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Campylobacter
Chapter 19
Campylobacter Chapter outline Properties of genus Antigenic characteristics Toxins and virulence factors produced Toxins Enterotoxin Cytotoxin Cytolethal distending toxin Transmission Diagnosis Laboratory examinations Characteristics of antimicrobial resistance Quinolone resistance
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Tetracycline resistance Macrolide resistance Aminoglycoside resistance b-Lactam antibiotic resistance Chloramphenicol resistance Sulphonamide resistance Trimethoprim resistance Streptothricin resistance Poultry Pigs Human References
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In 1886, Escherich observed Campylobacter-like organisms in stool samples of children with diarrhoea (Vandamme, 2000). In 1913, McFaydean and Stockman first confirmed them as Campylobacter in foetal tissues of aborted sheep. Confirmatory tests were also carried out by Smith (1919) when similar organisms (Vibrio foetus) were isolated from aborted bovine foetus. Vandamme (2000) and Doyle (1944) isolated Vibrio jejuni and Vibrio coli from cattle and pigs, respectively, suffering with diarrhoea (Doyle, 1944; Vandamme, 2000). Sebald and Véron (1963) differentiated the bacteria from Vibrionaceae family, and the new genus Campylobacter (‘curved rod’) under Campylobacteriaceae family was proposed due to low DNA base composition, nonfermentative metabolism and microaerophilic growth requirements. Campylobacter causes 400e500 million cases of infection in human each year throughout the world (García and Heredia, 2013). Campylobacteriosis is endemic among children in Asia, Africa and Middle East countries, and an increasing trend of occurrence was noticed in North America, Europe and Australia (Kaakoush et al., 2015). In the United States, prevalence of campylobacteriosis was detected as second highest after salmonellosis as foodborne infection, affecting 15% of the population, and was considered as a leading cause of hospitalization (Scallan et al., 2011; Crim et al., 2014). In European countries Campylobacter was considered as major pathogen associated with gastroenteritis with an incidence rate of 55.5 per 100,000 population (Gölz et al., 2014). Human campylobacteriosis is characterized by acute diarrhoea, abdominal pain and fever, which are mostly self-limiting. Few complicated cases may yield severe bloody diarrhoea, inflammatory bowel diseases, esophageal complications (Barrett’s oesophagus), periodontitis, cholecystitis, colon cancer and rarely GuillaineBarre syndrome (0.01%e0.03% cases), Miller Fisher syndrome and reactive arthritis (1%e5% cases). Bacteraemia, lung infections, meningitis and brain abscesses are also reported as extraintestinal complications (Man, 2011). Thermophilic Campylobacter (Campylobacter coli, Campylobacter jejuni) are mostly zoonotic and are transmitted through ingestion of raw or undercooked poultry meat, unpasteurized milk, contaminated drinking water and direct contact with animals.
Properties of genus Morphology: Campylobacter are Gram-negative, comma-shaped rods especially in infected tissues and young cultures. When two bacterial cells are found together in a microscopic field, it appears like the alphabet ‘S’ or ‘wing of gull’
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(‘flying seagull’). In older cultures, the chains of organisms appear as long spirals. They are motile by single unipolar/ bipolar unsheathed flagella. Motility is darting or corkscrew type, best observed under dark-field microscope. Some species contain a surface layer (S-layer), a paracrystalline protein structure composed of S-layer proteins (SLPs) external to the outer membrane. Classification: Campylobacteriaceae contains four genera namely Campylobacter, Arcobacter, Sulfurospirillum and Thiovulum. The genus Campylobacter currently consists of 26 species, 2 provisional species and 9 subspecies (Kaakoush et al., 2015). Major species with pathogenic significance in man and animals are Campylobacter fetus subsp. venerealis, C. fetus subsp. fetus, C. jejuni subsp. jejuni, C. jejuni subsp. doyeli, C. coli, Campylobacter concisus, Campylobacter hyointestinalis, Campylobacter mucosalis, Campylobacter lari, Campylobacter upsaliensis, Campylobacter helveticus, Campylobacter insulaenigrae, Campylobacter rectus, Campylobacter sputorum and Campylobacter ureolyticus. Among them, C. jejuni and C. coli are most frequently isolated from human gastroenteritis and poultry. Susceptibility to disinfectants: Campylobacter are sensitive to common disinfectants such as phenol, cresol, etc. Natural habitat: Campylobacter can be recovered from water, sewage, hay, manure and reservoir animals and birds. C. jejuni and C. coli can colonize the intestinal mucosa of food and companion animals, mucosal crypts of caeca and colon or to a lesser extent in small intestine, liver and organs of poultry (Hermans et al., 2012). In broilers C. jejuni is the predominant colonizer followed by C. coli in most of the countries except in Southeast Asian region where the reverse occurrence pattern was observed. In commercial turkeys and organic or free-range chicken, C. coli was reported as major species (Heuer et al., 2001). In birds, clinical symptoms are mild or absent in spite of extensive colonization of Campylobacter (109 colony-forming units/gram caecal contents) as the bacteria localize the intestinal crypts without invasion into the adjacent epithelial cells (Beery et al., 1988; Corry and Atabay, 2001). Experimental infections with Campylobacter developed diarrhoea and weight loss in birds (Humphrey et al., 2014). Occurrence of Campylobacter is uncommon in young birds aged less than 2e3 weeks because of the presence of maternal antibodies (Sahin et al., 2001). Probability of colonization is less in aged birds especially in layers having longer lifespan because of development of active immunity (Achen et al., 1998). Campylobacter are considered as a major source of poultry meat contamination and are responsible for 20%e40% foodborne infection in consumers. During processing of the poultry carcasses, the prevalence of Campylobacter increases after defeathering and evisceration and the rate decreases after scalding and chilling. C. fetus is commonly found in genital and intestinal tract of domestic animals (cattle, sheep). C. fetus subsp. venerealis resides at the prepuce of the bull and the vagina of the cow. In cows, this carriage rate is generally reduced after two breeding seasons. C. fetus ssp. fetus commonly inhabits intestinal tract of healthy small ruminants (sheep). Natural habitat of C. upsaliensis is intestinal tract of healthy puppies and kittens. Genome: The genome of Campylobacter is small in size (1.6e2 megabases) with GC content of 30.1e33.0 mol%. The genome contains several hypervariable regions harbouring genes required for biosynthesis or modification of capsule, lipooligosaccharide and flagellum (Parkhill et al., 2000). These hypervariable sequences consist of homopolymeric tracts and are heritable in nature. Variation in these sequences can produce phase variation, frameshift and point mutations, gene duplication or deletion which results in the generation of multiple serotypes in a single bird or a flock of birds (Parkhill et al., 2000; Linton et al., 2000). C. jejuni is naturally competent which can uptake plasmid or chromosomal DNA during colonization into the poultry. The natural transformation generates genome plasticity and helps in spread of antibiotic resistance genes even in absence of selection pressure (Boer et al., 2002). The natural transformation of C. jejuni is regulated by carbon dioxide and bacterial cell concentration and certain genes encoded by type II and type IV secretion systems. The complete sequencing of virulence plasmid (pVir) in C. jejuni revealed the presence of type IV secretion system, associated with cellular invasion and other roles in pathogenesis (Bacon et al., 2002). C. jejuni prefer to receive DNA from other strains of C. jejuni than any other bacterial species (Wilson et al., 2003).
Antigenic characteristics Campylobacter is antigenically heterogeneous group of bacteria. C. jejuni has heat-stable (somatic) and heat-labile (flagellin) antigens. The flagella of C. jejuni are unsheathed and composed of flagellin protein having molecular weight of 57,000e66,000 Da. They can be divided into more than 600 Penner serotypes (heat-stable antigens) and more than 100 Lior serotypes (heat-labile antigens) (García and Heredia, 2013). C. fetus has three major groups of antigens: somatic (O), flagellar (H) and SLPs. They have at least 50 heat-stable serotypes based on somatic and more than 36 heat-labile serotypes based on flagellar antigens. It has antigenic relationship with Brucella abortus.
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Toxins and virulence factors produced Toxins Enterotoxin The enterotoxin is produced by C. jejuni, C. coli and C. lari. It has structural and functional relationship with Escherichia coli heat-labile enterotoxin (LT) and cholera toxin (CT). Campylobacter enterotoxin is also heat-labile (inactivated at 56 C for 1 h or at 96 C for 10 min), trypsin and pH sensitive (pH two or 8) and has a molecular weight of 60e70 K Da. Like CT or LT, this toxin also attaches with ganglioside receptor of the host cell. It activates adenylate cyclase enzyme to increase the level of intracellular cAMP and disrupt the normal ion transport in the enterocytes, thus causing secreatory watery diarrhoea. Toxic activity of the crude toxin is progressively lost after storage for 1 month at 4 C or for 1 week at 20 or 70 C. The toxin can induce fluid accumulation in rabbit or rat ligated ileal loop assay.
Cytotoxin It is produced by C. jejuni, C. coli and C. lari. It is trypsin-sensitive and toxic for HeLa, Vero cells in vitro. The toxin is destroyed at 70 C temperature for 30 min exposure.
Cytolethal distending toxin It is heat-labile, trypsin-sensitive, nondialyzable cytotoxin with a molecular weight of 30 KDa and produced by C. jejuni, C. coli and C. lari. It is cytolethal to Chinese hamster ovary, Vero, HeLa, human epithelial carcinoma (Hep2) cell lines. The toxin cannot induce fluid accumulation in rabbit ligated ileal loop assay. The iron is required for expression of this toxin. Virulence factors: Major virulence factors of Campylobacter are described in Table 19.1.
Transmission C. jejuni is transmitted through faecaleoral route in poultry. After infection, caecum and colon are the major sites for bacterial multiplication followed by faecal shedding. The bacteria can contaminate the skin of the poultry carcass during slaughtering if an intestinal rupture takes place (Silva et al., 2011). Contaminated drinking water, old litter, farm animals such as cattle, sheep and pigs, wild animals, pets, house flies, insects (litter beetles), farm equipment, transport vehicles and farm workers act as potential source of infection (Sahin et al., 2015). Vertical route of transmission from breeder hen to chick is rare. Presence of Campylobacter was although detected in young hatchling (Chuma et al., 1997; Byrd et al., 2007), eggs laid by Campylobacter positive flocks (Doyle, 1984), reproductive tract of hens (Buhr et al., 2002) and semen of rooster (Cox et al., 2002). Among the farm animals, prevalence of Campylobacter was highest in cattle (6%e90%), especially the feedlot cattle harboured C. jejuni, C. coli, C. lari and Campylobacter lanienae (Horrocks et al., 2009). Occurrence of Campylobacter in pigs, sheep and goats varies 32.8%e85.0% and 6.8%e17.5%, respectively. Companion animals such as 58% of healthy dogs and 97% of diarrhoeic dogs also harboured Campylobacter spp. (Kaakoush et al., 2015). Human transmission of C. jejuni occurs because of extensive international travel, consumption of undercooked chicken or their products, unpasteurized milk, and contaminated water, direct contact with infected farm or companion animals (children) and environmental exposure (Kaakoush et al., 2015). Handling, processing and consumption of undercooked poultry meat or its products are responsible for 20%e30% of human cases (EFSA Panel on Biological Hazards, 2010).The poultry meat may contain high level of the bacteria at preharvest level, which is further contaminated during the time of slaughter and processing. Infective dose of Campylobacter in human is not determined but it was experimentally observed that 500 bacterial cells can cause the disease in human (Robinson, 1981). The susceptibility varies between individuals, foods carrying the organisms, and the children in general were found more susceptible than adults (Calva et al., 1988). Person to person transmission is reported at low frequency (Musher and Musher, 2004). Use of certain antibiotics specially quinolones in animals and birds as therapeutic agent or growth promoter was associated with transmission of resistant Campylobacter strains from animals to human (Endtz et al., 1991).
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TABLE 19.1 Major virulence factors of Campylobacter. Virulence factors
Function
Motility and chemotaxis factors: Flagellin (FlaA, FlaB), hook basal body protein (FliF), flagellar motor proteins (FliM, FliY), P ring protein (FlgI), L-ring protein (FlgH), hook components (FlgE, FliK), chemotaxis proteins (Che A, Che B, Che R, Che V, Che W, Che Z), methyl-accepting chemotaxis proteins (MCPs), Campylobacter energy taxis system proteins CetA (Tlp9) and CetB (Aer2)
Motility is required for survival under the different chemotactic conditions in the gastrointestinal tract and for colonization of the small intestine. Chemotaxis is required for colonization into mucus-filled crypts of the ceca in avian gut.
Adhesins: (i) CadF (Campylobacter adhesion to fibronectin [Fn])
It helps in binding of bacteria with fibronectin protein, found in extracellular matrix or regions of cell to cell contact. So it helps in bacterial adhesion with host tissues.
(ii) Periplasmic/membrane-associated protein (PEB1, PEB3)
Putative adhesin of Campylobacter jejuni.
(iii) CapA (Campylobacter adhesion protein A)
Acts as adhesin.
(iv) JlpA (jejuni lipoprotein A)
It helps in adherence of bacteria with human epithelial cells (Hep2).
(v) Cj1279c and Cj1349c protein
They act as fibronectin and fibrinogen-binding protein.
(vi) Type IV secretion system
Helps in adhesion of bacteria.
Invasion factors: (i) Flagellar proteins (FlhA, FlhB, FliO, FliP, FliQ, FliR)
Flagellar proteins also act as T3SS, an export apparatus required for invasion into the host.
(ii) FlaC protein
Colonization and invasion.
(iii) CiaB, CiaC, CiaI
Invasion and intracellular survival.
(iv) HtrA chaperone
Correct folding of adhesion proteins.
Capsule (capsular polysaccharide transport protein M, capsule biosynthesis proteins)
C. jejuni surface is covered with a capsule which helps in survival, adherence and evasion of the host immune system.
VirK protein
Protection against antimicrobial peptide.
Iron uptake system (i) Membrane ferric enterobactin (FeEnt) receptors (ii) CeuE lipoprotein (iron acquisition) (iii) Ferric uptake regulator (Fur) (iv) Outer membrane receptor for haemin and haemoglobin (ChuA)
Iron transport and regulation are required for survival of Campylobacter.
Major outer membrane protein (MOMP); encoded by porA gene
MOMP is known to allow passage of hydrophilic molecules across the outer membrane and provides structural stability to the outer membrane. It also helps in bacterial adhesion with host tissues.
Stress response factors [stringent control (spoT), catalase (katA), alkyl hydroperoxide reductase (AhpC), thiol peroxidase (Tpx), cytochrome c peroxidases, NADPH quinine reductase, heat shock protein]
These factors help in survival under oxidative stress such as starvation, heat, reduced pH occurred during food processing and storage. Campylobacter enter a viable but nonculturable state which is characterized by decreased metabolic activity, increased production of certain enzymes and cell shrinkage. This condition helps in survival of Campylobacter under unfavourable conditions.
Lipopolysaccharide (LPS)
LPS contains N-acetylneuraminic acid (NeuAc), responsible for serum resistance. ‘NeuAc’ is rarely found in prokaryotes although common in eukaryotic glycolipids.
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Diagnosis The infected poultry birds shed large numbers of organisms (>106 colony-forming units/g faeces). Clinical samples for isolation of Campylobacter are fresh faeces (without urine), caecal droppings or cloacal swabs and bile. Postmortem samples include caeca from poultry, intestinal content from cattle, sheep and pigs. The samples after collection should be carried in a transport media (CaryeBlair, Stuart, Amies, alkaline peptone water) into the laboratory to prevent the drying and oxygen exposure. The samples should be protected from light, freezing (<0 C) and high temperature (>20 C).
Laboratory examinations Direct examination: A smear can be prepared from clinical samples and stained by dilute carbol fuchsin. Campylobacter appears as pink-coloured small curved rod arranged in a pair to produce characteristic ‘S’ or ‘wing of gull’ appearance. The bacteria can also be demonstrated by wet mounts of faeces by phase contrast or dark-field microscopy. C. mucosalis and C. hyointestinalis can be demonstrated by modified ZiehleNeelsen stain. The organisms appear as pink-coloured, curved, intracellular rods. Isolation of Campylobacter spp.: Campylobacter can be isolated from clinical samples without any enrichment. The samples are filtered through 0.65 or 0.45 mm filters before inoculation into the media. Selective media for Campylobacter isolation is broadly categorized into two types, i.e., charcoal based and blood based. Charcoal and blood components remove toxic derivatives of oxygen from the media. Examples of charcoal-based selective media are modified charcoal, cefoperazone, deoxycholate agar (mCCDA), Karmali agar or charcoal selective medium. The blood-based media are Preston agar, Skirrow agar, Butzler agar and Campy Cefex agar. Commonly used nonselective media for Campylobacter isolation are blood agar with or without 0.1% sodium thioglycolate (used to reduce oxygen tension of the media) and antibiotics. The antibiotics used in the media are cephalosporins, trimethoprim, bacitracin, actidione, amphotericin B, etc. Actidione and amphotericin B are used to prevent the growth of yeasts and moulds. Campylobacter are microaerophilic in nature and require 3%e5% CO2 with 3%e15% O2 for growth. Optimum growth requires incubation at 37 C temperature for 2e5 days (24e48 h for C. jejuni and C. coli). Campylobacter spp. will not survive below a pH of 4.9 and above pH 9.0 and grow optimally at pH 6.5e7.5. Thermophilic Campylobacter (C. jejuni, C. coli) prefer to grow at 30e46 C in an atmosphere containing 10% CO2 and 5% O2. C. jejuni is nonhaemolytic and produces finely granular, irregular margin, flat, greyish colonies in blood agar. On charcoal-based media, the colonies may produce ‘metallic sheen’. Serological tests: Fluorescence in situ hybridization, latex agglutination test and a physical enrichment method (filtration) can detect Campylobacter in the food matrix (Baggerman and Koster, 1992; Hazeleger et al., 1992; Lehtola et al., 2006). Molecular biology: Multiplex polymerase chain reaction (PCR) is developed for detection of several Campylobacter species such as C. jejuni (23S RNA gene); C. coli, C. lari and C. upsaliensis (glyA gene) and sapB2 gene from C. fetus subsp. fetus (Wang et al., 2002). PCR combined with immunomagnetic separation can detect Campylobacter present in low numbers in the samples (Waller and Ogata, 2000). Real-time PCR can confirm Campylobacter in very low copies (1 cfu) in less than 2 hours (Debretsion et al., 2007).
Characteristics of antimicrobial resistance Erythromycin (macrolide) is the drug of choice for clinical campylobacteriosis, although fluoroquinolone, tetracyclines and gentamicin are also used for the treatment (Acheson and Allos, 2001). Increasing resistance of Campylobacter against common antibiotics is a public health concern. Intrinsic resistance in C. jejuni and C. coli was described against penicillins and cephalosporins, bacitracin, novobiocin, rifampin, streptogramin B and vancomycin (McNulty, 1987). The multidrug efflux pump (CmeABC) was detected to be associated with intrinsic resistance in Campylobacter (Lin et al., 2002). Mutation of the essential genes and horizontal transfer of resistance determinants are two major pathways associated with generation of antimicrobial resistance in Campylobacter. Absence of DNA repair molecules such as methyl-directed mismatch repair (mutH and mutL), recombination repair (sbcB), repair of pyrimidine dimmers (phr), very short patch repair (vsr) and protecting protein from UV-induced mutagenesis (umuCD) and alkylating agents (ada) in C. jejuni isolates further promote the mutations (Parkhill et al., 2000).
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Quinolone resistance Use of fluoroquinolones in animal and poultry farms in the United States, Europe, Australia and Asia was correlated with generation of quinolone-resistant human Campylobacter isolates (Endtz et al., 1991; Nachamkin et al., 2002; Hart et al., 2004). Conversion of fluoroquinolone-susceptible C. jejuni into resistant population was observed after exposure to enrofloxacin (McDermott et al., 2002). Amino acid substitution (Thr86Ile, Asp90Asn, Thr86Lys, Thr86Ala, Thr86Val, Asp90Tyr) in the quinolone resistancedetermining region (QRDR) of topoisomerase enzyme is associated with quinolone resistance of Campylobacter spp. Mutation (C257T) in gyrA gene and subsequent Thr86Ile amino acid substitution was detected as most common mechanism of quinolone resistance in Campylobacter spp. (Payot et al., 2006). This substitution (Thr86Ile) produced high level of resistance in C. jejuni and C. coli isolates against ciprofloxacin (Ge et al., 2005). The frequencies of emergence of fluoroquinolone-resistant mutants range from approximately 106 to 108/cell/generation (Yan et al., 2006). Strain to strain variation in emergence of mutant occurs as the mutation (C257T) might offer a ‘fitness benefit’ to one strain of C. jejuni but was ‘costly’ for a different strain (Luo et al., 2005). The multidrug efflux pump (CmeABC) was also detected to be associated with quinolone resistance in Campylobacter spp. in synergy with gyrA mutations. CmeABC is encoded by three genes, i.e., cmeA (periplasmic fusion protein), cmeB (drug transporter) and cmeC (outer membrane protein). Blocking the efflux pump in Campylobacter reduced the MIC value against ciprofloxacin in spite of mutation in gyrA (Luo et al., 2003). Mfd (mutant frequency decline), a transcription repair coupling factor associated with DNA repair, also develops quinolone-resistant Campylobacter strains (Han et al., 2008).
Tetracycline resistance Resistance to tetracyclines in Campylobacter is associated with tet(0) gene, present in a self-transmissible plasmid (45e58 kb) and prevalent in both C. jejuni and C. coli strains (Connell et al., 2003a). Campylobacter tet(0) gene was acquired by horizontal gene transfer from Streptomyces, Streptococcus and Enterococcus spp. (Batchelor et al., 2004). The tet(0) gene encodes ribosomal protection proteins which can bind with open ‘A’ site on the bacterial ribosome and produces a conformational change of the ribosome in such a manner that all the bound tetracycline molecules are released(Connell et al., 2003b). The conformational change did not hamper the protein synthesis of the bacterial ribosome.
Macrolide resistance Generation of macrolide resistance in Campylobacter is a stepwise process that requires exposure for a prolonged period. Exposure to quinolones although rapidly induces resistance in Campylobacter strains. Subtherapeutic exposure to tylosin, given continuously in feed, produced more macrolide resistance in C. coli isolates than therapeutic exposure (Schönberg-Norio et al., 2006; Ladely et al., 2007). Resistance to macrolides in Campylobacter is associated with modification of the ribosomal target, ribosomal proteins and enzymatic inactivation of the drug. Mutation in 23S rRNA gene (A2074C, A2074G, A2075G) is the common way to generate erythromycin resistance (MIC > 128 mg/L) in C. jejuni and C. coli isolates (Jeon et al., 2008). Modifications (substitution, insertion, deletion) of the ribosomal proteins (L4, L22) were associated with generation of low-level macrolide resistance in Campylobacter isolates (Cagliero et al., 2006). The multidrug efflux pump (CmeABC) was also detected to be associated with macrolide resistance in Campylobacter spp. in synergy with 23S rRNA mutations and modifications of L4, L22 proteins (Corcoran et al., 2006; Cagliero et al., 2006).The frequency of emergence of macrolide-resistant mutants is lower than fluoroquinolone-resistant mutants (1010/cell/generation) (Lin et al., 2007). Lower mutation rate, prolonged antibiotic exposure and required fitness cost are the probable explanations for the lower prevalence of macrolide resistance in Campylobacter isolates.
Aminoglycoside resistance Aminoglycoside-modifying enzymes (aminoglycoside phosphor transferase types I, III, IV and VII, aminoglycoside adenyl transferase, 6-amino glycoside adenyl transferase) detected in Campylobacter spp. can decrease the affinity of aminoglycosides for the rRNA A-site (Llano-Sotelo et al., 2002). Kanamycin-resistance phosphotransferase [APH (30 ) III and APH (30 ) IV] was detected in a 14 Kbp plasmid present in C. jejuni isolates (Tenover et al., 1989). This plasmid can offer resistance against tetracyclines also and is transferred between Campylobacter strains (Gibreel et al., 2004).
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b-Lactam antibiotic resistance Majority of Campylobacter strains are inherently resistant to penicillins and narrow spectrum cephalosporins (except amoxicillin and ampicillin) because of production of b-lactamase enzyme or mediated through multidrug efflux pump (CmeABC) (Tajada et al., 1996; Lin et al., 2002). C. jejuni/C. coli strains were found susceptible to cefotaxime, ceftazidime, cefpirome and imipenem (Van der Auwera et al., 1985).
Chloramphenicol resistance Plasmid-encoded chloramphenicol resistance gene (cat) was rarely detected in Campylobacter spp. (Wang and Taylor, 1990). The enzyme acetyltransferase, encoded by cat gene, modifies chloramphenicol in a way which prevents its binding with bacterial ribosomes. A recently explored mechanism suggested the synergistic role of efflux pump (CmeB) and radical S-adenosylmethionine enzyme in production of chloramphenicol resistance in C. jejuni strains (Li et al., 2017).
Sulphonamide resistance Resistance to sulphonamides in C. jejuni strains was associated with mutational substitution of amino acids in dihydropteroate synthase enzyme resulting in reduced affinity for sulphonamides (Gibreel and Sköld, 1999).
Trimethoprim resistance Resistance to trimethoprim in Campylobacter was associated with two dihydrofolate reductases (dfr1 and dfr9) acquired from Enterobacteriaceae (Gibreel and Sköld, 2000).
Streptothricin resistance The sat4 gene present in C. coli was found to be associated with streptothricin resistance in animal and clinical isolates in Germany (Bischoff and Jacob, 1996). Characteristics of antimicrobial resistance in Campylobacter isolates observed in poultry, pigs and human are discussed in the following section.
Poultry Occurrence of Campylobacter in healthy poultry gut is high and use of antibiotics in poultry can induce the generation of antibiotic-resistant strains. The fluoroquinolones (sarafloxacin and enrofloxacin) were licenced by the FDA for therapeutic use in poultry during 1990 which generated quinolone-resistant Campylobacter in poultry in the United States (Gupta et al., 2004). National Antimicrobial Resistance Monitoring System (NARMS) in the United States revealed an increasing trend (20.3% in 2001 to 23.1% in 2010) of ciprofloxacin resistance in C. jejuni isolated from the chicken at slaughter (NARMS, 2010). Subsequently the licence for fluoroquinolone use in poultry was cancelled in the United States in 2005 after prolonged legal battle (Nelson et al., 2007). Higher occurrence of fluoroquinolone-resistant Campylobacter was observed in conventional poultry and associated retail meat than organic poultry in the United States (Cui et al., 2005; Luangtongkum et al., 2006). Throughout the world, prevalence of fluoroquinolone-resistant Campylobacter varied widely (0%e99%) in broilers. The prevalence was at lower side (0%e11%) in poultry in Australia, Denmark and Norway (Iovine, 2013) and higher occurrence was observed in Spain and Thailand (80%e99%) (Sáenz et al., 2000; Chokboonmongkol et al., 2013). Increasing trend in occurrence of quinolone-resistant Campylobacter strains was observed in poultry during 1994 (47%) to 2008 (90%) in Poland (Wozniak, 2011). Macrolide resistance in poultry C. jejuni isolates was comparatively lower than C. coli in most of the countries (Gyles, 2008). The study in Portugal although revealed the higher rate of erythromycin resistance in C. jejuni (35%) isolates than C. coli (13%) in poultry (Fraqueza et al., 2014). Low erythromycin resistance (0%e10%, 2001e10) was observed in C. jejuni strains isolated from retail poultry meat in the United States (NARMS, 2010). Higher occurrence of macrolide-resistant C. coli (100%) than C. jejuni (9%e14%) was detected in poultry in China (Chen et al., 2010). In a systemic study in China, species shift from C. jejuni to C. coli was observed in poultry during 2008e14. Occurrence of macrolide-resistant C. jejuni strains reduced from 13.3% (2008e09) to 8.2% (2012e14), and subsequently, occurrence of resistant C. coli strains increased from 48.7% (2008e09) to 76.4% (2012e14). Excessive use of macrolides
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(tylosin, tilmicosin, erythromycin, kitasamycin, tulathromycin) in poultry and livestock industry in China was correlated with species shift of Campylobacter and increased macrolide resistance (Wang et al., 2015).
Pigs Ciprofloxacin-resistant C. coli were detected in pigs in China with higher occurrence (96%e99% of the isolates) (Qin et al., 2011). Increased macrolide use in swine industry in China was also correlated with increased prevalence (44% during 2008e09 to 59% during 2012e14) of macrolide-resistant C. coli (Wang et al., 2015).
Human Resistance to antibiotics (fluoroquinolone) was first detected in human Campylobacter isolates during late 1980s (Acheson and Allos, 2001). The resistance spreads rapidly throughout the world with introduction of fluoroquinolones in poultry and livestock industry. In the United States, fluoroquinolone resistance in human isolates raised from 1.3% in 1992 to 10.2% in 1998 (Nachamkin et al., 2002). Similar increasing trend of fluoroquinolone resistance in Campylobacter isolates was detected in Europe (Spain in 1993e2003, Germany in 1991e2002) (Luber et al., 2003; Ruiz et al., 2007) and Asia (India and Thailand, Hoge et al., 1998; Jain et al., 2005). In Denmark and Finland, a positive correlation between resistance to ciprofloxacin, nalidixic acid and tetracycline in human Campylobacter isolates and international travel (specially in Spain and Thailand) was detected (Hakanen et al., 2003; Skjøt-Rasmussen et al., 2009). In Australia, occurrence of resistant Campylobacter spp. in human was low because of restricted use of antibiotics both in human and food animals (Unicomb et al., 2003).
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Han, J., Sahin, O., Barton, Y.W., Zhang, Q., 2008. Key role of Mfd in the development of fluoroquinolone resistance in Campylobacter jejuni. PLoS Pathogens 4 (6), e1000083. Hart, W.S., Heuzenroeder, M.W., Barton, M.D., 2004. Antimicrobial resistance in Campylobacter spp., Escherichia coli and enterococci associated with pigs in Australia. Journal of Veterinary Medicine e Series B 51 (5), 216e221. Hazeleger, W.C., Beumer, R.R., Rombouts, F.M., 1992. The use of latex agglutination tests for determining Campylobacter species. Letters in Applied Microbiology 14 (4), 181e184. Hermans, D., Pasmans, F., Messens, W., Martel, A., Van Immerseel, F., Rasschaert, G., Heyndrickx, M., Van Deun, K., Haesebrouck, F., 2012. Poultry as a host for the zoonotic pathogen Campylobacter jejuni. Vector Borne and Zoonotic Diseases 12 (2), 89e98. Heuer, O.E., Pedersen, K., Andersen, J.S., Madsen, M., 2001. Prevalence and antimicrobial susceptibility of thermophilic Campylobacter in organic and conventional broiler flocks. Letters in Applied Microbiology 33 (4), 269e274. Hoge, C.W., Gambel, J.M., Srijan, A., Pitarangsi, C., Echeverria, P., 1998. Trends in antibiotic resistance among diarrheal pathogens isolated in Thailand over 15 years. Clinical Infectious Diseases 26 (2), 341e345. Horrocks, S.M., Anderson, R.C., Nisbet, D.J., Ricke, S.C., 2009. Incidence and ecology of Campylobacter jejuni and coli in animals. Anaerobe 15 (1e2), 18e25. Humphrey, S., Chaloner, G., Kemmett, K., Davidson, N., Williams, N., Kipar, A., Humphrey, T., Wigley, P., 2014. Campylobacter jejuni is not merely a commensal in commercial broiler chickens and affects bird welfare. mBio 5 (4) e01364-14. Iovine, N.M., 2013. Resistance mechanisms in Campylobacter jejuni. Virulence 4 (3), 230e240.
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Jain, D., Sinha, S., Prasad, K.N., Pandey, C.M., 2005. Campylobacter species and drug resistance in a north Indian rural community. Transactions of the Royal Society of Tropical Medicine and Hygiene 99 (3), 207e214. Jeon, B., Muraoka, W., Sahin, O., Zhang, Q., 2008. Role of Cj1211 in natural transformation and transfer of antibiotic resistance determinants in Campylobacter jejuni. Antimicrobial Agents and Chemotherapy 52 (8), 2699e2708. Kaakoush, N.O., Castaño-Rodríguez, N., Mitchell, H.M., Man, S.M., 2015. Global epidemiology of Campylobacter infection. Clinical Microbiology Reviews 28 (3), 687e720. Ladely, S.R., Harrison, M.A., Fedorka-Cray, P.J., Berrang, M.E., Englen, M.D., Meinersmann, R.J., 2007. Development of macrolide-resistant Campylobacter in broilers administered subtherapeutic or therapeutic concentrations of tylosin. Journal of Food Protection 70 (8), 1945e1951. Lehtola, M.J., Pitkänen, T., Miebach, L., Miettinen, I.T., 2006. Survival of Campylobacter jejuni in potable water biofilms: a comparative study with different detection methods. Water Science and Technology 54 (3), 57e61. Li, H., Wang, Y., Fu, Q., Wang, Y., Li, X., Wu, C., Shen, Z., Zhang, Q., Qin, P., Shen, J., Xia, X., 2017. Integrated genomic and proteomic analyses of high-level chloramphenicol resistance in Campylobacter jejuni. Scientific Reports 7 (1), 16973. Lin, J., Michel, L.O., Zhang, Q., 2002. CmeABC functions as a multidrug efflux system in Campylobacter jejuni. Antimicrobial Agents and Chemotherapy 46 (7), 2124e2131. Lin, J., Yan, M., Sahin, O., Pereira, S., Chang, Y.J., Zhang, Q., 2007. Effect of macrolide usage on emergence of erythromycin-resistant Campylobacter isolates in chickens. Antimicrobial Agents and Chemotherapy 51 (5), 1678e1686. Linton, D., Gilbert, M., Hitchen, P.G., Dell, A., Morris, H.R., Wakarchuk, W.W., Gregson, N.A., Wren, B.W., 2000. Phase variation of a b-1, 3 galactosyltransferase involved in generation of the ganglioside GM1-like lipo-oligosaccharide of Campylobacter jejuni. Molecular Microbiology 37 (3), 501e514. Llano-Sotelo, B., Azucena Jr., E.F., Kotra, L.P., Mobashery, S., Chow, C.S., 2002. Aminoglycosides modified by resistance enzymes display diminished binding to the bacterial ribosomal aminoacyl-tRNA site. Chemistry & Biology 9 (4), 455e463. Luangtongkum, T., Morishita, T.Y., Ison, A.J., Huang, S., McDermott, P.F., Zhang, Q., 2006. Effect of conventional and organic production practices on the prevalence and antimicrobial resistance of Campylobacter spp. in poultry. Applied and Environmental Microbiology 72 (5), 3600e3607. Luber, P., Wagner, J., Hahn, H., Bartelt, E., 2003. Antimicrobial resistance in Campylobacter jejuni and Campylobacter coli strains isolated in 1991 and 2001e2002 from poultry and humans in Berlin, Germany. Antimicrobial Agents and Chemotherapy 47 (12), 3825e3830. Luo, N., Pereira, S., Sahin, O., Lin, J., Huang, S., Michel, L., Zhang, Q., 2005. Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure. Proceedings of the National Academy of Sciences 102 (3), 541e546. Luo, N., Sahin, O., Lin, J., Michel, L.O., Zhang, Q., 2003. In vivo selection of Campylobacter isolates with high levels of fluoroquinolone resistance associated with gyrA mutations and the function of the CmeABC efflux pump. Antimicrobial Agents and Chemotherapy 47 (1), 390e394. Man, S.M., 2011. The clinical importance of emerging Campylobacter species. Nature Reviews Gastroenterology & Hepatology 8 (12), 669. McDermott, P.F., Bodeis, S.M., English, L.L., White, D.G., Walker, R.D., Zhao, S., Simjee, S., Wagner, D.D., 2002. Ciprofloxacin resistance in Campylobacter jejuni evolves rapidly in chickens treated with fluoroquinolones. The Journal of Infectious Diseases 185 (6), 837e840. McNulty, C.A., 1987. The treatment of Campylobacter infections in man. Journal of Antimicrobial Chemotherapy 19 (3), 281e284. Musher, D.M., Musher, B.L., 2004. Contagious acute gastrointestinal infections. New England Journal of Medicine 351 (23), 2417e2427. Nachamkin, I., Ung, H., Li, M., 2002. Increasing fluoroquinolone resistance in Campylobacter jejuni, Pennsylvania, USA, 1982e2001. Emerging Infectious Diseases 8 (12), 1501. National Antimicrobial Resistance Monitoring System-Enteric Bacteria (NARMS), 2010. Executive Report. U.S. Department of Health and Human Services, Food and Drug Administration, Rockville, MD. Available at: https://www.fda.gov/downloads/animalveterinary/safetyhealth/ antimicrobialresistance/nationalantimicrobialresistancemonitoringsystem/ucm312360.pdf. Nelson, J.M., Chiller, T.M., Powers, J.H., Angulo, F.J., 2007. Fluoroquinolone-resistant Campylobacter species and the withdrawal of fluoroquinolones from use in poultry: a public health success story. Clinical Infectious Diseases 44 (7), 977e980. Parkhill, J., Wren, B.W., Mungall, K., Ketley, J.M., Churcher, C., Basham, D., Chillingworth, T., Davies, R.M., Feltwell, T., Holroyd, S., Jagels, K., 2000. The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature 403 (6770), 665. Payot, S., Bolla, J.M., Corcoran, D., Fanning, S., Mégraud, F., Zhang, Q., 2006. Mechanisms of fluoroquinolone and macrolide resistance in Campylobacter spp. Microbes and Infection 8 (7), 1967e1971. Qin, S.S., Wu, C.M., Wang, Y., Jeon, B., Shen, Z.Q., Wang, Y., Zhang, Q., Shen, J.Z., 2011. Antimicrobial resistance in Campylobacter coli isolated from pigs in two provinces of China. International Journal of Food Microbiology 146 (1), 94e98. Robinson, D.A., 1981. Infective dose of Campylobacter jejuni in milk. British Medical Journal(Clinical Research Edition) 282 (6276), 1584. Ruiz, J., Marco, F., Oliveira, I., Vila, J., GascON, J., 2007. Trends in antimicrobial resistance in Campylobacter spp. causing traveler’s diarrhea. Acta Pathologica Microbiologica et Immunologica Scandinavica 115 (3), 218e224. Sáenz, Y., Zarazaga, M., Lantero, M., Gastañares, M.J., Baquero, F., Torres, C., 2000. Antibiotic resistance in Campylobacter strains isolated from animals, foods, and humans in Spain in 1997e1998. Antimicrobial Agents and Chemotherapy 44 (2), 267e271. Sahin, O., Kassem, I.I., Shen, Z., Lin, J., Rajashekara, G., Zhang, Q., 2015. Campylobacter in poultry: ecology and potential interventions. Avian Diseases 59 (2), 185e200. Sahin, O., Zhang, Q., Meitzler, J.C., Harr, B.S., Morishita, T.Y., Mohan, R., 2001. Prevalence, antigenic specificity, and bactericidal activity of poultry anti-Campylobacter maternal antibodies. Applied and Environmental Microbiology 67 (9), 3951e3957. Scallan, E., Hoekstra, R.M., Angulo, F.J., Tauxe, R.V., Widdowson, M.A., Roy, S.L., Jones, J.L., Griffin, P.M., 2011. 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Schönberg-Norio, D., Hänninen, M.L., Katila, M.L., Kaukoranta, S.S., Koskela, M., Eerola, E., Uksila, J., Pajarre, S., Rautelin, H., 2006. Activities of telithromycin, erythromycin, fluoroquinolones, and doxycycline against Campylobacter strains isolated from Finnish subjects. Antimicrobial Agents and Chemotherapy 50 (3), 1086e1088. Sebald, M., Veron, M., 1963. Base DNA content and classification of Vibrios. Annales de l’Institut Pasteur 105, 897e910. Silva, J., Leite, D., Fernandes, M., Mena, C., Gibbs, P.A., Teixeira, P., 2011. Campylobacter spp. as a foodborne pathogen: a review. Frontiers in Microbiology 2, 200. Skjøt-Rasmussen, L., Ethelberg, S., Emborg, H.D., Agersø, Y., Larsen, L.S., Nordentoft, S., Olsen, S.S., Ejlertsen, T., Holt, H., Nielsen, E.M., Hammerum, A.M., 2009. Trends in occurrence of antimicrobial resistance in Campylobacter jejuni isolates from broiler chickens, broiler chicken meat, and human domestically acquired cases and travel associated cases in Denmark. International Journal of Food Microbiology 131 (2e3), 277e279. Smith, T., 1919. The etiological relation of spirilla (Vibrio fetus) to bovine abortion. Journal of Experimental Medicine 30 (4), 313e323. Tajada, P., Gomez-Graces, J.L., Alos, J.I., Balas, D., Cogollos, R., 1996. Antimicrobial susceptibilities of Campylobacter jejuni and Campylobacter coli to 12 beta-lactam agents and combinations with beta-lactamase inhibitors. Antimicrobial Agents and Chemotherapy 40 (8), 1924e1925. Tenover, F.C., Gilbert, T., O’Hara, P., 1989. Nucleotide sequence of a novel kanamycin resistance gene, aphA-7, from Campylobacter jejuni and comparison to other kanamycin phosphotransferase genes. Plasmid 22 (1), 52e58. Unicomb, L., Ferguson, J., Riley, T.V., Collignon, P., 2003. Fluoroquinolone resistance in Campylobacter absent from isolates, Australia. Emerging Infectious Diseases 9 (11), 1482. Van der Auwera, P., Scorneaux, B., 1985. In vitro susceptibility of Campylobacter jejuni to 27 antimicrobial agents and various combinations of betalactams with clavulanic acid or sulbactam. Antimicrobial Agents and Chemotherapy 28 (1), 37e40. Vandamme, P., 2000. Taxonomy of the family campylobacteraceae. In: Namchamkin, I., Blaser, M.J. (Eds.), Campylobacter. ASM, Washington, DC, pp. 3e27. Waller, D.F., Ogata, S.A., 2000. Quantitative immunocapture PCR assay for detection of Campylobacter jejuni in foods. Applied and Environmental Microbiology 66 (9), 4115e4118. Wang, G., Clark, C.G., Taylor, T.M., Pucknell, C., Barton, C., Price, L., Woodward, D.L., Rodgers, F.G., 2002. Colony multiplex PCR assay for identification and differentiation of Campylobacter jejuni, C. coli, C. lari, C. upsaliensis, and C. fetus subsp. fetus. Journal of Clinical Microbiology 40 (12), 4744e4747. Wang, Y., Taylor, D.E., 1990. Chloramphenicol resistance in Campylobacter coli: nucleotide sequence, expression, and cloning vector construction. Gene 94 (1), 23e28. Wang, Y., Dong, Y., Deng, F., Liu, D., Yao, H., Zhang, Q., Shen, J., Liu, Z., Gao, Y., Wu, C., Shen, Z., 2015. Species shift and multidrug resistance of Campylobacter from chicken and swine, China, 2008e14. Journal of Antimicrobial Chemotherapy 71 (3), 666e669. Wilson, D.L., Bell, J.A., Young, V.B., Wilder, S.R., Mansfield, L.S., Linz, J.E., 2003. Variation of the natural transformation frequency of Campylobacter jejuni in liquid shake culture. Microbiology 149 (12), 3603e3615. Wozniak, A., 2011. Fluoroquinolones resistance of Campylobacter jejuni and Campylobacter coli isolated from poultry in 1994e1996 and 2005e2008 in Poland. Bulletin of the Veterinary Institute in Pulawy 55 (1), 15e20. Yan, M., Sahin, O., Lin, J., Zhang, Q., 2006. Role of the CmeABC efflux pump in the emergence of fluoroquinolone-resistant Campylobacter under selection pressure. Journal of Antimicrobial Chemotherapy 58 (6), 1154e1159.
Campylobacter Chapter outline Properties of genus Antigenic characteristics Toxins and virulence factors produced Toxins Enterotoxin Cytotoxin Cytolethal distending toxin Transmission Diagnosis Laboratory examinations Characteristics of antimicrobial resistance Quinolone resistance
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Tetracycline resistance Macrolide resistance Aminoglycoside resistance b-Lactam antibiotic resistance Chloramphenicol resistance Sulphonamide resistance Trimethoprim resistance Streptothricin resistance Poultry Pigs Human References
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In 1886, Escherich observed Campylobacter-like organisms in stool samples of children with diarrhoea (Vandamme, 2000). In 1913, McFaydean and Stockman first confirmed them as Campylobacter in foetal tissues of aborted sheep. Confirmatory tests were also carried out by Smith (1919) when similar organisms (Vibrio foetus) were isolated from aborted bovine foetus. Vandamme (2000) and Doyle (1944) isolated Vibrio jejuni and Vibrio coli from cattle and pigs, respectively, suffering with diarrhoea (Doyle, 1944; Vandamme, 2000). Sebald and Véron (1963) differentiated the bacteria from Vibrionaceae family, and the new genus Campylobacter (‘curved rod’) under Campylobacteriaceae family was proposed due to low DNA base composition, nonfermentative metabolism and microaerophilic growth requirements. Campylobacter causes 400e500 million cases of infection in human each year throughout the world (García and Heredia, 2013). Campylobacteriosis is endemic among children in Asia, Africa and Middle East countries, and an increasing trend of occurrence was noticed in North America, Europe and Australia (Kaakoush et al., 2015). In the United States, prevalence of campylobacteriosis was detected as second highest after salmonellosis as foodborne infection, affecting 15% of the population, and was considered as a leading cause of hospitalization (Scallan et al., 2011; Crim et al., 2014). In European countries Campylobacter was considered as major pathogen associated with gastroenteritis with an incidence rate of 55.5 per 100,000 population (Gölz et al., 2014). Human campylobacteriosis is characterized by acute diarrhoea, abdominal pain and fever, which are mostly self-limiting. Few complicated cases may yield severe bloody diarrhoea, inflammatory bowel diseases, esophageal complications (Barrett’s oesophagus), periodontitis, cholecystitis, colon cancer and rarely GuillaineBarre syndrome (0.01%e0.03% cases), Miller Fisher syndrome and reactive arthritis (1%e5% cases). Bacteraemia, lung infections, meningitis and brain abscesses are also reported as extraintestinal complications (Man, 2011). Thermophilic Campylobacter (Campylobacter coli, Campylobacter jejuni) are mostly zoonotic and are transmitted through ingestion of raw or undercooked poultry meat, unpasteurized milk, contaminated drinking water and direct contact with animals.
Properties of genus Morphology: Campylobacter are Gram-negative, comma-shaped rods especially in infected tissues and young cultures. When two bacterial cells are found together in a microscopic field, it appears like the alphabet ‘S’ or ‘wing of gull’
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(‘flying seagull’). In older cultures, the chains of organisms appear as long spirals. They are motile by single unipolar/ bipolar unsheathed flagella. Motility is darting or corkscrew type, best observed under dark-field microscope. Some species contain a surface layer (S-layer), a paracrystalline protein structure composed of S-layer proteins (SLPs) external to the outer membrane. Classification: Campylobacteriaceae contains four genera namely Campylobacter, Arcobacter, Sulfurospirillum and Thiovulum. The genus Campylobacter currently consists of 26 species, 2 provisional species and 9 subspecies (Kaakoush et al., 2015). Major species with pathogenic significance in man and animals are Campylobacter fetus subsp. venerealis, C. fetus subsp. fetus, C. jejuni subsp. jejuni, C. jejuni subsp. doyeli, C. coli, Campylobacter concisus, Campylobacter hyointestinalis, Campylobacter mucosalis, Campylobacter lari, Campylobacter upsaliensis, Campylobacter helveticus, Campylobacter insulaenigrae, Campylobacter rectus, Campylobacter sputorum and Campylobacter ureolyticus. Among them, C. jejuni and C. coli are most frequently isolated from human gastroenteritis and poultry. Susceptibility to disinfectants: Campylobacter are sensitive to common disinfectants such as phenol, cresol, etc. Natural habitat: Campylobacter can be recovered from water, sewage, hay, manure and reservoir animals and birds. C. jejuni and C. coli can colonize the intestinal mucosa of food and companion animals, mucosal crypts of caeca and colon or to a lesser extent in small intestine, liver and organs of poultry (Hermans et al., 2012). In broilers C. jejuni is the predominant colonizer followed by C. coli in most of the countries except in Southeast Asian region where the reverse occurrence pattern was observed. In commercial turkeys and organic or free-range chicken, C. coli was reported as major species (Heuer et al., 2001). In birds, clinical symptoms are mild or absent in spite of extensive colonization of Campylobacter (109 colony-forming units/gram caecal contents) as the bacteria localize the intestinal crypts without invasion into the adjacent epithelial cells (Beery et al., 1988; Corry and Atabay, 2001). Experimental infections with Campylobacter developed diarrhoea and weight loss in birds (Humphrey et al., 2014). Occurrence of Campylobacter is uncommon in young birds aged less than 2e3 weeks because of the presence of maternal antibodies (Sahin et al., 2001). Probability of colonization is less in aged birds especially in layers having longer lifespan because of development of active immunity (Achen et al., 1998). Campylobacter are considered as a major source of poultry meat contamination and are responsible for 20%e40% foodborne infection in consumers. During processing of the poultry carcasses, the prevalence of Campylobacter increases after defeathering and evisceration and the rate decreases after scalding and chilling. C. fetus is commonly found in genital and intestinal tract of domestic animals (cattle, sheep). C. fetus subsp. venerealis resides at the prepuce of the bull and the vagina of the cow. In cows, this carriage rate is generally reduced after two breeding seasons. C. fetus ssp. fetus commonly inhabits intestinal tract of healthy small ruminants (sheep). Natural habitat of C. upsaliensis is intestinal tract of healthy puppies and kittens. Genome: The genome of Campylobacter is small in size (1.6e2 megabases) with GC content of 30.1e33.0 mol%. The genome contains several hypervariable regions harbouring genes required for biosynthesis or modification of capsule, lipooligosaccharide and flagellum (Parkhill et al., 2000). These hypervariable sequences consist of homopolymeric tracts and are heritable in nature. Variation in these sequences can produce phase variation, frameshift and point mutations, gene duplication or deletion which results in the generation of multiple serotypes in a single bird or a flock of birds (Parkhill et al., 2000; Linton et al., 2000). C. jejuni is naturally competent which can uptake plasmid or chromosomal DNA during colonization into the poultry. The natural transformation generates genome plasticity and helps in spread of antibiotic resistance genes even in absence of selection pressure (Boer et al., 2002). The natural transformation of C. jejuni is regulated by carbon dioxide and bacterial cell concentration and certain genes encoded by type II and type IV secretion systems. The complete sequencing of virulence plasmid (pVir) in C. jejuni revealed the presence of type IV secretion system, associated with cellular invasion and other roles in pathogenesis (Bacon et al., 2002). C. jejuni prefer to receive DNA from other strains of C. jejuni than any other bacterial species (Wilson et al., 2003).
Antigenic characteristics Campylobacter is antigenically heterogeneous group of bacteria. C. jejuni has heat-stable (somatic) and heat-labile (flagellin) antigens. The flagella of C. jejuni are unsheathed and composed of flagellin protein having molecular weight of 57,000e66,000 Da. They can be divided into more than 600 Penner serotypes (heat-stable antigens) and more than 100 Lior serotypes (heat-labile antigens) (García and Heredia, 2013). C. fetus has three major groups of antigens: somatic (O), flagellar (H) and SLPs. They have at least 50 heat-stable serotypes based on somatic and more than 36 heat-labile serotypes based on flagellar antigens. It has antigenic relationship with Brucella abortus.
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Toxins and virulence factors produced Toxins Enterotoxin The enterotoxin is produced by C. jejuni, C. coli and C. lari. It has structural and functional relationship with Escherichia coli heat-labile enterotoxin (LT) and cholera toxin (CT). Campylobacter enterotoxin is also heat-labile (inactivated at 56 C for 1 h or at 96 C for 10 min), trypsin and pH sensitive (pH two or 8) and has a molecular weight of 60e70 K Da. Like CT or LT, this toxin also attaches with ganglioside receptor of the host cell. It activates adenylate cyclase enzyme to increase the level of intracellular cAMP and disrupt the normal ion transport in the enterocytes, thus causing secreatory watery diarrhoea. Toxic activity of the crude toxin is progressively lost after storage for 1 month at 4 C or for 1 week at 20 or 70 C. The toxin can induce fluid accumulation in rabbit or rat ligated ileal loop assay.
Cytotoxin It is produced by C. jejuni, C. coli and C. lari. It is trypsin-sensitive and toxic for HeLa, Vero cells in vitro. The toxin is destroyed at 70 C temperature for 30 min exposure.
Cytolethal distending toxin It is heat-labile, trypsin-sensitive, nondialyzable cytotoxin with a molecular weight of 30 KDa and produced by C. jejuni, C. coli and C. lari. It is cytolethal to Chinese hamster ovary, Vero, HeLa, human epithelial carcinoma (Hep2) cell lines. The toxin cannot induce fluid accumulation in rabbit ligated ileal loop assay. The iron is required for expression of this toxin. Virulence factors: Major virulence factors of Campylobacter are described in Table 19.1.
Transmission C. jejuni is transmitted through faecaleoral route in poultry. After infection, caecum and colon are the major sites for bacterial multiplication followed by faecal shedding. The bacteria can contaminate the skin of the poultry carcass during slaughtering if an intestinal rupture takes place (Silva et al., 2011). Contaminated drinking water, old litter, farm animals such as cattle, sheep and pigs, wild animals, pets, house flies, insects (litter beetles), farm equipment, transport vehicles and farm workers act as potential source of infection (Sahin et al., 2015). Vertical route of transmission from breeder hen to chick is rare. Presence of Campylobacter was although detected in young hatchling (Chuma et al., 1997; Byrd et al., 2007), eggs laid by Campylobacter positive flocks (Doyle, 1984), reproductive tract of hens (Buhr et al., 2002) and semen of rooster (Cox et al., 2002). Among the farm animals, prevalence of Campylobacter was highest in cattle (6%e90%), especially the feedlot cattle harboured C. jejuni, C. coli, C. lari and Campylobacter lanienae (Horrocks et al., 2009). Occurrence of Campylobacter in pigs, sheep and goats varies 32.8%e85.0% and 6.8%e17.5%, respectively. Companion animals such as 58% of healthy dogs and 97% of diarrhoeic dogs also harboured Campylobacter spp. (Kaakoush et al., 2015). Human transmission of C. jejuni occurs because of extensive international travel, consumption of undercooked chicken or their products, unpasteurized milk, and contaminated water, direct contact with infected farm or companion animals (children) and environmental exposure (Kaakoush et al., 2015). Handling, processing and consumption of undercooked poultry meat or its products are responsible for 20%e30% of human cases (EFSA Panel on Biological Hazards, 2010).The poultry meat may contain high level of the bacteria at preharvest level, which is further contaminated during the time of slaughter and processing. Infective dose of Campylobacter in human is not determined but it was experimentally observed that 500 bacterial cells can cause the disease in human (Robinson, 1981). The susceptibility varies between individuals, foods carrying the organisms, and the children in general were found more susceptible than adults (Calva et al., 1988). Person to person transmission is reported at low frequency (Musher and Musher, 2004). Use of certain antibiotics specially quinolones in animals and birds as therapeutic agent or growth promoter was associated with transmission of resistant Campylobacter strains from animals to human (Endtz et al., 1991).
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TABLE 19.1 Major virulence factors of Campylobacter. Virulence factors
Function
Motility and chemotaxis factors: Flagellin (FlaA, FlaB), hook basal body protein (FliF), flagellar motor proteins (FliM, FliY), P ring protein (FlgI), L-ring protein (FlgH), hook components (FlgE, FliK), chemotaxis proteins (Che A, Che B, Che R, Che V, Che W, Che Z), methyl-accepting chemotaxis proteins (MCPs), Campylobacter energy taxis system proteins CetA (Tlp9) and CetB (Aer2)
Motility is required for survival under the different chemotactic conditions in the gastrointestinal tract and for colonization of the small intestine. Chemotaxis is required for colonization into mucus-filled crypts of the ceca in avian gut.
Adhesins: (i) CadF (Campylobacter adhesion to fibronectin [Fn])
It helps in binding of bacteria with fibronectin protein, found in extracellular matrix or regions of cell to cell contact. So it helps in bacterial adhesion with host tissues.
(ii) Periplasmic/membrane-associated protein (PEB1, PEB3)
Putative adhesin of Campylobacter jejuni.
(iii) CapA (Campylobacter adhesion protein A)
Acts as adhesin.
(iv) JlpA (jejuni lipoprotein A)
It helps in adherence of bacteria with human epithelial cells (Hep2).
(v) Cj1279c and Cj1349c protein
They act as fibronectin and fibrinogen-binding protein.
(vi) Type IV secretion system
Helps in adhesion of bacteria.
Invasion factors: (i) Flagellar proteins (FlhA, FlhB, FliO, FliP, FliQ, FliR)
Flagellar proteins also act as T3SS, an export apparatus required for invasion into the host.
(ii) FlaC protein
Colonization and invasion.
(iii) CiaB, CiaC, CiaI
Invasion and intracellular survival.
(iv) HtrA chaperone
Correct folding of adhesion proteins.
Capsule (capsular polysaccharide transport protein M, capsule biosynthesis proteins)
C. jejuni surface is covered with a capsule which helps in survival, adherence and evasion of the host immune system.
VirK protein
Protection against antimicrobial peptide.
Iron uptake system (i) Membrane ferric enterobactin (FeEnt) receptors (ii) CeuE lipoprotein (iron acquisition) (iii) Ferric uptake regulator (Fur) (iv) Outer membrane receptor for haemin and haemoglobin (ChuA)
Iron transport and regulation are required for survival of Campylobacter.
Major outer membrane protein (MOMP); encoded by porA gene
MOMP is known to allow passage of hydrophilic molecules across the outer membrane and provides structural stability to the outer membrane. It also helps in bacterial adhesion with host tissues.
Stress response factors [stringent control (spoT), catalase (katA), alkyl hydroperoxide reductase (AhpC), thiol peroxidase (Tpx), cytochrome c peroxidases, NADPH quinine reductase, heat shock protein]
These factors help in survival under oxidative stress such as starvation, heat, reduced pH occurred during food processing and storage. Campylobacter enter a viable but nonculturable state which is characterized by decreased metabolic activity, increased production of certain enzymes and cell shrinkage. This condition helps in survival of Campylobacter under unfavourable conditions.
Lipopolysaccharide (LPS)
LPS contains N-acetylneuraminic acid (NeuAc), responsible for serum resistance. ‘NeuAc’ is rarely found in prokaryotes although common in eukaryotic glycolipids.
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Diagnosis The infected poultry birds shed large numbers of organisms (>106 colony-forming units/g faeces). Clinical samples for isolation of Campylobacter are fresh faeces (without urine), caecal droppings or cloacal swabs and bile. Postmortem samples include caeca from poultry, intestinal content from cattle, sheep and pigs. The samples after collection should be carried in a transport media (CaryeBlair, Stuart, Amies, alkaline peptone water) into the laboratory to prevent the drying and oxygen exposure. The samples should be protected from light, freezing (<0 C) and high temperature (>20 C).
Laboratory examinations Direct examination: A smear can be prepared from clinical samples and stained by dilute carbol fuchsin. Campylobacter appears as pink-coloured small curved rod arranged in a pair to produce characteristic ‘S’ or ‘wing of gull’ appearance. The bacteria can also be demonstrated by wet mounts of faeces by phase contrast or dark-field microscopy. C. mucosalis and C. hyointestinalis can be demonstrated by modified ZiehleNeelsen stain. The organisms appear as pink-coloured, curved, intracellular rods. Isolation of Campylobacter spp.: Campylobacter can be isolated from clinical samples without any enrichment. The samples are filtered through 0.65 or 0.45 mm filters before inoculation into the media. Selective media for Campylobacter isolation is broadly categorized into two types, i.e., charcoal based and blood based. Charcoal and blood components remove toxic derivatives of oxygen from the media. Examples of charcoal-based selective media are modified charcoal, cefoperazone, deoxycholate agar (mCCDA), Karmali agar or charcoal selective medium. The blood-based media are Preston agar, Skirrow agar, Butzler agar and Campy Cefex agar. Commonly used nonselective media for Campylobacter isolation are blood agar with or without 0.1% sodium thioglycolate (used to reduce oxygen tension of the media) and antibiotics. The antibiotics used in the media are cephalosporins, trimethoprim, bacitracin, actidione, amphotericin B, etc. Actidione and amphotericin B are used to prevent the growth of yeasts and moulds. Campylobacter are microaerophilic in nature and require 3%e5% CO2 with 3%e15% O2 for growth. Optimum growth requires incubation at 37 C temperature for 2e5 days (24e48 h for C. jejuni and C. coli). Campylobacter spp. will not survive below a pH of 4.9 and above pH 9.0 and grow optimally at pH 6.5e7.5. Thermophilic Campylobacter (C. jejuni, C. coli) prefer to grow at 30e46 C in an atmosphere containing 10% CO2 and 5% O2. C. jejuni is nonhaemolytic and produces finely granular, irregular margin, flat, greyish colonies in blood agar. On charcoal-based media, the colonies may produce ‘metallic sheen’. Serological tests: Fluorescence in situ hybridization, latex agglutination test and a physical enrichment method (filtration) can detect Campylobacter in the food matrix (Baggerman and Koster, 1992; Hazeleger et al., 1992; Lehtola et al., 2006). Molecular biology: Multiplex polymerase chain reaction (PCR) is developed for detection of several Campylobacter species such as C. jejuni (23S RNA gene); C. coli, C. lari and C. upsaliensis (glyA gene) and sapB2 gene from C. fetus subsp. fetus (Wang et al., 2002). PCR combined with immunomagnetic separation can detect Campylobacter present in low numbers in the samples (Waller and Ogata, 2000). Real-time PCR can confirm Campylobacter in very low copies (1 cfu) in less than 2 hours (Debretsion et al., 2007).
Characteristics of antimicrobial resistance Erythromycin (macrolide) is the drug of choice for clinical campylobacteriosis, although fluoroquinolone, tetracyclines and gentamicin are also used for the treatment (Acheson and Allos, 2001). Increasing resistance of Campylobacter against common antibiotics is a public health concern. Intrinsic resistance in C. jejuni and C. coli was described against penicillins and cephalosporins, bacitracin, novobiocin, rifampin, streptogramin B and vancomycin (McNulty, 1987). The multidrug efflux pump (CmeABC) was detected to be associated with intrinsic resistance in Campylobacter (Lin et al., 2002). Mutation of the essential genes and horizontal transfer of resistance determinants are two major pathways associated with generation of antimicrobial resistance in Campylobacter. Absence of DNA repair molecules such as methyl-directed mismatch repair (mutH and mutL), recombination repair (sbcB), repair of pyrimidine dimmers (phr), very short patch repair (vsr) and protecting protein from UV-induced mutagenesis (umuCD) and alkylating agents (ada) in C. jejuni isolates further promote the mutations (Parkhill et al., 2000).
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Quinolone resistance Use of fluoroquinolones in animal and poultry farms in the United States, Europe, Australia and Asia was correlated with generation of quinolone-resistant human Campylobacter isolates (Endtz et al., 1991; Nachamkin et al., 2002; Hart et al., 2004). Conversion of fluoroquinolone-susceptible C. jejuni into resistant population was observed after exposure to enrofloxacin (McDermott et al., 2002). Amino acid substitution (Thr86Ile, Asp90Asn, Thr86Lys, Thr86Ala, Thr86Val, Asp90Tyr) in the quinolone resistancedetermining region (QRDR) of topoisomerase enzyme is associated with quinolone resistance of Campylobacter spp. Mutation (C257T) in gyrA gene and subsequent Thr86Ile amino acid substitution was detected as most common mechanism of quinolone resistance in Campylobacter spp. (Payot et al., 2006). This substitution (Thr86Ile) produced high level of resistance in C. jejuni and C. coli isolates against ciprofloxacin (Ge et al., 2005). The frequencies of emergence of fluoroquinolone-resistant mutants range from approximately 106 to 108/cell/generation (Yan et al., 2006). Strain to strain variation in emergence of mutant occurs as the mutation (C257T) might offer a ‘fitness benefit’ to one strain of C. jejuni but was ‘costly’ for a different strain (Luo et al., 2005). The multidrug efflux pump (CmeABC) was also detected to be associated with quinolone resistance in Campylobacter spp. in synergy with gyrA mutations. CmeABC is encoded by three genes, i.e., cmeA (periplasmic fusion protein), cmeB (drug transporter) and cmeC (outer membrane protein). Blocking the efflux pump in Campylobacter reduced the MIC value against ciprofloxacin in spite of mutation in gyrA (Luo et al., 2003). Mfd (mutant frequency decline), a transcription repair coupling factor associated with DNA repair, also develops quinolone-resistant Campylobacter strains (Han et al., 2008).
Tetracycline resistance Resistance to tetracyclines in Campylobacter is associated with tet(0) gene, present in a self-transmissible plasmid (45e58 kb) and prevalent in both C. jejuni and C. coli strains (Connell et al., 2003a). Campylobacter tet(0) gene was acquired by horizontal gene transfer from Streptomyces, Streptococcus and Enterococcus spp. (Batchelor et al., 2004). The tet(0) gene encodes ribosomal protection proteins which can bind with open ‘A’ site on the bacterial ribosome and produces a conformational change of the ribosome in such a manner that all the bound tetracycline molecules are released(Connell et al., 2003b). The conformational change did not hamper the protein synthesis of the bacterial ribosome.
Macrolide resistance Generation of macrolide resistance in Campylobacter is a stepwise process that requires exposure for a prolonged period. Exposure to quinolones although rapidly induces resistance in Campylobacter strains. Subtherapeutic exposure to tylosin, given continuously in feed, produced more macrolide resistance in C. coli isolates than therapeutic exposure (Schönberg-Norio et al., 2006; Ladely et al., 2007). Resistance to macrolides in Campylobacter is associated with modification of the ribosomal target, ribosomal proteins and enzymatic inactivation of the drug. Mutation in 23S rRNA gene (A2074C, A2074G, A2075G) is the common way to generate erythromycin resistance (MIC > 128 mg/L) in C. jejuni and C. coli isolates (Jeon et al., 2008). Modifications (substitution, insertion, deletion) of the ribosomal proteins (L4, L22) were associated with generation of low-level macrolide resistance in Campylobacter isolates (Cagliero et al., 2006). The multidrug efflux pump (CmeABC) was also detected to be associated with macrolide resistance in Campylobacter spp. in synergy with 23S rRNA mutations and modifications of L4, L22 proteins (Corcoran et al., 2006; Cagliero et al., 2006).The frequency of emergence of macrolide-resistant mutants is lower than fluoroquinolone-resistant mutants (1010/cell/generation) (Lin et al., 2007). Lower mutation rate, prolonged antibiotic exposure and required fitness cost are the probable explanations for the lower prevalence of macrolide resistance in Campylobacter isolates.
Aminoglycoside resistance Aminoglycoside-modifying enzymes (aminoglycoside phosphor transferase types I, III, IV and VII, aminoglycoside adenyl transferase, 6-amino glycoside adenyl transferase) detected in Campylobacter spp. can decrease the affinity of aminoglycosides for the rRNA A-site (Llano-Sotelo et al., 2002). Kanamycin-resistance phosphotransferase [APH (30 ) III and APH (30 ) IV] was detected in a 14 Kbp plasmid present in C. jejuni isolates (Tenover et al., 1989). This plasmid can offer resistance against tetracyclines also and is transferred between Campylobacter strains (Gibreel et al., 2004).
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b-Lactam antibiotic resistance Majority of Campylobacter strains are inherently resistant to penicillins and narrow spectrum cephalosporins (except amoxicillin and ampicillin) because of production of b-lactamase enzyme or mediated through multidrug efflux pump (CmeABC) (Tajada et al., 1996; Lin et al., 2002). C. jejuni/C. coli strains were found susceptible to cefotaxime, ceftazidime, cefpirome and imipenem (Van der Auwera et al., 1985).
Chloramphenicol resistance Plasmid-encoded chloramphenicol resistance gene (cat) was rarely detected in Campylobacter spp. (Wang and Taylor, 1990). The enzyme acetyltransferase, encoded by cat gene, modifies chloramphenicol in a way which prevents its binding with bacterial ribosomes. A recently explored mechanism suggested the synergistic role of efflux pump (CmeB) and radical S-adenosylmethionine enzyme in production of chloramphenicol resistance in C. jejuni strains (Li et al., 2017).
Sulphonamide resistance Resistance to sulphonamides in C. jejuni strains was associated with mutational substitution of amino acids in dihydropteroate synthase enzyme resulting in reduced affinity for sulphonamides (Gibreel and Sköld, 1999).
Trimethoprim resistance Resistance to trimethoprim in Campylobacter was associated with two dihydrofolate reductases (dfr1 and dfr9) acquired from Enterobacteriaceae (Gibreel and Sköld, 2000).
Streptothricin resistance The sat4 gene present in C. coli was found to be associated with streptothricin resistance in animal and clinical isolates in Germany (Bischoff and Jacob, 1996). Characteristics of antimicrobial resistance in Campylobacter isolates observed in poultry, pigs and human are discussed in the following section.
Poultry Occurrence of Campylobacter in healthy poultry gut is high and use of antibiotics in poultry can induce the generation of antibiotic-resistant strains. The fluoroquinolones (sarafloxacin and enrofloxacin) were licenced by the FDA for therapeutic use in poultry during 1990 which generated quinolone-resistant Campylobacter in poultry in the United States (Gupta et al., 2004). National Antimicrobial Resistance Monitoring System (NARMS) in the United States revealed an increasing trend (20.3% in 2001 to 23.1% in 2010) of ciprofloxacin resistance in C. jejuni isolated from the chicken at slaughter (NARMS, 2010). Subsequently the licence for fluoroquinolone use in poultry was cancelled in the United States in 2005 after prolonged legal battle (Nelson et al., 2007). Higher occurrence of fluoroquinolone-resistant Campylobacter was observed in conventional poultry and associated retail meat than organic poultry in the United States (Cui et al., 2005; Luangtongkum et al., 2006). Throughout the world, prevalence of fluoroquinolone-resistant Campylobacter varied widely (0%e99%) in broilers. The prevalence was at lower side (0%e11%) in poultry in Australia, Denmark and Norway (Iovine, 2013) and higher occurrence was observed in Spain and Thailand (80%e99%) (Sáenz et al., 2000; Chokboonmongkol et al., 2013). Increasing trend in occurrence of quinolone-resistant Campylobacter strains was observed in poultry during 1994 (47%) to 2008 (90%) in Poland (Wozniak, 2011). Macrolide resistance in poultry C. jejuni isolates was comparatively lower than C. coli in most of the countries (Gyles, 2008). The study in Portugal although revealed the higher rate of erythromycin resistance in C. jejuni (35%) isolates than C. coli (13%) in poultry (Fraqueza et al., 2014). Low erythromycin resistance (0%e10%, 2001e10) was observed in C. jejuni strains isolated from retail poultry meat in the United States (NARMS, 2010). Higher occurrence of macrolide-resistant C. coli (100%) than C. jejuni (9%e14%) was detected in poultry in China (Chen et al., 2010). In a systemic study in China, species shift from C. jejuni to C. coli was observed in poultry during 2008e14. Occurrence of macrolide-resistant C. jejuni strains reduced from 13.3% (2008e09) to 8.2% (2012e14), and subsequently, occurrence of resistant C. coli strains increased from 48.7% (2008e09) to 76.4% (2012e14). Excessive use of macrolides
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(tylosin, tilmicosin, erythromycin, kitasamycin, tulathromycin) in poultry and livestock industry in China was correlated with species shift of Campylobacter and increased macrolide resistance (Wang et al., 2015).
Pigs Ciprofloxacin-resistant C. coli were detected in pigs in China with higher occurrence (96%e99% of the isolates) (Qin et al., 2011). Increased macrolide use in swine industry in China was also correlated with increased prevalence (44% during 2008e09 to 59% during 2012e14) of macrolide-resistant C. coli (Wang et al., 2015).
Human Resistance to antibiotics (fluoroquinolone) was first detected in human Campylobacter isolates during late 1980s (Acheson and Allos, 2001). The resistance spreads rapidly throughout the world with introduction of fluoroquinolones in poultry and livestock industry. In the United States, fluoroquinolone resistance in human isolates raised from 1.3% in 1992 to 10.2% in 1998 (Nachamkin et al., 2002). Similar increasing trend of fluoroquinolone resistance in Campylobacter isolates was detected in Europe (Spain in 1993e2003, Germany in 1991e2002) (Luber et al., 2003; Ruiz et al., 2007) and Asia (India and Thailand, Hoge et al., 1998; Jain et al., 2005). In Denmark and Finland, a positive correlation between resistance to ciprofloxacin, nalidixic acid and tetracycline in human Campylobacter isolates and international travel (specially in Spain and Thailand) was detected (Hakanen et al., 2003; Skjøt-Rasmussen et al., 2009). In Australia, occurrence of resistant Campylobacter spp. in human was low because of restricted use of antibiotics both in human and food animals (Unicomb et al., 2003).
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