Campylobacter jejuni and fetus

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Campylobacter jejuni subspecies jejuni and Campylobacter fetus subspecies fetus—gram-negative rods in the family Campylobacteraceae

What is the best treatment?

Preferred anti-infective treatment

C. jejuni

• The preferred anti-infective agent for acute gastroenteritis or colitis in immunocompetent adults is a macrolide, such as azithromycin, which can be given as a daily oral dose of 500mg for 5 days. Children can receive azithromycin at 10mg/kg/day for 5 days.

• Erythromycin is equally effective as azithromycin, but more frequently causes gastrointestinal side effects and requires four doses per day compared to once daily for azithromycin. Clarithromycin is likely to be as effective as azithromycin, but less data exists to support its use.

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• Antacids containing aluminum or magnesium reduce the absorption of macrolides, particularly azithromycin, and should be avoided.

• Fluoroquinolones are an alternative to macrolides, but should be used only when susceptibility has been established, because resistance rates can be as high as 20%. For sensitive organisms, however, ciprofloxacin can be given to adults as a 500mg dose twice daily for 5 days. However, it should be noted that fluoroquinolone resistance has emerged during treatment, so it should only be used when no other option is feasible.

• Alternative agents in children include clindamycin given as 10 to 40mg/kg/day, depending on age and disease severity, in four divided doses for 5 days. Tetracycline is also an alternative in children older than 8 years of age and can be given 25 to 50mg/kg/day in four divided doses for 7 days.

C. fetus

• Since this organism usually causes systemic disease (as opposed to localized gastrointestinal disease caused by C. jejuni), the preferred anti-infective approach is parenteral. Ampicillin may be given 100mg/kg/day in four divided doses for 3 weeks for infections involving the central nervous system or 4 weeks for endovascular infections, for both adults and children. Patients with isolated diarrheal illness can be treated for 2 weeks.

• For penicillin-allergic patients, gentamicin may be given at 1 to 1.7mg/kg/day every 8 hours; children can receive 2.5mg/kg every 12 hours, both for the time courses mentioned above. Close renal monitoring is required, given the potential for nephrotoxicity and ototoxicity.

• For immunocompromised patients or patients who are critically ill, combination therapy with ampicillin and gentamicin is reasonable.

• Although studies show that more than 95% of C. fetus isolates are susceptible to carbapenems, these agents should not be initiated empirically, because they are broad-spectrum and their indiscriminate use needlessly contributes to the problem of antibiotic resistance.

• Because of the propensity for relapse, prolonged treatment of C. fetus is recommended as previously outlined.

Antibiotic resistance issues

C. jejuni

• Fluoroquinolone resistance is increasing, both domestically and abroad, reaching levels as high as 20%. This has been driven by indiscriminate use of antimicrobials in humans, as well as in animal husbandry.

C. fetus

• Resistance to cephalosporins, macrolides, tetracyclines, and fluoroquinolones is unacceptably high, and these agents should not be used to treat C. fetus infections.

Mechanisms of resistance

C. jejuni

• The most common mechanism of resistance to fluoroquinolones involves mutations in the DNA gyrase gene (gyrA). Previously, it was thought that occasional mutations to topoisomerase IV (parC and parE) were the basis for fluoroquinolone resistance, but sequencing of the C. jejuni genome shows that it lacks those genes.

• Resistance to macrolides is likely due to alterations of 23S rRNA genes.

• Tetracycline resistance occurs via ribosomal protection encoded by the gene tetO.

• The multidrug efflux pump (CmeABC) may also contribute to fluoroquinolone, macrolide, and tetracycline resistance.

• Beta-lactam resistance mainly occurs because of beta-lactamase production; outer membrane porins may also limit access of some beta-lactam antibiotics.

C. fetus

• Much less is known about antibiotic resistance mechanisms of C. fetus. However, unlike C. jejuni, beta-lactamases were not identified in 111 C. fetus strains in one study.

• With regard to resistance to host defenses, the well-described serum resistance of C. fetus is due to the presence of a proteinaceous S-layer, which forms a paracrystalline array on the surface of the organism. This S-layer is comprised of acidic high molecular weight proteins and prevents the deposition of the key opsonin C3b. C. fetus can vary the S proteins, thereby delaying opsonization by antibody deposition. By these mechanisms, the S-layer allows C. fetus to avoid killing by serum and phagocytosis.

Detection of resistance

• Standard microbiologic testing will detect antibiotic resistance in C. jejuni and C. fetus. It is notable that all C. fetus isolates from humans possess a functional S-layer, rendering them serum-resistant.

• In patients who are hypogammaglobulinemic and have recurrent C. jejuni diarrhea, oral immunoglobulin (Ig) has been used by some with success, as has fresh frozen plasma, but the evidence for these approaches is limited. However, it is notable that intravenous immune globulin is not useful to treat C. fetus bacteremia, because, as a rare disease, antibodies to C. fetus are not normally present in the general population. Antimotility agents should be avoided for diarrheal disease, as some studies suggest that their use may prolong symptoms and have been associated with increased mortality.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

Both C. jejuni and C. fetus are zoonoses. C. jejuni is often food-borne and affects immunocompetent and immunocompromised persons, whereas C. fetus is usually only seen in immunocompromised patients. Neither is a reportable disease in the United States.

C. jejuni

• Infection caused by C. jejuni is common and is the second-leading cause of food-borne illness in the United States. Although most illnesses are not laboratory-confirmed, an estimate based on the surveillance pyramid model used by the FoodNet section of the US Centers for Disease Control and Prevention (CDC) predicts about 1,250,000 illnesses due to Campylobacter occur annually, an incidence rate of 432 cases per 100,000 persons. (This estimate includes all Campylobacter species.) The case fatality rate is low at 0.11%, or 11 per 100,000 culture-confirmed cases, based on FoodNet data.

• These infections occur year-round but peak in July and August, similar to other food-borne illnesses in the United States. This occurs seasonally, because most outdoor cooking, group picnics, and water activities occur during the summer months.

• The animal reservoirs for infection include poultry and cattle. Most sporadic infections are acquired through the improper handling/cooking of chicken and turkey; outbreaks have been described in connection with ingestion of unpasteurized milk. Since the excreta of infected animals may contaminate water sources, drinking untreated water is another major source of C. jejuni infection. Also, increased rainfall has been associated with C. jejuni infections, mostly in tropical areas.

• Household pets have been implicated in transmission of C. jejuni.

• Although fecal-oral person-to-person transmission is possible, it is not a major mode of transmission. Populations at most risk for this uncommon occurrence are those who care for incontinent persons, including infants and the elderly.

• C. jejuni infections occur worldwide. In developing nations, most children have multiple Campylobacter infections by 2 years of age, and the majority of the population has been exposed by 5 years of age. In rural areas of developed nations, a similar pattern is observed. However, in most of the developed world, the prevalence is less than 1%. There is still a peak of infection in infants under 1 year of age, and a second peak in the group 15 to 29 years of age.

• Campylobacteriosis should be considered as a cause of acute diarrheal illness in travelers. Estimates of C. jejuni as a cause of traveler’s diarrhea range from 1 to 2% in travelers to Mexico to as high as 28% in travelers to Thailand.

• In the developing world, the incidence of C. jejuni infection is stable. However, in the United States, the incidence began to decline in 1996, a trend that continued through 2005, after which it has mostly stabilized at current levels. This decline can be largely attributed to improved hygienic practices on farms and slaughterhouses consequent to the Hazard Analysis Critical Control Point (HAACP) program promulgated by the US Food and Drug Administration (FDA).

C. fetus

• C. fetus infections are uncommon and typically occur in immunocompromised persons.

• These infections also follow a seasonal pattern similar to C. jejuni, although the peak is less marked. It is not clear why this seasonality exists, as many infections are not food-borne.

• The animal reservoirs include cattle, pigs, sheep, and other farm animals, as well as reptiles; persons in regular contact with these animals are at increased risk for contracting C. fetus infection.

• Eating improperly prepared meats from infected animals and working in slaughterhouses has been associated with C. fetus infection.

• Nosocomial and laboratory-acquired infection have also been described.

• The mode of transmission for many C. fetus infections is unclear, because some persons do not report contact with farm animals or other obvious risk factors.

• Although diarrhea due to C. fetus can be seen in immunocompetent persons, the most common presentation of C. fetus disease is systemic illness in an immunocompromised person, particularly those with acquired immunodeficiency syndrome (AIDS) or hypogammaglobulinemia. Persons who have undergone bone marrow transplantation who are cirrhotic or diabetic, are also at increased risk.

Infection control issues

• When caring for patients with diarrhea due to Campylobacter, contact precautions are advised; otherwise, standard precautions should be employed.

• No vaccine is available.

What host factors protect against this infection?

C. jejuni

• Infection occurs in all age groups, although there is a peak of infection in infants younger than 1 year of age and a second peak in the group 15 to 29 years of age. Persons with AIDS are 40 times more likely to develop diarrheal disease from C. jejuni, and persons with hypogammaglobulinemia are also well-recognized to be at increased risk for infection.

• C. jejuni is susceptible to killing by reactive nitrogen species, whose generation begins when salivary nitrate is acidified by gastric acid. C. jejuni is directly killed by gastric acid as well. In the small intestine, cationic antimicrobial peptides (defensins and cathelicidins) produced by enterocytes contribute to innate host defense. Toll-like receptors and nucleotide oligomerization domain (NOD) proteins afford extra- and intracellular recognition of C. jejuni, while marshaling additional soluble and cellular components of host defense. Tissue macrophages, dendritic cells, and recruited neutrophils affect killing of C. jejuni by the production of reactive nitrogen and oxygen species, as well as additional cationic antimicrobial peptides and proteins.

• C. jejuni is serum-sensitive, which underlies the observation that bacteremia is rarely observed in immunocompetent hosts. It can be opsonized by complement and/or antibody and is subject to phagocytosis and subsequent killing by phagocytes in blood as in intestinal tissues.

• In previously exposed persons, serum and intestinal IgA and serum IgG confer protection. Cell-mediated immunity may play a role in immune defense, but specific mechanisms have not been clearly described.

• Although the innate immune response is usually able to clear the initial infection, subsequent protection requires humoral immunity. Persons who have recovered from C. jejuni infection have been documented to have increased serum levels of C. jejuni-specific IgA, IgM, and IgG, as well as IgA in intestinal secretions. The importance of humoral immunity is underscored by the observation that persons with hypogammaglobulinemia are at particular risk for C. jejuni infection and severe disease, as are AIDS patients, who do not mount a robust C. jejuni-specific humoral immune response. Protective serum antibodies begin to appear at about the fifth day of illness and increase for 2 to 4 weeks before declining to a basal level over months.

• Although cell-mediated immunity (including intestinal dendritic cells) may also directly contribute to resolution of infection, the specific role it may play is not yet clear.

• Breast milk contains fucosylated sugars that form a chemical barrier that inhibits the binding of C. jejuni to intestinal cells.

• C. jejuni is bile-tolerant and colonizes the small bowel and then the colon. Examination of infected tissue shows an exudative, bloody enteritis with an inflammatory infiltrate of neutrophils, mononuclear cells, and eosinophils. Although this innate immune response is necessary to clear the infection, it also contributes to tissue pathology and leads to substantial submucosal edema, ulceration, and crypt abscesses. These features are similar to what may be seen in inflammatory bowel disease or salmonellosis. Also, these histological findings are consistent with direct tissue invasion by C. jejuni. Whether this occurs by disruption of tight junctions, direct invasion of individual enterocytes, or a combination of both is not clear.

C. fetus

• Persons in close contact with infected farm animals or reptiles are at increased risk of contracting C. fetus. Most of these patients have an underlying immunocompromising condition, such as diabetes, cirrhosis, alcoholism, asplenia, AIDS, or bone marrow transplantation, or require chronic steroids.

• Since the majority of patients who develop illness due to C. fetus infection suffer from conditions that impair multiple aspects of the innate and adaptive immune systems (i.e., diabetes, alcoholism, bone marrow transplant recipients, AIDS), it is difficult to attribute a single host defense element as key to prevention of infection. However, in animal studies, C. fetus-specific antibody against S-layer proteins protects against subsequent infection, suggesting that a similar process may occur in humans.

• Some of the antibodies are directed against relatively conserved regions of the S-layer proteins, raising the possibility that a vaccine may be feasible.

• Although the lipopolysaccharide (LPS) of C. fetus has variable biological activity among strains, they are less potent compared to classical Enterobacteriaceae LPS and may assist the organism in evasion of host defense.

• The organism has a predilection for the vasculature and endothelium, manifested by its association with thrombophlebitis, mycotic aneurysm, and endocarditis; however, the molecular underpinnings of these phenomenae are not understood.

• The histopathology reflects the tissue type affected and includes abscesses, cardiac valvular vegetations, meningoenchephalitis, osteomyelitis, enteritis, and placentitis.

What are the clinical manifestations of infection with this organism?

C. jejuni

• A self-limited, gastroenteritis accounts for the majority of cases and cannot be clinically distinguished from other common enteritides. The usual incubation period extends from a few hours to 8 days, with a mean of about 3 days after ingestion of contaminated food or water. In most cases, there is a prodromal phase consisting of fever, myalgia, malaise, and/or headache 21 to 24 hours before the onset of diarrhea and crampy abdominal pain, usually in the right lower quadrant. These intestinal symptoms usually last between 1 and 7 days before spontaneously resolving in the majority of patients. In some cases, diarrhea may be severe, and/or bloody, with concomitant tenesmus, which may last longer than 1 week. In its most fulminant form, C. jejuni can mimic enteric fever and may progress to toxic megacolon.

• It is notable that not all exposures to C. jejuni lead to symptomatic disease.

• Bacteremia remains rare (<1%) in immunocompetent persons.

• Persons with AIDS are at approximately 40-fold increased risk for Campylobacter infection and are also more likely to have severe disease or chronic carriage. Also, approximately 10% of persons with human immunodeficiency virus (HIV)/AIDS were found to be bacteremic in one study. Patients with hypogammaglobulinemia are also at high risk for severe and/or recurrent enteritis, and optimal treatment likely requires antimicrobial therapy combined with an IgM-containing immunoglobulin preparation (i.e., Pentaglobulin).

• In infants, C. jejuni disease may present as fever or vomiting only or with grossly bloody stools. Severe disease may mimic necrotizing enterocolitis.

• Patients may excrete organisms for several weeks after the illness has resolved. This is not thought to contribute to disease spread, since fecal-oral transmission is unusual, although it may occur in incontinent persons (i.e., the elderly and infants).

C. fetus

• This organism is usually associated with systemic disease in immunocompromised hosts, and bacteremia is the most common manifestation. This ability to cause systemic disease is tightly linked to production of an antiphagocytic and serum-resistant S-layer that acts like a proteinaceous capsule. Bacteremia likely occurs secondary to gastrointestinal infection, and these patients present, as do other patients, with sepsis and may have fever, rigors, chills, and myalgia. These symptoms may become recurrent if untreated.

• C. fetus demonstrates an affinity for the vasculature and has been associated with mycotic aneurysms, septic thrombophlebitis, endocarditis, and placentitis. In pregnant patients, the occurrence of fetal loss can be as high as 70%, even with appropriate antimicrobial therapy. Fetal loss can occur even if the mother is only mildly ill.

• Meningoencephalitis is the second most common manifestation of C. fetus infection and may occur secondary to unrecognized bacteremia. The cerebrospinal fluid usually shows a neutrophil predominance, mildly depressed glucose, and mildly elevated protein. Patients may also develop brain abscess, cerebral infarction, or hemorrhage.

• Pneumonia, arthritis, cellulitis, and peritonitis due to C. fetus have also been described.

• In immunocompromised hosts, C. fetus is capable of establishing latent infection in various sites, leading to relapse. This is especially likely if the patient did not receive a prompt, sufficient course of antibiotics during the initial infection. The mechanism by which C. fetus can evade the immune system is not completely understood but probably involves antigenic variation of its S-layer proteins and the low biological activity of the Lipid A portion of its LPS.

• Overall, mortality due to C. fetus reaches approximately 20%. The key to limiting mortality due to systemic C. fetus disease is the prompt administration of appropriate antibiotics.

• C. fetus may also cause diarrheal disease and is indistinguishable from C. jejuni-mediated diarrheal disease. Occasionally, the diagnosis of C. fetus enteritis is made after a person has clinically recovered, which may occur in the absence of treatment (no further treatment is needed in that scenario).

What common complications are associated with infection with this pathogen?

C. jejuni

• The most common early-onset complication associated with C. jejuni enteritis is bacteremia, although it is still an uncommon occurrence (<1% of infections). Rare complications include appendicitis, toxic megacolon, intestinal hemorrhage, cholecystitis, hepatitis (mild), pancreatitis, hemolytic-uremic syndrome, nephritis, urticarial rash, septic abortion, and perinatal infection. Bacteremia is much more common in AIDS patients, reaching as high as 10%. The most common late-onset complications are reactive arthritis/Reiter syndrome, Guillain-Barré syndrome (GBS), and irritable bowel syndrome (IBS).

  Reactive arthritis/Reiter syndrome consists of migratory joint inflammation involving the knees, ankles, hands, and feet and may occur up to 6 weeks post-infection. Patients recover from this arthritis without sequelae. A minority of these patients will also have uveitis/conjunctivitis and urethritis/cervicitis (Reiter syndrome). For both complications, an association with human leukocyte antigen (HLA)-B27 is evident.

  Although GBS occurs in only approximately 0.05% of C. jejuni infections, these infections are antecedent in about 30 to 50% of GBS cases. It is associated with certain LPS serotypes and is due to molecular mimicry between certain sugar groups on LPS that are similar to those on certain nerves. This leads to a polyradiculoneuropathy with weakness and diminished reflexes and occurs 2 to 4 weeks after diarrheal illness. There is no HLA association. The disease may be severe; up to 33% of patients cannot ambulate independently for as long as 6 months after the onset of disease, and this impairment may be irreversible.

  IBS is characterized by cramping, abdominal pain, bloating, gas, diarrhea and/or constipation and follows many episodes of infectious enteric illness in addition to Campylobacter. The cause is unclear, and the treatment is symptomatic.

C. fetus

• Disease relapse is the most common complication of C. fetus infections and may manifest as recurrent bouts of enteritis, peritonitis, arthritis, or bacteremia. In pregnancy, fetal loss is a common complication of maternal infection.

How should I identify the organism?

• Campylobacters are motile, non-spore-forming, small, gram-negative curved rods with dipolar flagella. Although conventional Gram staining is often used, the safranin counter stain does not stain Campylobacter particularly well; use of carbol fuchsin or 0.1% aqueous basic fuchsin is preferred, especially for stool samples.

• All campylobacters will grow at 37°C, are fastidious and microaerophilic; they grow best in an environment of 5% oxygen, 10% carbon dioxide, and 85% nitrogen. However, in the clinical microbiology lab, Campylobacter is usually grown on plates in a closed chamber containing an insert that produces an enriched, carbon dioxide atmosphere of 10 to 15%. There are several solid media that support the growth of most Campylobacter species; commonly used is “Campy-BAP.” This media contains 5 antimicrobials (vancomycin, cephalothin, trimethoprim, polymyxin B, and amphotericin) to suppress the growth of other organisms that may be found in stool. The plates are incubated at 42°C, a temperature at which C. jejuni and most other campylobacters will grow, but not C. fetus or most other non-Campylobacter organisms. Even under ideal conditions, visible growth of the flat, grey-white colonies usually requires at least 48 hours and can take as long as 5 days. The colonies may have a glistening appearance but are not mucoid. Most strains are nonhemolytic, but occasionally beta or alpha hemolysis can be seen with extended incubation. For diarrheal disease, a stool specimen is superior to a rectal swab. Although the sensitivity of a single stool culture is high, two stool samples may be needed to rule out Campylobacter disease.

• Optimal conditions for collection of blood culture samples, which are particularly relevant for suspected C. fetus infections, have not been extensively studied. However, standard blood culture systems, such as BACTEC or BacTAlert, support the growth of most campylobacters. If a pure culture of gram-negative, curved rods is observed from a blood culture, the suspicion for C. fetus infection is high. Aliquots from the blood cultures are swabbed onto nonselective sheep blood agar plates, followed by microaerophilic incubation at 25, 37, and 42°C. C. fetus will grow under the first two temperatures but not at 42°C, differentiating it from C. jejuni. If C. fetus infection is suspected, the blood culture bottles should be held for 2 weeks, as it grows slowly even under ideal conditions.

• Direct Gram stain of the stool obtained from the acute phase of diarrheal illness showing small curved organisms ranges from 64 to 94%, and is greater than 95% specific. Stool antigen tests are also available and have sensitivities between 80 and 96%, and specificity greater than 97% (compared to culture).

• Other methods for detection and isolation of campylobacters in liquid media have been reported with varying success, including filtration methods and enrichment broths. Molecular testing, including polymerase chain reaction (PCR), is investigational and not yet commercially available.

• All campylobacters reduce nitrate and are oxidase positive. Campylobacter do not ferment or oxidize carbohydrates but rather obtain energy from amino acids or intermediates generated in the tricarboxylic acid pathway. C. jejuni is distinct from other campylobacters in that it hydrolyzes hippurate. C. jejuni (and C. lari and C. coli) are resistant to cephalothin, whereas C. fetus is susceptible to this antibiotic.

How does this organism cause disease?

C. jejuni

• The infective dose is approximately 500 to 800 organisms, but the larger the inoculum, the shorter the incubation period. C. jejuni adheres to intestinal tissue via several adhesions, followed by tissue injury throughout the small bowel, colon, and rectum. The mechanism includes tissue invasion, occurring probably both directly through enterocytes, as well as via disruption of tight junctions. Many strains produce a cytolethal distending toxin, but it is not clear that this protein is required for virulence. Some studies have shown an association between carriage of the pVir plasmid, which encodes a type IV secretion system, but the effector(s) that contribute to the disease process are not described. The flagellar export apparatus can deliver the Campylobacter invasion proteins, effector molecules that aid in the uptake and intracellular survival of C. jejuni.

• In symptomatic patients, the sequence of events in symptomatic disease is:

  ingestion→intestinal colonization→intestinal invasion→inflammatory response→resolution

• The organism is transmitted mainly through ingestion of contaminated food, milk, or water and is not typically passed person-to-person. It can survive at low temperatures if the oxygen tension is low.

• Cross-contamination of food items can occur and lead to disease, such as preparing raw chicken on the same cutting board that is later used to prepare vegetables.

• In many cases, the disease may be subclinical or mild and never come to clinical attention. A minority will develop serious, post-infectious complications, including GBS or reactive arthritis/Reiter syndrome.

C. fetus

• Although C. fetus is a well-known veterinary pathogen, as a human pathogen, it is not well-studied and the infective human dose is not known. In vitro evidence suggests that it invades intestinal epithelium, although it is not clear if this includes disruption of the tight junctions or only direct invasion. However, it is clear that the S-layer, a proteinaceous capsule surrounding the organism, is key to its virulence. Only strains that express this S-layer can cause systemic disease, as it prevents deposition of the opsonin C3b. Once antibodies to the S-layer form, then the organism can be opsonized and then ingested by phagocytes. However, the organism is capable of antigenic variation of its S-layer genes (sap), which permits evasion of the adaptive immune response. This strategy may also support disease relapses associated with C. fetus infections.

• The cytolethal distending toxin causes in vitro cytotoxicity, but its contribution to human disease is not known.

• In immunocompromised hosts, the sequence of events in human disease likely follows this pathway:

  ingestion→intestinal colonization→intestinal invasion→local inflammatory response→bactermia→inadequate systemic inflammatory response→seeding of tissues and sepsis

• In immunocompetent hosts, the infection may cease at the local level in the intestine or a transient bacteremia may occur that is contained by an adequate systemic inflammatory response. In some immunocompetent persons, the disease may be subclinical or very mild and never come to clinical attention.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Allos, B, Blaser, MJ, Mandell, GL, Bennett, JE, Dolin, R. ” and related species”. Principles and practice of infectious diseases. vol. 2. 2010. pp. 2793-802.

Black, RE, Levine, MM, Clements, ML, Hughes, TP, Blaser, MJ. “Experimental infection in humans”. J Infect Dis. vol. 157. 1988. pp. 472-9.

Nachamkin, I, Szymanski, CM, Blaser, MJ. Campylobacter. 2008.

“FoodNet-Foodborne Diseases Active Surveillance Network”.

“Infectious Diseases Related to Travel”.

Guerrant, RL, Van Gilder, T, Steiner, TS. “Practice guidelines for the management of infectious diarrhea”. Clin Infect Dis. vol. 32. 2001. pp. 331-51.

Molina, J, Casin, I, Hausfater, P. ” infections in HIV-infected patients: clinical and bacteriologic features”. AIDS. vol. 9. 1995. pp. 881-5.

“Hazard Analysis & Critical Control Points (HACCP)”.

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