Campylobacter species

Campylobacter is considered to be the most common cause of bacterial gastroenteritis worldwide, the single most common inciting agent for Guillain-Barre Syndrome, and an important cause of post-infectious Irritable Bowel Syndrome. Because of its fastidious nature, the sensitivity of culture for Campylobacter is variable, and the application of culture-independent diagnostic tests has led to further upward revision of the estimated burden of disease from this pathogen. While C. jejuni is thought to be the predominant agent of gastroenteritis, a broad range of Campylobacter species have been implicated in intestinal and extra-intestinal disease.

MICROBIOLOGY

Campylobacters are described as motile, non-spore-forming, spiral or comma-shaped gram-negative rods. They were initially thought to be members of the Vibrio genus, but in 1963 were assigned to the new genus, Campylobacter (113). Campylobacter jejuni and Campylobacter coli, which account for most human Campylobacter isolates in the U.S., are both thermophilic, in that they grow best at 42 degrees C, and microaerophilic, in that they grows best in an atmosphere containing 5% to 10% oxygen. These optimal growth conditions are likely a legacy of the evolutionary avian host and vary among emerging Campylobacter species such as C. upsaliensis, C. concisus, C. hyointestinalis, C. fetus, C. ureolyticus and C. lari, which have different animal reservoirs and differing optimal growth conditions.

EPIDEMIOLOGY

Campylobacter is a leading cause of bacterial diarrhea in developed countries, second to Salmonella as an agent of foodborne diarrheal illness in the United States (159) and the leading cause of foodborne bacterial illness worldwide, accounting for 96 million cases in 2010 (160). It is a leading etiology of diarrhea in children in developing countries, where morbidity and mortality due to diarrheal diseases is highest (161, 162). In developed countries, infections are sporadic, with a peak incidence in early adulthood, and marked seasonality can be seen (163). The principal route of transmission of C. jejuni in developed countries is through eating and consuming chicken; the greatest risk may come from eating chicken prepared outside the home (30). Strikingly, interventions aimed at reducing poultry-related exposures on a national level in New Zealand in 2007-2008 were associated with a 54% decline in annual illness, including a 74% reduction in cases attributable to poultry, such that rural exposure to ruminants became the leading cause of C. jejuni infection in that country (164). In contrast, in developing countries, Campylobacter infections are hyper-endemic, with peak incidence in young children. Asymptomatic infection is exceedingly common, source attribution is difficult and is suggestive of more diffuse environmental exposure, and there is little to no seasonality noted (165). Other potential sources of C. jejuni infection include unpasteurized milk, other foods of animal origin, contaminated water, and animal contact, including household pets, farm animals, and petting zoos (166, 167). While domesticated poultry is the principle host for C. jejuni, a range of primary hosts have been described across the Campylobacter genus. Established hosts include pigs for C. coli and C. hyointestinalis, wild birds for C. lari, cattle for C. fetus, C. ureolyticus, and C. jejuni, dogs and cats for C. upsaliensis, and the human oral cavity for C. concisus, C. gracilis, and C. hominis.

CLINICAL MANIFESTATIAONS

The typical infection with C. jejuni is characterized by an acute diarrheal illness associated with fever and abdominal cramps and is clinically indistinguishable from gastroenteritis caused by Salmonella, Shigella, or other enteric bacterial pathogens. In contrast to viral gastroenteritis, vomiting is not common. The diarrhea may be quite severe, and grossly bloody diarrhea is seen. Occasionally, diarrhea is minimal or absent and the abdominal pain (which can be intense) may be mistakenly attributed to appendicitis. Even without specific antibiotic treatment, resolution of symptoms in most patients occurs within one week, however, 20% experience more prolonged or relapsing illness lasting several weeks (17, 57). Although C. jejuni bacteremia occurs in only about 1.5 per 1,000 intestinal infections, it is possible that transient bacteremia occurs in many cases but is not detected because blood cultures are not routinely done in healthy patients with uncomplicated diarrheal illness. The case-fatality rate for Campylobacter infections is 0.05 per 1,000 infections (122, 123). Sigmoidoscopic examination reveals diffuse colonic inflammation; Campylobacter enteritis may be confused with early inflammatory bowel disease (168). Although the peripheral white blood cell count may be mildly elevated, other laboratory findings, including liver function tests, serum electrolytes, and hematocrit are normal..

Extra-intestinal illness is well described, most classically with C. fetus, although species that are associated with gastrointestinal illness, including C. jejuni, have also been implicated (169). For example, C. jejuni was the most frequently identified bacteria from blood in a study of severe illness in infants in Pakistan (170). Campylobacter infection has also been strongly associated with a range of post-infectious sequelae, including Guillain-Barre Syndrome (GBS), post-infectious irritable bowel syndrome (IBS), and reactive arthritis. GBS associated with Campylobacter is of the acute motor axonal neuropathy variant (171) and occurs following every one in 1,000-5,000 infections (172). This is thought to be caused by molecular mimicry of pathogen antigens, leading to auto-antibodies against gangliosides. As a result, the syndrome is particularly associated with specific Campylobacter strains, most commonly Penner O19 and O41.13 About 25% of patients develop respiratory insufficiency and may show signs of autonomic dysfunction.14 Because Campylobacter infections are common, they are estimated to account for 30% of cases of GBS occurring in the U.S. each year (79). Post-infectious IBS has been described after an array of enteropathogen infections, including many bacteria (173). It is now thought that antibodies against the active subunit of the cytolethal distending toxin (CdtB) produced by many of these agents cross-react with vinculin in the host gut, leading to reduced gut motility (174). Reactive arthritis has been estimated to follow Campylobacter infection with an incidence of about 1 per 100 cases, typically occurs within four weeks of the intestinal infection, and affects the ankles, knees, wrists and small joints of the hands (175, 176). Campylobacter infection may be an important cause of child growth shortfalls in children in developing countries (177).

LABORATORY DIAGNOSIS

Because the syndrome of diarrhea is frequently self-limited, clinical guidelines for the diagnosis, management and treatment of acute diarrheal infections recommend the use of diagnostic tests only for specific clinical scenarios. For example, guidelines from the American College of Gastroenterology for acute diarrhea in adults suggest that microbiologic assessment be considered in immunocompetent adults only for dysentery without fever (to evaluate for shiga-toxin producing E. coli), non-travel associated severe dysentery with fever, and moderate-to-severe watery diarrhea with fever and of greater than three days duration (178). Campylobacter spp. are generally fastidious organisms that require 72 to 96 hours for isolation from stool. Isolation from blood takes even longer; up to two weeks may be required for certain species (41). Although some Campylobacter species grow best at 37C, such as C. fetus, and C. hyointestinalis, the optimal temperature for C. jejuni growth is 42C. Because most C. jejuni strains are resistant to cephalothin, they may be isolated from stools using a cephalothin-containing medium. Such Campylobacter-selective media will permit the growth of most C. jejuni strains while inhibiting growth of other stool organisms. However, many non-jejuni Campylobacter species, and even some C. jejuni strains, are susceptible to cephalothin and will not be identified on media containing this antibiotic. Therefore, culturing stools on an antibiotic-free medium using a filtration technique may be a better way to isolate these organisms. The filtration technique takes advantage of the small size of Campylobacter species; 0.45-0.65 um filters will allow passage of Campylobacter while retaining other stool flora. The use of filtration culture in South Africa showed a substantial increase in yield for non-jejuni/coli Campylobacter species, such that C. jejuni represented only 40% of all isolates from children with diarrhea (179). In practice, a broad range of culture approaches are used. A survey of clinical laboratories in Pennsylvania showed significant variation in all aspects of Campylobacter culture including incubation length, media, temperature, atmosphere, use of enrichment broth, and biochemical tests of identification (180). For these reasons, as well as efficiency and cost, interest in culture-independent diagnostic tests has increased. Several enzyme immunoassay (EIA) stool antigen tests have been developed, with early studies showing excellent performance in comparison to culture (181). However, routine use of these tests in clinical microbiology laboratories has revealed a high false-positivity rate (182, 183). Detection of non-jejuni/coli Campylobacter species may largely contribute to these false positive detections. In particular, there is good evidence that these tests detect C. upsaliensis, C. concisus, C. hyointestinalis, and C. helveticus among others (184, 185). Thus a clear understanding of the clinical context is needed to interpret the EIA result. Since 2013, several nucleic-acid based diagnostic panels have been FDA-approved for detection of enteric pathogens, all of which include Campylobacter, and which are specific for C. jejuni and C. coli (178). While the analytical specificity of these tests has been demonstrated to be high (186)., the clinical specificity may not be, and this problem will be exacerbated in settings with high rates of asymptomatic carriage of these pathogens (162).

PATHOGENESIS

Ingesting as few as 500 organisms might be sufficient to produce illness, however, usually > 104 organisms are needed to produce symptoms. The typical incubation period is from 2 to 4 days (14). Following infection, colonization of the small bowel precedes that of the colon. There are multiple factors that have been implicated in adhesion, among them CadF which binds to host fibronectin as well as the C. jejuni polycassharide capsule (CPS) which alters adherence in vitro. The flagella also appears to be necessary for both successful adhesion and colonization (187). Additionally, the flagellar components function as a type III secretion system and secrete a number of proteins through a central filament, including Cia (Campylobacter invasion antigens) proteins (188). The flagella proteins FlaC and FspA have been found to be important in the modulation of the invasion of epithelial cells in different experimental systems (189). The best characterized virulence factor of C. jejuni is cytolethal distending toxin (Cdt), a tripartite toxin that arrests intestinal epithelial cells in G2 phase of the cell cycle through the action of the active subunit CdtB which is transported to the host cell nucleus where it induces double strand breaks in DNA, a factor that is believed to be critical in increasing host pathogen contact time and is associated with IL-8 secretion from infected epithelial cells. There is extensive data supporting the disruption of intestinal tight junctions and increased intestinal permeability during and following Campylobacter infections, but the mechanisms involved are poorly understood (190).

On gross examination, the intestines appear edematous and hemorrhagic (12,121); microscopic examination reveals infiltration of the lamina propria by neutrophils and mononuclear cells (16) and fecal myeloperoxidase is elevated (177). Serum IgA, IgG, and IgM responses peak within 2 weeks, then rapidly decline (15,49).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Agents

Campylobacters are susceptible in vitro to a wide variety of antimicrobial agents (58,148,149,154), but they are inherently resistant to trimethoprim-sulfamethoxazole and increasingly resistant to fluoroquinolones in most geographic areas, so that traditional first line therapies for the management of presumed bacterial enteritis employed by many practitioners often and predictably fail in patients with Campylobacter enteritis or traveler’s diarrhea caused by Campylobacter. Macrolides are the most active agents against C. jejuni (65,118,141,147) the species for which the largest amount of data are available, but C. coli is becoming progressively resistant, particularly in China as well as other parts of Asia. In special circumstances, as when a patient is intolerant of many agents or when a strain has an unusual antibiotic resistance pattern, alternative agents such as chloramphenicol may be used; nearly all campylobacters are susceptible to chloramphenicol (105,109). Clindamycin usually is effective against Campylobacter although this drug is not recommended for neonates (42). Carbapenems also are active against Campylobacter and may be used in serious infections; most in vitro data would favor meropenem. Aminoglycosides are effective in the treatment of systemic Campylobacter infections; in most studies, resistance to gentamicin has not been observed (5,8,102,108). Tetracycline resistance is too common for this to be considered an alternative in the absence of susceptibility testing (104,105). Ampicillin and amoxicillin have activity against Campylobacter, but in general, rates of resistance are too high for these drugs to be useful. Furthermore, the organism may produce b-lactamase making the use of ampicillin or amoxicillin suboptimal, especially in serious infections (58). More than twenty percent of strains in India and almost 30% of strains in Spain are resistant to ampicillin (10,85,97,108). In Spain, the rate of resistance to ampicillin has ranged from 18 to 69% (86). The mechanism of resistance is thought to be chromosomally mediated (97). Campylobacters are almost always susceptible to ampicillin-clavulanic acid (42,95,128), however, relatively high doses are required to be effective (64). Even in areas with very high rates of resistance to B-lactam antibiotics, imipenem displayed high in vitro activity against Campylobacter strains (105).

Although campylobacters are microaerophilic, not anaerobes, some but not all strains may be susceptible to metronidazole (11). C. jejuni is not susceptible to most cephalosporins, although other non-jejuni campylobacters often are (42,141). However, even C. jejuni may be moderately susceptible to other cephalosporins including cefotaxime, ceftazidime, and cefpirome (22,141). Campylobacters are inherently resistant to trimethoprim, vancomycin, and rifampin. Interestingly, however, rifabutin exhibits some anti-Campylobacter activity; the incidence of Campylobacter infection among patients with AIDS who were treated with rifabutin prophylaxis was reported to be decreased when compared with untreated controls although this would not be the preferred suppressive agent (100).

Combination Drugs

Because combination therapy is not required and rarely used to treat most Campylobacter infections, there are few data on in vitro susceptibilities for combinations of agents. Specific scenarios in which combination therapy should be considered are discussed below.

ANTIMICROBIAL THERAPY

General Approach

The most important tenet of treatment of patients with acute gastroenteritis in the absence of systemic infection or clinical dysentery due to C. jejuni or any other microbe is not treatment with antibiotics, but maintenance of proper hydration and electrolyte balance. In nearly all cases, this can be accomplished by encouraging proper oral intake of liquids; occasionally, intravenous fluids are required, especially in the very young or elderly.

Many Campylobacter infections are asymptomatic or produce a self-limited illness that does not require treatment with antimicrobial agents in the normal host. In an often cited study, children in Thailand with acute diarrheal disease caused by Campylobacter and treated with erythromycin experienced no decrease in duration of diarrhea when compared with age-matched Campylobacter-infected controls treated with no antibiotics (134), but over 65% of the strains in the treatment group were resistant to erythromycin.  More recent studies done with a single high dose of azithromycin of 30 mg/kg/day in children in Croatia do demonstrate clinical effectiveness in a similar patient population, where azithromycin was found to be more effective than erythromycin (191). Moreover, the syndrome of dysentery, namely the presence of visible blood in the stool of a febrile patient warrants antimicrobial therapy. If empiric it should cover both Shigella and Campylobacter, this therapy would most likely be azithromycin; if culture results are present antimicrobial therapy may be tailored. Peruvian children with bloody diarrhea caused by Campylobacter infection recovered more quickly if they were treated with erythromycin soon after the onset of symptoms (110). Those patients in whom antibiotic therapy is indicated include those with bloody stools, high fevers, prolonged symptoms (lasting > 1 week), worsening symptoms, or relapses. Prompt administration of antibiotics also should be used for patients with HIV infection or another immunocompromising condition. Because pregnant women may experience severe consequences of C. jejuni infection, including septic abortion or stillbirths, and because their neonates are in effect compromised hosts, pregnant women also should be treated with antimicrobial agents and have clearance of infection documented by post-treatment cultures for proof of cure. Relapse of infection following treatment, even in non-immunocompromised populations is well documented and clinicians should counsel patients accordingly.

Drug of Choice

After a brief period in which fluoroquinolones were considered as the treatment of choice for Campylobacter infections, the rapidly increasing resistance of campylobacters to these agents has made macrolides once again the optimal therapy. Years of testing for antimicrobial resistance in many parts of the world has demonstrated that the resistance rate to erythromycin among human C. jejuni isolates has changed very little (86,102,120,150), although there is an upward trend in erythromycin-resistance among C. jejuni isolates from Thailand (120) and Sweden (48). In the Netherlands, the United Kingdom, and Spain, the rate of erythromycin resistance is negligible (31,105,138). In most developed countries the rate of resistance has remained under 10% (21,130,153). The rate of erythromycin resistance (range 13 to 93) is substantially higher among C. coli strains (47,105,108,134,138,154). Very high rates of resistance (>50% for C. jejuni, >90% for C. coli) have been reported from institutionalized children in developing countries such as Thailand (134) but rates remain relatively low in other places such as in an India (97, 192). Local patterns of antibiotic use in both humans and animals may explain these differences. Strains that are resistant to macrolides are nearly always resistant to quinolones, tetracycline, clindamycin and have a higher than expected probability of being resistant to amoxacillin-clavulonate (193).

The mechanism of Campylobacter's resistance to erythromycin is a point mutation in a ribosomal proteins L4 and L22 (32) although the presence of the CmeABC efflux pump is an important codeterminant of phenotypic resistance that likely explains the high level of correlation between macrolide resistance and resistance to other antibiotics of different classes (194).  The use of macrolide antibiotics analogous to erythromycin (e.g., tylosin) to increase weight gain in swine intended for human consumption may have contributed to the emergence of erythromycin resistance among C. coli (21). Swine are an important host for C. coli.

Other advantages of erythromycin include its low cost, safety, ease of administration, and narrow spectrum of activity. Unlike the fluoroquinolones and tetracyclines, erythromycin may be used safely in children and pregnant women and is less likely than many agents to exert an inhibitory effect on other fecal flora. Erythromycin stearate is acid resistant, stable, and incompletely absorbed. Therefore, in addition to its systemic effects, it may be capable of exerting a contact effect throughout the bowel. The recommended dose in adults is 500 mg orally two times per day for five days. For children, the recommended dose is 40 mg per kg per day in two divided doses for five days. Azithromycin is a reasonable and practical alternative, dosed at either a single 1 g dose in adults or a 3 day course of 500 mg per day or in pediatrics at a single dose of 30 mg/kg or 10 mg/kg for 3 days.

Special Infections

Campylobacter fetus

C. fetus usually causes serious extra-intestinal infections, most commonly in immunocompromised hosts (45). Typical clinical presentations include bacteremia, vascular infections, abscesses, and central nervous system (CNS) infections (81,83,92). C. fetus also causes perinatal infection and fetal loss in both humans and animals (116,152). Because of the serious nature of these infections, treatment with a single agent is not recommended; treatment with erythromycin alone may not eradicate C. fetus bacteremia. Furthermore, if the strain is multi-drug resistant, infection may result in serious illness or death before effective treatment is started (9). Carbapenems, ampicillin and third-generation cephalosporins can be effective against serious C. fetus infections (87,140). However, resistance to ampicillin, ceftriaxone, and fluoroquinolones has been described (40,75, 195, 196). C. fetus bacteremia may be successfully treated with 2 weeks of treatment, but at least in part reflecting the population affected, relapses are not uncommon. Relapsing or persistent infections, however, require prolonged use of antimicrobial agents. When treating endocarditis or other vascular infections caused by C. fetus, addition of an aminoglycoside should be considered. Four to 6 weeks of antimicrobial therapy is required. CNS infections due to C. fetus should be treated with a drug that penetrates the blood brain barrier for at least 2 to 3 weeks, with carbapenems as the drug of choice pending susceptibility data (197). Ampicillin and ceftriaxone are alternative agents for susceptible isolates.

Campylobacter upsaliensis

C. upsaliensis infection usually causes a diarrheal illness (20,55), however, immunocompromised persons are more likely than others to develop bacteremia (25,54,68,91). As with uncomplicated gastroenteritis caused by C. jejuni infection, many C. upsaliensis infections do not require specific antimicrobial therapy. Because a large proportion of C. upsaliensis isolates are resistant to erythromycin, when drug therapy is required, fluoroquinolones are considered the agents of choice (26, 99), though resistance has been described (198). Other effective agents may include doxycycline and amoxicillin-clavulanate (91).

Campylobacter hyointestinalis

Infection with C. hyointestinalis produces watery diarrhea, especially in homosexual men (29,78). Infections also may be asymptomatic. All human clinical isolates tested have been susceptible to erythromycin (29), though isolates from beef cattle have demonstrated low rates of resistance (199). Resistance to fluoroquinolones has been described (200). Other antimicrobial agents with in vitro activity versus C. hyointestinalis include metronidazole and amoxicillin-clavulanate.

Campylobacter concisus

Primarily a cause of periodontal disease in humans, several studies have also implicated C. concisus as a cause of predominantly watery diarrhea (201, 202, 203). In Denmark, rates of isolation from diarrheal stools have been described to be similar to C. jejuni (204). There is also some evidence that C. concicus may trigger the onset and relapse of inflammatory bowel disease (205). Resistance to fluoroquinolones and erythromycin have been described, and alternative agents may include doxycycline and amoxicillin-clavulanate (198).

Campylobacter lari

Infections with C. lari may cause gastroenteritis in immunocompetent hosts or bacteremia in immunocompromised ones (19,23,71,82, 206, 207, 208). As with C. jejuni, increased reports of fluoroquinolone resistance have made these agents less useful (35), while macrolides should remain susceptible. For invasive disease, carbapenem and aminoglycoside therapy can be considered.

Other Campylobacters species

Campylobacter ureolyticus has been described as an important cause of gastrointestinal infection, in particular in studies from Ireland (). Campylobacter mucosalis is not an important human pathogen, however, it has substantial economic impact because it causes proliferative enteritis in pigs and lambs (69,74). Nevertheless, isolation of C. mucosalis from the blood of a human has been reported; the organism was susceptible to cephalothin, nalidixic acid, erythromycin, doxycycline, and chloramphenicol (125). Two patients with C. mucosalis-associated diarrhea have been reported; both recovered completely with no antimicrobial therapy (38). Like C. concisus, C. gracilis and rectus are predominantly associated with periodontal disease in humans but invasive disease has been described (210, 211, 212). Ampicillin/sulbactam, ceftriaxone, and carbapenems can be considered for empiric therapy.

Related organisms

Infections with H. cinaedi and H. fennelliae (formerly called Campylobacter-like organisms) cause proctocolitis or enterocolitis in homosexual men or bacteremia in immunocompromised persons (66,89,101,135). Nosocomial transmission has been described (213). These organisms are commonly resistant to erythromycin. While fluoroquinolones have been considered the drug of choice (107), increasing rates of resistance has been described (214). Alternative empiric therapy choices include carbapenems and aminoglycosides for invasive infection as well as doxycycline. Successful treatment has also been described with ceftazidime and ampicillin/sulbactam (50). Recurrent infection is common, and a longer duration of therapy (at least 2 weeks) is recommended. Arcobacter butzleri, A. skirrowi, and more rarely, A. cryaerophila, have been associated with diarrheal disease in humans, especially among children (60,129,146). Bacteremia also has been reported, primarily in immunocompromised patients (50,88,157, 215). Fluoroquinolones are the drug of choice, though resistance has been described (216).

Special Situations

Travelers

C. jejuni is an important cause of diarrhea among persons traveling from highly industrialized countries to developing areas. During the fall and winter, C. jejuni infection may be the most common bacterial cause of travelers' diarrhea in many locales (34,73). Antibiotic prophylaxis for persons traveling to high-risk areas is not recommended except in very specific clinical situations. Instead, travelers should be advised to practice ordinary precautions such as drinking only treated or bottled water, avoiding raw foods of animal origin, and eating only cooked or peeled fruits and vegetables. If diarrhea accompanied by fever develops, antimotility agents such as loperamide should not be used, as a paradoxical worsening of symptoms may occur due to intestinal invasion with Campylobacter, Salmonella, or Shigella (27). If antibiotic treatment of travelers' diarrhea is considered necessary, azithromycin is a better choice than fluoroquinolones in most common destinations in the developing world as it treats Campylobacter in addition to Shigella and enterovirulent E. coli.

Life-Threatening Campylobacter Infections

Campylobacter infections usually may be treated with a single agent; combination therapy is infrequently required. One exception may be when it is necessary to treat a life-threatening, blood-borne Campylobacter infection with systemic complications. In such cases it might be reasonable to treat with an aminoglycoside and a carbapenem while awaiting susceptibility results.

Pregnancy

Most Campylobacter infections in pregnant women are mild and self-limited with no severe adverse consequences for the mother or baby (156,158). However, neonatal sepsis and death can occur if a woman is infected during the third trimester as babies can be infected during birth if the mother is excreting Campylobacter at the time of delivery (7,59,116). Neonates may experience only benign infection but they also may develop severe enteritis or meningitis (44,46,143). Even earlier in pregnancy, infection with C. jejuni may produce spontaneous abortion or premature labor (115). Therefore, all Campylobacter infections in pregnant women should be promptly treated with antibiotics. Fluoroquinolones and tetracyclines are not recommended in this setting as these agents are not safe for the developing fetus. Erythromycin is the drug of choice; for women with a history of hypersensitivity to erythromycin, amoxicillin-clavulanate should be used. However, although erythromycin, chloramphenicol, and amoxicillin-clavulanate have no known teratogenic effects, controlled trials in pregnant women establishing their safety have not been done.

HIV/AIDS

Campylobacter infections as well as other common foodborne infections occur at a high rate among persons infected with human immunodeficiency virus (HIV). The reported incidence of Campylobacter infections among persons infected with HIV in Los Angeles was almost 40 times higher than that observed in the general population (126). The prevalence of Campylobacter infections among hospitalized HIV-infected persons was 2.2%, substantially higher than the expected rate among HIV antibody-negative hospitalized patients (82). In addition to an increased incidence and prevalence, the severity and duration of Campylobacter infections are more likely to be increased among HIV-infected persons (93,126). Bacteremia was detected in 17% of C. jejuni-infected HIV antibody positive patients (80). Other campylobacters and Campylobacter-like organisms (e.g. C. hyointestinalis, H. cinaedi, H. fennelliae) also are far more common among homosexual men. Therefore, HIV-infected persons should almost always receive antibiotics for Campylobacter enteritis. Furthermore, because of differences in optimal treatments, species determination, especially in patients with persistent, recurrent, or severe infections, should be done whenever Campylobacter is isolated. Defects in humoral immunity may contribute to the persistence and severity of Campylobacter infections among patients with HIV. Chronic Campylobacter infections lasting several months despite repeated courses of antibiotics are commonly seen among patients with HIV (13,28,80,93) although brief infections occur as well. Initial resistance to antibiotics used, acquisition of resistance during therapy, and insufficient duration of therapy may play a role in some treatment failures. Close monitoring of patients with repeated culture and susceptibility testing and prolonged treatment (e.g., many months or life-long) may be necessary in some patients. Campylobacter infection should be considered in the differential diagnosis of HIV patients with persistent diarrhea even if the organism is not identified in stools. Failure to culture Campylobacter from stools does not rule out their presence as the organisms are sometimes difficult to isolate.

Other Immunocompromised Hosts

Although the serum-resistant organism, C. fetus, is a known opportunist in immunocompromised persons, C. jejuni, which usually is serum-susceptible, also can produce bacteremia and severe illness in such patients. Patients with acquired or congenital hypogammaglobulinemia may develop severe, recurrent Campylobacter enteritis (4,70,76,96). Hypogammaglobulinemic patients also are particularly susceptible to extra-intestinal C. jejuni infections (e.g., bacteremia, skin infections, osteomyelitis), suggesting that immunoglobulins are important in the defense against Campylobacter infections (24,56,127,142). Indeed, in one study of 41 hypogammaglobulinemic patients, 5 (12%) had experienced at least one episode of documented C. jejuni septicemia (61). Patients with hypogammaglobulinemia likely lack serum bactericidal activity against Campylobacter, as the organism usually is serum susceptible (18). Therefore, treatment with antibiotics alone may fail to eradicate the infection. Although administration of IgG preparations has not restored the serum bactericidal activity against Campylobacter in hypogammaglobulinemic patients, this activity may be restored by infusions of plasma substitution therapy (61, 142). Perhaps this is because plasma substitution therapy restores IgM, which is most efficient for complement activation leading to serum killing (18). Combination treatment with immunoglobulin (plasma) and antimicrobial therapy may be needed to achieve cure in certain cases. For very ill patients with sepsis, immunocompromise, or both, use of a carbapenem, to which Campylobacter is exquisitely susceptible, is warranted. The addition of an aminoglycoside may be considered in seriously ill patients with normal renal function.

Alternative Therapy

Amoxacillin-Clavulanate

Given the emerging resistance to quinolones, second line oral therapy for Campylobacter species, amoxicillin-clavulanate is now the preferred second line agent for mild- moderate disease for use in macrolide resistant disease. Although in a recent study of multidrug resistant Campylobacter isolates from Finland, amoxicillin-clavulanate resistance was noted in 31% of macrolide resistant isolates and 18% of macrolide sensitive isolates, this compares favorably to other options. Other studies document lower resistance (217). Clavulanic acid has been shown to increase the susceptibility of Campylobacter to amoxicillin and thus amoxicillin-clavulanate is preferred over amoxicillin alone.

Fluoroquinolones

Fluoroquinolones have been considered as among the agents of choice for empiric treatment of travelers' diarrhea and of bacterial gastroenteritis in general. However, after initial interest in the use of these agents, they are no longer considered appropriate for the treatment of Campylobacter infections because of increasing primary resistance. Not surprisingly, secondary (in vivo) resistance to quinolones emerges rapidly in patients requiring prolonged treatment (2,114). However, even in healthy hosts with limited illnesses, an initially susceptible strain may become resistant after only a brief (< 2 weeks) duration of therapy (3, 111, 155).

Tetracyclines

Plasmids are responsible for the increasing level of Campylobacter resistance to tetracyclines. More than half of campylobacters were found to be resistant in some studies (86,109,149), but in others, fewer than 15% of isolates exhibited resistance to tetracycline (108,128). The rate of resistance is higher for C. coli than for C. jejuni and is higher among campylobacters isolated from humans than from animals (1,105,109). More than 80% of tetracycline resistant strains possess tet(O), the ribosomal resistance factor, on a conjugative plasmid which mediates resistance to this drug although chromosomal presence of tetO has also been documented (8,131,132,134,136,137).

Chloramphenicol

Chloramphenicol remains a useful alternative to erythromycin for treatment of C. jejuni infections, both because of its effectiveness and low cost where it is still available. C. jejuni are almost always susceptible to chloramphenicol35 although a small proportion of C. coli strains are resistant (53,77,149,109,153). Occasional resistance is mediated by production of chloramphenicol acetyl transferase, which is encoded on a transferable plasmid (109,126). This agent should never be used routinely but can be reserved for patients with recurrent infections, who are immunocompromised, or have extra-intestinal infections.

Cephalosporins

Nearly all C. jejuni and C. coli strains are resistant to first generation cephalosporins such as cephalothin, cefazolin, and cefuroxime (151). They may be susceptible to cefotaxime, ceftazidime, and ceftriaxone, but they are inferior options to carbapenems for severe disease and should not be used empirically.

Alternative agents for severe or disseminated disease

Resistance rates to carbapenems, tigecycline, and aminoglycosides among Campylobacter species have remained under 1%. For very ill patients with sepsis, immunocompromise, or both, use of an intravenous agent such as meropenem, to which Campylobacter is exquisitely susceptible, may be needed. Addition of an aminoglycoside can be considered in seriously ill patients.

ADJUNCTIVE THERAPY

As discussed previously, most Campylobacter infections produce a self-limited illness and do not require treatment with antimicrobial agents. In severely ill persons or the very young or old who are especially prone to becoming dehydrated, intravenous fluids may be necessary. For most infected persons however, maintaining proper hydration and electrolyte balance can be accomplished by encouraging proper oral intake of liquids.

Supportive care of patients who are critically ill or septic due to infection with Campylobacter is not different from care of other critically ill persons. Surgical treatment is not a component of care in treatment of Campylobacter infections. Even patients with toxic megacolon are best managed with antibiotics and supportive care. In addition to treatment with antibiotics, patients with hypogammaglobulinemia may benefit from plasma substitution therapy for successful treatment of disseminated Campylobacter infection.

ENDPOINTS OF MONITORING THERAPY

Most patients with Campylobacter infection who require antimicrobial therapy respond promptly to treatment. Repeat cultures with drug susceptibility testing should be performed on any patient with worsening symptoms or symptoms lasting longer than one week, or presence of bloody stools or high fevers despite therapy. If such testing is not immediately available, empiric change or adding to the antimicrobial regimen may be required for patients who are seriously ill and not responding to therapy. Even in severely ill patients, one week usually is sufficient to eradicate infection. However, in patients with persistent or recurrent infections, especially those occurring in immunocompromised patients, prolonged use of antibiotics (perhaps months) may be required. Documentation of eradication of bacteria from stools of pregnant women is needed as there may be severe consequences to the neonate if the mother is still excreting Campylobacter at the time of delivery.

VACCINES

Currently there is no commercially available vaccine for Campylobacter for human use. There are ongoing efforts to develop vaccines in both humans and in poultry. The pattern of human disease in communities where Campylobacter is endemic support the acquisition of immunity as do some, but not all, human challenge studies. Vaccine development is severely hampered by a lack of understanding of pathogenesis, the identity of key epitopes that establish effective and protective immune responses and the diversity of these epitopes among disease causing strains. Added to these barriers are safety concerns regarding formulations that may induce GBS, reactive arthritis, or IBS. Currently development has focused on a capsular polysaccharide conjugate vaccine, which would allay many safety concerns as the capsular polysaccharides do not have ganglioside mimics, but the distribution of capsular polysaccharides is diverse and just now being defined (218). A recombinant vaccine directed at amino acid transporter PEB1 was shown to be protective in a non-diarrheal mouse model, but further reports on its development are lacking (219). It does not appear that a human vaccine will be available in the near future (220).

The development of poultry vaccines appears more feasible at this time. As source attribution studies clearly and consistently link human C. jejuni infections to poultry the implementation of such a vaccine may have important disease control implications in the U.S. and Europe. In poultry, there are several different vaccines in early phases of development.  A chitosan-DNA intranasal vaccine has resulted in 2-3 log reductions in intestinal and cecal counts of Campylobacter following administration of a Campylobacter jejuni strain (221) whereas newer glycoconjugate vaccines have demonstrated more robust reductions in cecal carriage following controlled infections (222, 223).

PREVENTION

Person-to-person transmission of C. jejuni infection is unusual; nevertheless all persons should wash their hands after using the bathroom, especially if they have diarrhea. Similarly, all people, but especially those who handle pets or other animals, should wash their hands before eating. Persons with any acute diarrheal illness should avoid preparation and handling of food until their illness resolves. To date, there have been no reports of transmission of Campylobacter infection by asymptomatic excretors. Asymptomatically infected food handlers or hospital employees need not be excluded from work, but the importance of hand-washing should be stressed to these individuals. Stool cultures of asymptomatic contacts are not recommended. The most common route of transmission of C. jejuni infection to humans in the U.S. and Europe is from eating or handling poultry. Therefore, the most effective preventive strategies are those that interrupt this transmission. Observing careful food preparation habits in the kitchen is important in preventing infections. Chicken should be thoroughly cooked. Cutting boards and utensils used in handling uncooked poultry or other meats should be washed with hot soapy water before being used for preparation of salads or other foods eaten raw. The near universal contamination of poultry with Campylobacter and the heavy bacterial burden in these flocks make elimination of Campylobacter in chickens impractical if not impossible (49). However, strategies that alter the amount of contamination allowed has been demonstrated to reduce the burden of human disease in New Zealand and the expansion of this type of legislation appears to be warranted in similar epidemiologic contexts such as Europe and the United States. This is not feasible in most parts of the developing world, where the disease burden in greatest and likely a result of sustained human to human transmission. Prevention of many outbreaks of C. jejuni infection could be accomplished by avoiding consumption of unpasteurized milk; this should be emphasized to pregnant women, the elderly, immunocompromised persons, or other persons in whom C. jejuni infection may have serious consequences. Travelers to developing countries and campers should be cautioned against drinking untreated water and to practice frequent handwashing. Routine use of antibiotic prophylaxis to prevent Campylobacter infections is not recommended.

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