originally, this organism was classified in the genus Corynebacterium, but analysis of DNA and cell wall components revealed closer homology to Nocardia and Mycobacteria than Corynebacteria, and it was reclassified in the genus Rhodococcus in 1980.(40) R. equi is a well-known cause of bronchopneumonia and pulmonary abscesses in foals, and adenitis in swine. It has been isolated from the feces and intestines of many other mammals, but it only rarely causes disease. The first human case was reported in 1967 in a patient receiving corticosteroids for chronic hepatitis.(41) The main risk factor for R. equi infection appears to be impaired host defense mechanisms. The majority of cases originally reported were in patients who were immunocompromised due to malignancies, organ transplants,immunosuppressive drugs, diabetes, or chronic alcoholism. In 1986, the first case of R. equi pneumonia in an HIV-infected patient appeared in the literature.(42) The AIDS epidemic, as well as a heightened awareness on the part of the microbiology laboratory, has resulted in an increase in the reported cases of R. equi infection. In AIDS patients with R. equi infection, the average CD4 count is 50 and a CD4 count greater than 200 is unusual.(43,44)

Pneumonia is the most common manifestation of infection; however, extrapulmonary disease in the presence or absence of pulmonary disease can occur. Pulmonary infection occurs by inhalation of the organism. Rarely, R. equi has caused enteritis and mesenteric lymphadenitis in foals without evidence of pulmonary involvement, raising the possibility of ingestion of organisms as a route of transmission.(40,45) Traumatic inoculation or superinfection of wounds can also lead to infection.(46) The role of exposure to farm animals or manure is unclear as only one third to one half of cases recall a history of exposure.(40,43,46,47) Two cases of R. equi pneumonia in whom the only risk factor was contact with other infected patients raise the possibility of human-to-human transmission.(43)

Pathogenesis

R. equi is a facultative intracellular pathogen that infects macrophages. Persisting within the macrophage, R. equi inhibits phagosome-lysosome fusion and continues to replicate, eventually destroying the host cell. The mechanisms of virulence are unknown. Virulence has been associated with cell wall mycolic acids, cholesterol oxidase, and capsular polysaccharide.(48) In foals and mice, the expression of plasmid-encoded 15- to 17-kDa antigens is associated with virulence.(49) In an in vitro macrophage assay, R. equi expressing the 17-kDa antigen survive and replicate, whereas a strain lacking the plasmid-encoded protein replicates poorly.(50) The function of this protein has not been identified but may be related to the ability to replicate within the macrophage. In contrast to isolates found in foals and mice, Takai et al. demonstrated that a minority of R. equi isolates from AIDS patients express the 15- to 17-kDa antigens. The majority of isolates express a 20-kDa antigen with reduced virulence in a mouse model, and some isolates were avirulent.(49)

The role of humoral immunity in R. equi disease is unclear. AIDS patients who recover from R. equi pneumonia produce antibodies to the major protein antigens of R. equi, whereas patients with a variable course have a weaker humoral response.(51) Interestingly, one study found that patients' sera reacted with a 15-kDa protein, but not with the diffuse 15- to 17-kDa protein band.(52) As the above illustrates, the exact determinants of virulence and the role of specific antibodies have yet to be elucidated.

Clinical Manifestations

Pneumonia is the most common manifestation of R. equi infection. Fever, cough, pleuritic chest pain, and dyspnea are frequent presenting complaints; hemoptysis and weight loss may also occur. Extrapulmonary disease is not uncommon. In one review, extrapulmonary disease without pulmonary involvement was seen in 24% of cases.(46) Subcutaneous, renal, pelvic, and brain abscesses have all been reported as well as osteomyelitis, mycetoma, and post-traumatic endophthalmitis.(46,53,54) The onset is typically subacute with symptoms lasting from days to weeks before presentation. Some patients may present with fever without a source of infection and the diagnosis is made by positive blood cultures.(44,46,53)

Pneumonia, endopthalmitis, and post-traumatic wound infections have occurred in immunocompetent persons and respond well to therapy without progression of disease or relapse.(46) In contrast, clearance of R. equi is impaired in the immunocompromised host and relapses are common despite maintenance antibiotic therapy. Relapses of pneumonia have been described in up to 82% of cases.(43) Relapses may also occur at extrapulmonary sites including the central nervous system, kidney, bone, and subcutaneous tissue.(46)

Diagnosis

The diagnosis of R. equi infection ultimately relies on the isolation of the organism by the laboratory. The history and physical examination are both nonspecific. A history of exposure to farm animals or manure may or may not be present. Examination of the lungs can be normal, even in the presence of pulmonary disease. Chest radiographs may reveal consolidation (without lobar predilection),(43,45,46) cavities (in up to 75%, often with air fluid levels), mass lesions, or pleural effusions (18 to 35% of cases).(43,45,46) An interstitial pattern may precede the development of consolidation or cavity formation.(43)

Sputum and blood cultures will be positive for R. equi over 50% of the time. Invasive procedures such as bronchoscopy or biopsy may be necessary when all cultures are sterile. R. equi grows as large mucoid salmon-pink colonies within 24 to 72 hours.(40,53) Unfortunately, a delay in the diagnosis of R. equi infection is not uncommon. The organism may be improperly identified by the laboratory as a contaminant or as a commensal due to its diptheroid appearance. Acid-fast smears are variably positive with younger colonies more likely to be acid fast compared to older colonies or subcultures. If a specimen is weakly acid fast, it might be confused as tuberculosis or mycobacteria other than tuberculosis. Histology reveals a necrotizing granulomatous reaction with macrophages, neutrophils, and intracellular gram-positive organisms. Occasionally, malacoplakia, a chronic granulomatous inflammation, or features of Whipple's disease may be present.(46,53,55)

When evaluating a patient with symptoms and a chest radiograph consistent with tuberculosis, fungal disease, or Nocardia, or a clinical specimen that reveals granulomas, one must consider R. equi in the differential diagnosis.

Treatment and Outcome

The overwhelming majority of human isolates are resistant to penicillin and first generation cephalosporins. Even if the organism is sensitive initially, resistance will develop during the course of therapy.(40,46,56) Most isolates are sensitive to rifampin, erythromycin, vancomycin, imipenem, and aminoglycosides.(43,45,46,56) Susceptibility to ciprofloxacin, chloramphenicol, tetracycline, clindamycin, and sulfonamides tends to be more variable and probably should not be used empirically until susceptibilities are known.(43,45,46,56) Isolates are sensitive to ceftriaxone, ampicillin-sulbactam, and amoxicillin-clavulanate in vitro, but clinical experience is lacking.(56)

Various combinations and numbers of antibiotics have been used to treat rhodococcal infections. The combination of erythromycin and rifampin is successful in the treatment of pneumonia in foals, but experience in humans has been mixed.(40,43,47,57,58) The inclusion of vancomycin in the regimen or the use of vancomycin plus imipenem has been effective.(59,60) The use of gentamicin plus rifampin or erythromycin should probably not be used as these combinations are antagonistic in vitro.(46,48) Using one drug with extracellular activity such as vancomycin, teicoplanin, or imipenem along with a drug with intracellular activity such as erythromycin, rifampin, or ciprofloxacin has been proposed.(43)

The optimal drug regimen and duration of treatment have not been established. Antimicrobial susceptibility testing must guide the choice of antibiotics. At least two antibiotics to which R. equi is sensitive should be used, because drug resistance has developed during monotherapy.(60) Given that R. equi is an intracellular pathogen, it is best to use at least one agent that achieves a high intracellular concentration. Selecting at least one drug with central nervous system penetration is theoretically beneficial as relapses frequently occur in the brain.(46) It has been proposed that initial therapy be given for at least 2 months, preferably with intravenous antibiotics.(43,47) Maintenance therapy should be given for months and probably for life with two antibiotics to which the organism is known to be susceptible.

Outcome is related to host immune status. Infections are typically cured in immunocompetent hosts in contrast to relapses and chronic disease seen in the immunocompromised. An average survival time of 11.4 months has been reported in HIV-infected patients.(43) Overall mortality is approximately 25% with HIV-infected persons suffering mortality rates up to 55%.(43-45,53) Surgical resection has been performed when no clinical improvement was noted after antibiotic therapy, however no increase in survival has been shown.(43,45)

Salmonellae

Epidemiology

Salmonellae cause a wide variety of clinical syndromes, including gastroenteritis, enteric fever, and focal infections. The classification of the salmonellae can be quite confusing. Salmonella is a single genus that can be divided into seven distinct subgroups. Most of the Salmonella that cause human infection belong to subgroup 1. There are nine serogroups designated A through I based on specific O (cell surface) antigens. The serogroups, formerly known as species, are further divided into over 2,000 serotypes, based on three major antigens: flagellar (H), somatic (O), and Vi. Serotypes S. typhi and S. paratyphi only colonize humans, whereas nontyphoidal Salmonella can infect a wide variety of animal hosts. Food products such as poultry, eggs, and unpasteurized milk are the largest sources of human infection. Person-to-person transmission can also occur via the fecal-oral route and outbreaks have occurred in hospitals and day care centers.(61)

Infections with non-typhoidal Salmonella have been described in patients with impaired host defenses, such as those with neoplastic disease, transplantation, cirrhosis, collagen vascular disease, renal failure requiring hemodialysis, and need for immunosuppressive drugs. An increased incidence of nontyphoidal salmonellosis in HIV-infected persons was originally noted in the early 1980s and nontyphoidal Salmonella septicemia became an AIDS-defining illness in 1987. Bacteremia, relapses, and severe disease are unusual in the immunocompetent host but characteristic of Salmonella infection in the HIV-infected population. Salmonellosis and bacteremia occur at an increased rate in persons with HIV.(62-67) A characteristic feature of salmonellosis in AIDS is the relapses that occur despite appropriate antibiotic therapy.(63,65,67-70) S. typhimurium and S. enteritidis are the two most common serotypes isolated from the blood of patients with AIDS in the United States.(65,71)

Before HAART, a decrease occurred in the incidence of Salmonella infections in HIV-infected patients. Both the use of zidovudine and trimethoprim/sulfamethoxazole for P. carinii prophylaxis probably contribute to this decline. Zidovudine has in vitro activity against gram-negative bacteria, including Salmonella, and has been shown to prevent relapses of Salmonella bacteremia in persons with AIDS.(72,73)

Pathogenesis

Salmonellae are usually acquired by oral ingestion. A median infectious dose of 10⁶ to 10⁹ organisms, depending on the serotype, is required for infection. Host defenses include gastric acidity, the normal gastrointestinal flora, and peristalsis.(61) A lower dose can cause infection in conditions where the gastric acidity is altered or there is a change in the normal flora or motility. Bacteria pass from the stomach into the bowel and invade intestinal epithelial cells. If not contained, they can spread to the mesenteric lymph nodes, the thoracic lymph, and disseminate via the systemic circulation. The exact host defenses against Salmonella infection are unknown but include cell-mediated immunity, macrophages, and polymorphonuclear leukocytes.(61,74) Various bacterial virulence factors have been described including the Vi capsular polysaccharide of S. typhi, the lipid A component of lipopolysaccharide, and the virulence plasmid.(61,74) The defects found in the immune system in AIDS most likely contribute to the inability to contain and eradicate Salmonella, so it is not surprising to see persistent and relapsing infection.

Clinical Manifestations

In the immunocompetent host, salmonellosis can be divided into four clinical syndromes: gastroenteritis, enteric fever, septicemia, and an asymptomatic carrier state. The majority of Salmonella infections in AIDS patients manifest as severe gastroenteritis, bacteremia, or extraintestinal focal infection. HIV-infected patients present with diarrhea, fever, and bacteremia. In the normal host, bacteremia accompanies gastroenteritis approximately 5% of the time,(75) whereas in AIDS, the incidence of bacteremia is much higher.(62,63,65,68) It has been noted previously that in patients with underlying disease, bacteremia occurs more frequently, and in the majority of cases, it occurs without gastrointestinal symptoms.(75) This syndrome of fever and nontyphoidal Salmonella bacteremia without gastroenteritis has also been observed in persons with AIDS.(64,65,68-70)

Salmonella can cause focal infections in both the immunocompetent and immunocompromised host. Cases of endovascular infection, lung abscess, peritonitis, septic arthritis, osteomyelitis, brain abscess, subdural empyema, and meningitis have all been reported in persons with AIDS.(76,77)

Diagnosis

The diagnosis of Salmonella infection relies on isolation of the organism because physical examination and routine laboratory analysis are nonspecific in nontyphoidal salmonellosis. The differential diagnosis of diarrhea in an HIV-infected person is extensive. Blood cultures must be obtained in all febrile patients with diarrhea because Salmonella may be isolated in the blood when stool cultures are negative. Salmonella should also be considered in the HIV-infected patient presenting with sepsis. The occurrence of Salmonella bacteremia should prompt one to consider the diagnosis of HIV infection, keeping in mind that it can occur before other opportunistic infections.(65)

Treatment and Prevention

In the immunocompetent patient with self-limited gastroenteritis, antibiotic therapy is usually not recommended as it does not significantly improve symptoms or outcome, and may actually increase the relapse rate.(61) Given the increased severity, potential for extraintestinal spread, and the high relapse rate, salmonellosis requires treatment in HIV-infected persons. The classic drugs used to treat Salmonella infections are chloramphenicol, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole. There has been an increase in resistance to these antibiotics and treatment must now be guided by antimicrobial susceptibilities. Intravenous ceftriaxone (1 to 2 g) every 24 hours as well as oral ciprofloxacin (750 mg) twice daily have been shown to be efficacious in AIDS patients with Salmonella infections.(65,78,79) Ciprofloxacin is effective in persons developing breakthrough bacteremia while receiving other antibiotics and offers the advantage of oral administration.(79) The efficacy of initial therapy with ciprofloxacin is unclear, but would probably depend on the severity and extent of disease and the ability to absorb oral medication. The appropriate route and duration of therapy for an episode of salmonellosis is unknown. Chronic suppressive therapy after an initial course of intravenous antibiotics has been successful, but relapses tend to occur once the antibiotic is stopped.(63,65,68) As with other infections, life-long maintenance therapy may be required to prevent relapses regardless of antibiotic therapy.

Persons with HIV should be counseled regarding the risks of eating uncooked or inadequately cooked food, including eggs, poultry, meat, seafood, and unpasteurized dairy products. Exposure to pets including reptiles have been associated with cases of salmonellosis and the potential risks and recommendations should be explained.(80)

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