19a Other bacterial diseasesDiseases caused by corynebacteria and related organisms

The genus Corynebacterium contains the species Corynebacterium diphtheriae and the non-diphtherial corynebacteria. C. diphtheriae is the major human pathogen in this genus, but several species of nondiphtheria corynebacteria appear to be emerging as important pathogens.

Zoonotic corynebacteria rarely cause disease in humans, but recent reports have indicated that the frequency and severity of infection associated with Corynebacterium ulcerans has increased in many countries. In the past most human C.ulcerans infections have occurred through close contact with farm animals or by consumption of unpasteurized dairy products. However, recently, there have been cases of human infection following close contact with household pets. Rhodococcus equi appears to be emerging as an important pathogen in immunocompromised patients, especially those with acquired immunodeficiency syndrome (AIDS). Human infections caused by Corynebacterium pseudotuberculosis is still a very rare occurrence.

Antibiotics in combination with surgery and vaccination are the treatment of choice for human infection. Control of human infection is best achieved by raising awareness in those at risk (e.g. domestic pet owners, sheep shearers, the immunocompromised), clinicians involved in treating these groups and by vaccination. Reducing prevalence in the animal population could be achieved by improving hygiene in farms and husbandry practices, reducing minor injuries (e.g. cuts and abrasions) during routine procedures, and by vaccination.

The genus Corynebacterium is derived from the Greek words koryne, meaning club, and bacterion, meaning little rod. The genus Corynebacterium was first proposed by Lehmann and Neumann in 1896 (Skerman et al. 1980) to include the diphtheria bacillus and other morphologically similar organisms. Corynebacterium species are found in soil and water, and reside on the skin and mucous membranes of humans and animals.

C. pseudotuberculosis (previously known as Corynebacterium. ovis) was also called the Preisz-Nocard bacillus in honour of the researchers who first isolated the organism in the early 1890s (Lipsky et al. 1982). C. pseudotuberculosis was originally identified as the causative microorganism of caseous lymphadenitis (CLA) in sheep and goats, but this bacterium has also been isolated from horses, cattle, camels, swine, buffaloes and humans (Dorella et al. 2006). Human infection caused by C. pseudotuberculosis was first reported in 1966 (Lopez et al. 1966).

C. ulcerans was first isolated in 1926 from human throat lesions (Gilbert and Stewart 1926). The organism has been recovered from cattle, wild animals and recently from domestic cats and dogs (Hommez et al. 1999; Fox et al. 1974; De Zoysa et al. 2005; Lartigue et al. 2005). C. ulcerans can produce diphtheria toxin which is immunologically identical to that of C. diphtheriae (Lipsky et al. 1982) and may cause human infections mimicking cutaneous and classical respiratory diphtheria.

Corynebacterium kutscheri was first described by Kutscher in 1894 (Noble and Smith 1990). It has since been described as a commensal bacterium in mice, rats, and voles and has been identified in the oral cavity, oesophagus, colon, rectum, and submaxillary lymph nodes of these rodents (Bonsfield and Callely 1978). It can cause pulmonary infection in mice and rats (Giddens et al. 1968). Human infection caused by C. kutscheri has been reported. However in some cases a definitive identification was not established (Holmes and Korman 2007).

Corynebacterium bovis was first isolated in 1916 by Evans who named the organsim Bacillus abortus var. lipolyticus (Evans 1916). Bergey et al. (1923) renamed the organism C. bovis. It is a commensal of the bovine udder and can cause bovine mastitis and may contaminate milk (Smith 1966). Only nine human cases have been reported (Achermann et al. 2009; Dalal et al. 2008; Bolton et al. 1975; Vale and Scott 1977).

Arcanobacterium pyogenes, formerly classified as Corynebacterium pyogenes, and Actinomyces pyogenes was first described by Lucet in 1983 (Noble and Smith 1990). A. pyogenes is a well known animal pathogen causing a variety of pyogenic infections in many species (Smith 1966). Few zoonotic cases of human infections with A. pyogenes have been reported (Gahrn-Hansen and Frederiksen 1992).

Rhodococcus equi formerly classified as Corynebacterium equi was first isolated from foals in 1923. Infection in a human caused by R. equi was first reported in 1967 in a 29 year old man with plasma cell hepatitis receiving immunosuppressants. Since then R. equi has become an important opportunistic pathogen in immunocompromised patients, mainly those with AIDS (Fierer et al. 1987; Mandarino et al. 1994; Cardoso et al. 1996; Martin-Dávila et al. 1998).

C. ulcerans, C. pseudotuberculosis, C. bovis, and C. kutscheri are zoonotic corynebacteria that are known to cause clinical disease to varying extents in humans and their animal hosts. For the purpose of this review, Rhodococcus equi, formerly classified as Corynebacterium equi, and Arcanobacterium pyogenes, initially classified as Corynebacterium pyogenes, have also been included.

C. diphtheriae is the major human pathogen within the genus Corynebacterium and is the causative agent of diphtheria. Though C. diphtheriae is traditionally considered a non-zoonotic pathogen the organism has occasionally been isolated from equine wound infections, the udder and teats of cows, and equids, and canids (Henricson et al. 2000). C. diphtheriae can, when lysogenised by certain bacteriophages, produce diphtheria toxin which is the major virulence determinant.

The uncertain taxonomic status of C. ulcerans was resolved by Riegel et al. (1995). On the basis of DNA-DNA homology and rRNA gene sequences, they demonstrated that C. ulcerans is a distinct species. Phylogenetically C. ulcerans together with C. pseudotuberculosis is the closest relative of C. diphtheriae (Pascual et al. 1995; Ruimy et al. 1995). C. ulcerans can also harbour the diphtheria toxin. When lysogenic for a tox⁺ carrying phage, the organism produces two exotoxins in varying proportions (Petrie et al. 1934; Carne and Onon 1982). One is identical to C. diphtheriae toxin and is neutralized by diphtheria anti-toxin. The other is identical to C. pseudotuberculosis toxin Phospholipase D (PLD) which is unaffected by diphtheria antitoxin. The majority of the strains isolated from humans produce diphtheria toxin.

Over 10% of the C. pseudotuberculosis isolates produce the diphtheria toxin (Maximescu et al. 1974). However, there have not been any clinical cases of diphtheria attributed to infection with C. pseudotuberculosis (MacGregor 2000). PLD is the main virulence factor of C. pseudotuberculosis. PLD facilitates the persistence and spread of the organism within the host. The organism also possesses a toxic lipid coat on the surface which protects it from hydrolytic enzymes in the host and allows it to persist inside host cells. The fagBCD operon is another known virulence factor in C. pseudotuberculosis (Billington et al. 2002).

A. pyogenes produces several virulence factors that may contribute to its pathogenicity. These include, a haemolysin (Pyolysin PLO), neuraminadases and collagen binding proteins for adhesion and colonizing host tissue (Jost et al. 1999, 2001, 2002; Pietrocola et al. 2007).

Zoonotic corynebacteria that have been known to cause the most economic losses are C. pseudotuberculosis, A. pyogenes and R. equi. C. pseudotuberculosis is the etiological agent of CLA in sheep and goats worldwide (Williamson 2001). The organism has also been isolated from horses with lymphanginitis and from cattle, camels, swine, and buffaloes, with pigeon fever (Yeruham et al. 2004; Selim 2001; Peel et al. 1997). Most human cases have been related to occupational exposure (Peel et al. 1997). CLA causes significant economic losses to sheep and goat producers in the world. External CLA is characterized by abscess formation in superficial lymph nodes and subcutaneous tissues. The abscesses can also develop in the lungs, kidneys, liver and the spleen characterizing visceral CLA.

Infections in humans caused by C. pseudotuberculosis are very rare. Human infections have been recorded in farm workers and vets exposed to infected animals, usually manifesting as lymphadenitis (Goldberger et al. 1981; Richards and Hurse 1985; House et al. 1986; Peel et al. 1997; Mills et al. 1997). Most of the reported episodes of human infection with C. pseudotuberculosis have been reported from Australia (Peel et al. 1997), where the patients have had extensive contact with animals (especially sheep), except for one case of eosinophilic pneumonia after exposure to C. pseudotuberculosis in a laboratory (Keslin et al. 1979).

Transmission among sheep and goats mainly occur through contamination of superficial wounds, which can appear during shearing, castration, and ear tagging (Dorella et al. 2006). Bacteria may be present in faeces of infected sheep which leads to a reservoir being present in soil. In cattle, transmission may occur through houseflies (Yeruham et al. 1996).

C. ulcerans causes mastitis in cattle and goats. Cattle are a known reservoir for C. ulcerans and may shed the organism for months to years. The organism has been isolated from other wild animals and domestic pets (Hommez et al. 1999; Fox et al. 1974; De Zoysa et al. 2005; Lartigue et al. 2005; Hogg et al. 2009). Toxigenic strains of C. ulcerans have been associated with classical and cutaneous diphtheria, pharyngitis, sinusitis, and extrapharygeal disease (Ahmad, et al. 2000; Hart 1984; Barrett 1986; Pers 1987; Kisely et al. 1994), and it has been recommended that the public health response to human infection with C. ulcerans should be the same as for C. diphtheriae. Usually human infections are acquired through contact with farm animals or by ingestion of unpasteurized dairy products (Bostock et al.  1984  ;  Hart 1984; Barrett et al. 1986  ). Previously it was thought that person-to-person spread of toxigenic C. ulcerans did not occur (Meers 1979) but in 1996 C. ulcerans was isolated from siblings, and in 1998, the organism was isolated from a father and son (Bonnet and Begg 1999; White et al. 2001). Recently domestic animals have been identified as possible sources of human C. ulcerans infection. De Zoysa et al. (2005) reported the isolation of toxigenic C. ulcerans from domestic cats with bilateral nasal discharge in the UK, and Hogg et al. (2009) reported a fatal human case of diphtheria resulting from a possible zoonotic transmission of toxigenic C. ulcerans from a dog in the UK. C. kutscheri causes latent infection in healthy rats and mice, but can cause severe illness in immunocompromised or nutritionally deficient rodents. Illness is characterized by bacteremia with septic emboli and end-organ disease in lungs of rats and kidneys and liver of mice (Amao et al. 2002; Pierce-Chase et al. 1964). Three cases of human infection have been reported, a case of chorioamnionitis and funisitis, septic arthritis, and soft tissue infection (Fitter et al. 1979; Messina et al. 1989; Natasha et al. 2007). It has been suggested that the organism may transmit via aerosol droplet, faecal-oral or by direct contact. Experimentally it has been shown that mice can shed the organism in faeces for up to 5 months (Amao et al. 2008).

C. bovis is a commensal of the bovine udder and may cause bovine mastitis, and in severe cases may result in loss of the udder or even death of the animal. The mode of transmission to humans is unclear; the organism appears to be a sporadic opportunistic agent of human disease (Bernard et al. 2002). To date, eight human cases with C. bovis have been reported, including ventriculojugular shunt nephritis, line-related sepsis, meningitis, leg ulcers, otitis media, epidural abscess, and endocarditis (Bolton et al. 1975; Dalal et al. 2008; Vale and Scott 1977).

A. pyogenes, initially classified as Corynebacterium pyogenes, is a common inhabitant of the upper respiratory and genital tracts of cattle sheep, swine, and many other species (Billington et al. 2002; Azawi and Azar 2003; Gröhn et al. 2004; Ertas¸ et al. 2005). It is one of the most important bacterial pathogens of cattle, causing liver abscesses, mastitis, infertility, abortion, and postpartum urine infections (Lechtenberg et al. 1988; Hillerton and Bramley 1989; Semambo 1991; Ruder et al. 1981). Contact of teats with a contaminated environment such as milking apparatus may cause the spread of mastitis. A pyogenes may also be transmitted by biting flies. It is also an opportunistic pathogen associated with suppurative or granulomatous lesions in domestic animals and avian species (Timoney et al. 1988; Brinton et al. 1993).

Human infections due to A. pyogenes are very rare. Human disease has been reported in people living in rural areas with underlying diseases such as cancer or diabetes (Plamondon et al. 2007). Types of human infections reported have been abdominal abscesses, otitis media, septic arthritis, endocarditis, and pneumonia (Plamondon et al. 2007; Levy et al. 2009). Cases have also been reported after organ and hematopoietic stem cell transplantation and patients with liver disease (Chen et al. 2009).

R. equi, previously known as Corynebacterium equi, is one of the most important causes of zoonotic infections in grazing animals, mainly horses and foals. It causes chronic suppurative bronchopneumonia, lymphadenitis and ulcerative enteritis in foals up to six months and the organism is considered as one of the most significant pathogens in the equine breeding industry (Hébert et al. 2010). The organism has also been isolated from cats and dogs (Jang et al. 1975; Farias et al. 2007; Cantor et al. 1998). R. equi is an important opportunistic pathogen in immunocompromised patients, especially those with AIDS. Infection with R. equi is associated with significant mortality. The organism is a soil inhabitant and exposure to soil contaminated with manure is the most likely route of both animal and human infection. Exposure is usually through inhalation, but may occur via ingestion or direct inoculation.

C. ulcerans has been isolated from a wide range of domestic and wild animals. Diphtheria-like illness caused by toxigenic C. ulcerans appears to be increasingly recognized in many industrialized countries including the UK, France, Germany, Japan, Italy, and the USA (Hogg et al. 2009; Elden et al. 2007; Bonmarin et al. 2009; Sing et al. 2005; Hatanaka et al. 2003; von Hunolstein et al. 2003; Tiwari et al. 2008). In the UK, between 1986 and 2007, a total of 56 clinical isolates of toxigenic C. ulcerans were submitted to the WHO Streptococcus and Diphtheria Reference Unit, Health Protection Agency for identification. Amongst the 56 isolates, seven were from cases of classical diphtheria, and more than three deaths in the UK have been attributed to such infection (Tiwari et al. 2008).

Previous reports have usually linked human C. ulcerans infections to consumption of unpasteurized milk to having close contact with infected farm animals (Hart 1984; Higgs et al. 1967) but more recently a lack of association with farming or ingestion of raw milk products has been a notable feature. Toxigenic C. ulcerans have now been isolated from domestic cats with bilateral nasal discharge and dogs with rhinorrhoea (Taylor et al. 2002; Lartigue et al. 2005) and cases have now been recognized of human infection believed to have been contracted from contact with domestic cats and dogs (Hogg et al. 2009; Bonmarin et al. 2009; Lartigue et al. 2005; Hatanaka et al. 2003).

Epidemiological studies have shown a high prevalence of CLA in adult sheep (26%) in Australia (Paton et al. 2003) and in Canada (21%) (Arsenault et al. 2003). A study carried out in the UK showed that 45% of the farmers interviewed had seen abscesses on their sheep, possibly due to CLA, but only a few farmers had determined the cause of the abscesses (Binns et al. 2002). CLA remains a veterinary concern throughout the world.

Most of the reported episodes of human infection with C. pseudotuberculosis have been reported from Australia (Peel et al. 1997) where the patients have had extensive contact with sheep. To date, approximately 25 cases of human infection caused by C. pseudotuberculosis have been reported (Liu et al. 2005; Mills et al. 1997; Peel et al. 1997). Infected humans presented with lymphadenitis, abscesses and constitutional symptoms (Peel et al. 1997). A case of human necrotizing granulomatous lymphadentis in a boy following contact with infected animals, and a case of eye infection due to an ocular implant have also been reported (Mills et al. 1997; Liu et al. 2005).

R. equi primarily causes zoonotic infections in horses and foals. Between 1967 and 1982 only 12 cases were reported (Lipsky et al. 1982). However with the AIDS epidemic the number of human infections has greatly increased (Weinstock and Brown 2002). The mortality rate among HIV infected patients is approximately 50–55% compared with 11% among immunocompetent patients.

Human infections due to A. pyogenes are very rare in the UK, however in other countries it may be a cause of significant morbidity. Between 1966 and 2007 approximately 13 cases of human infection have been reported, as reviewed by Plamondon et al. (2007). Most cases had an underlying illness such as cancer or diabetes and were also exposed to farm animals.

A. pyogenes is an important bacterial pathogen of cattle, causing liver abscesses, mastitis, abortion and infertility (Lechtenberg et al. 1988; Hillerton et al. 1989; Semambo et al. 1991). While not a major cause of mastitis the incidence of A. pyogenes mastitis within a herd can be high as 18% (Jones and Ward 1989). In a study carried out in the East of Turkey, it was reported that A. pyogenes was isolated from 40 out of 100 cattle with kidney abscesses at a local abattoir (Ertas et al. 2005).

The mainstay of treatment for clinical diphtheria caused by toxigenic C. ulcerans is equine diphtheria anti-toxin (DAT). DAT is promptly administered to the patient, after testing for sensitivity to DAT. Antibiotics are not substitutes for DAT. The antibiotics of choice for diphtheria-like illness caused by C. ulcerans are erythromycin and penicillin. Tiwari (2008) reported a strain of C. ulcerans which was resistant to erythromycin and clindomycin but susceptible to penicillin, vancomycin, ciprofloxacin, and cephalosporins. This highlights the importance of testing strains of this organism for susceptibility to antimicrobials used for treatment. In the UK, there is no licensed erythromycin product for use in domestic pets. Hogg et al. (2009) reported the use of spiramycin in combination with metronidazole for eliminating C. ulcerans infection in dogs. Cattle have classically been considered as the main reservoir of C. ulcerans and infection can be prevented by eliminating consumption of unpasteurized milk and milk products and also by raising awareness amongst those at risk such as domestic pet owners.

C. pseudotuberculosis infection in humans can be prevented by covering cuts and abrasions when handling animals and also by raising awareness amongst sheep shearers, butchers and clinicians. Surgical excision of the affected lymph glands in human cases of lymphadenitis is the mainstay of management, and antibiotic treatment is additional. The use of a combined toxoid vaccine against caseous lymphadenitis in sheep may result in a decrease in the number of human cases of this zoonoses (Peel et al. 1997; Paton et al. 1995).

Treatment of R. equi infection in humans requires prolonged combination antibiotic therapy, and sometimes surgical therapy. Combination antibiotic therapy may decrease the risk of developing resistance. The use of a carbapenem such as meropenem and a glycopeptide such as vancomycin and use of macrolides in combination with rifampicin are good choices (Tse et al. 2008; Prescott 1991). Increasing awareness of R. equi infection among those with weakened immune systems, and taking precautions such as reducing dust levels on farms and covering wounds may help to avoid transmission of R. equi. Experimentally it has been shown that the combination of clarithromycin and rifampicin is superior to azithromycin-rifampicin and erythromycin-rifampicin for treatment of pneumonia caused by R. equi in foals (Giguere et al. 2004). Control measures for A. pyogenes infection include fly control programmes, maintaining cows in clean and dry calving areas and removing affected cows from the herd. Once infected, the prognosis is poor as antibiotic therapy is often ineffective.