**1.2 Transmission of antimicrobial-resistant bacteria from dairy farms to human**

Most studies showed that there is no widespread, emerging resistance among mastitis pathogens [2–4] in dairy farms. However, dairy farms may serve as a source of antimicrobial-resistant human pathogenic bacteria. Extensive use of thirdgeneration cephalosporins (3GCs) in dairy cattle for the prevention and treatment of mastitis [3, 25, 28] and other diseases of dairy cattle [31, 32] can result in the carriage of extended-spectrum beta-lactamase producing *Enterobacteriaceae* (ESBL Ent) [50, 51]. Third- and fourth-generation cephalosporins are commonly used for the treatment of invasive Gram-negative bacterial infections in humans [52–54]. In 2017, there were an estimated 197,400 cases of ESBL Ent among hospitalized patients and 9100 estimated deaths in the US alone [55]. Among *Enterobacteriaceae, Escherichia coli* (*E. coli*) is the most common bacteria that reside in the gut as normal microflora or opportunist pathogen of animals and humans. However, certain pathogenic strains can cause diseases such as mastitis in cattle, neonatal calf diarrhea in calves and hemorrhagic enteritis, and more life-threatening conditions such as hemolytic uremic syndrome and urinary tract infections in humans. New strains of multi-drug resistant foodborne pathogens that produce extended-spectrum

**187**

*Current Status of Antimicrobial Resistance and Prospect for New Vaccines against Major…*

strains that are resistant to all or most available antimicrobials [59, 60].

as a reservoir of ESBLs producing *E. coli* (ESBLs *E. coli*) for human.

beta-lactamases that inactivate nearly all beta-lactam antibiotics have been reported [30]. Ceftiofur is the most common 3GC used in dairy cattle operations [56]. The 3GCs are also critically important antibiotics for the treatment of serious infections caused by *Enterobacteriaceae* such as *Escherichia coli (E. coli)* and *Salmonella* spp. in humans [57, 58]. The use of structurally and chemically similar antibiotics in dairy cattle production and human medicine may lead to co-resistance or cross-resistance [52–54]. Some of the species of Gram-negative environmental mastitis pathogens, such as *E. coli*, *Klebsiella pneumoniae*, *Acinetobacter* spp., *Pseudomonas* spp., *Enterobacter* spp. are the greatest threat to human health due to the emergence of

The resistance of *Enterobacteriaceae* to 3GC is mainly mediated by the production of extended-spectrum beta-lactamase enzymes (ESBLs) that breakdown 3GC [61]. *E. coli* is one of the most frequently isolated *Enterobacteriaceae* carrying ESBL genes (*bla*CTX-M*, bla*SHV*, bla*TEM, *and bla*OXA) families [62–64]. These ESBL genes are usually carried on mobile plasmids along with other resistance genes such as tetracycline, quinolones, and aminoglycosides. *E. coli* resides in the gastrointestinal tract of cattle as normal or opportunistic microflora, but some strains (for e.g., 0157:H7) cause serious infection in humans [58], indicating that cattle could serve

In the US, the occurrence of ESBLs *E. coli* in the dairy cattle was reported a decade ago from Ohio [52] and few previous studies reported the occurrence and an increase in the trend of ESBLs *E. coli* in the dairy cattle production system [52, 53, 65–67]. However, recent studies increasingly showed the rise of ESBLs *E. coli* in the cattle [51, 52, 65, 67]. Similarly, reports from the Center for Disease Control (CDC) showed a continuous increase in the number of community-associated human infections caused by ESBLs-producing *Enterobacteriaceae* [55]. This CDC report showed a 9% average annual increase in the number of hospitalized patients from ESBLs pathogens in six consecutive years (from 2012 to 2017)*.* As a result, the human health sector tends to blame dairy farms that routinely use the 3GC for the rise of ESBLs pathogens such as *E. coli* [55, 68]. However, despite the general believe of possibility of transmission of antimicrobial-resistant bacteria from dairy farms to humans directly through contact or indirectly through food chain, there was no clear evidence-based data that showed the spread of antimicrobial-resistant bacteria from the dairy production system to humans. The opinion of the scientific community on the factors that drive the emergence and spread of antimicrobial-resistant bacteria also varies [69]. Transmission of an antimicrobial-resistant pathogen to humans could occur if contaminated unpasteurized milk and/or undercooked meat from culled dairy cows due to chronic mastitis is consumed [70]. So it is crucial to pasteurize milk or cook meat properly to reduce the risk of infection by antimicrobial-resistant bacteria [71]. It is not known, if pasteurization or proper cooking prevents the transfer of resistant genes from milk or meat to commensal or opportunistic bacteria in the human gastrointestinal tract (GIT), or the GIT of calves fed pasteurized waste milk. Mechanisms of antibiotic resistance gene transfer from resistant to susceptible bacteria are not well known, and killing resistant pathogens alone may not be good enough to prevent the transfer of the resistance gene. Non-prudent use of antimicrobials in dairy farms increases selection pressure, which could result in the emergence, persistence, and horizontal transfer of antimicrobial-resistant determinants from resistant to non-resistant bacteria. Bacteria exchange resistance genes through mobile genetic elements such as plasmids, bacteriophages, pathogenicity islands, and these genes may ultimately enter bacteria pathogenic to humans or commensal or opportunistic bacterial pathogens. The prudent use of antimicrobials in dairy farms requires identification of the pathogen causing

*DOI: http://dx.doi.org/10.5772/intechopen.94227*

### *Current Status of Antimicrobial Resistance and Prospect for New Vaccines against Major… DOI: http://dx.doi.org/10.5772/intechopen.94227*

beta-lactamases that inactivate nearly all beta-lactam antibiotics have been reported [30]. Ceftiofur is the most common 3GC used in dairy cattle operations [56]. The 3GCs are also critically important antibiotics for the treatment of serious infections caused by *Enterobacteriaceae* such as *Escherichia coli (E. coli)* and *Salmonella* spp. in humans [57, 58]. The use of structurally and chemically similar antibiotics in dairy cattle production and human medicine may lead to co-resistance or cross-resistance [52–54]. Some of the species of Gram-negative environmental mastitis pathogens, such as *E. coli*, *Klebsiella pneumoniae*, *Acinetobacter* spp., *Pseudomonas* spp., *Enterobacter* spp. are the greatest threat to human health due to the emergence of strains that are resistant to all or most available antimicrobials [59, 60].

The resistance of *Enterobacteriaceae* to 3GC is mainly mediated by the production of extended-spectrum beta-lactamase enzymes (ESBLs) that breakdown 3GC [61]. *E. coli* is one of the most frequently isolated *Enterobacteriaceae* carrying ESBL genes (*bla*CTX-M*, bla*SHV*, bla*TEM, *and bla*OXA) families [62–64]. These ESBL genes are usually carried on mobile plasmids along with other resistance genes such as tetracycline, quinolones, and aminoglycosides. *E. coli* resides in the gastrointestinal tract of cattle as normal or opportunistic microflora, but some strains (for e.g., 0157:H7) cause serious infection in humans [58], indicating that cattle could serve as a reservoir of ESBLs producing *E. coli* (ESBLs *E. coli*) for human.

In the US, the occurrence of ESBLs *E. coli* in the dairy cattle was reported a decade ago from Ohio [52] and few previous studies reported the occurrence and an increase in the trend of ESBLs *E. coli* in the dairy cattle production system [52, 53, 65–67]. However, recent studies increasingly showed the rise of ESBLs *E. coli* in the cattle [51, 52, 65, 67]. Similarly, reports from the Center for Disease Control (CDC) showed a continuous increase in the number of community-associated human infections caused by ESBLs-producing *Enterobacteriaceae* [55]. This CDC report showed a 9% average annual increase in the number of hospitalized patients from ESBLs pathogens in six consecutive years (from 2012 to 2017)*.* As a result, the human health sector tends to blame dairy farms that routinely use the 3GC for the rise of ESBLs pathogens such as *E. coli* [55, 68]. However, despite the general believe of possibility of transmission of antimicrobial-resistant bacteria from dairy farms to humans directly through contact or indirectly through food chain, there was no clear evidence-based data that showed the spread of antimicrobial-resistant bacteria from the dairy production system to humans. The opinion of the scientific community on the factors that drive the emergence and spread of antimicrobial-resistant bacteria also varies [69]. Transmission of an antimicrobial-resistant pathogen to humans could occur if contaminated unpasteurized milk and/or undercooked meat from culled dairy cows due to chronic mastitis is consumed [70]. So it is crucial to pasteurize milk or cook meat properly to reduce the risk of infection by antimicrobial-resistant bacteria [71]. It is not known, if pasteurization or proper cooking prevents the transfer of resistant genes from milk or meat to commensal or opportunistic bacteria in the human gastrointestinal tract (GIT), or the GIT of calves fed pasteurized waste milk. Mechanisms of antibiotic resistance gene transfer from resistant to susceptible bacteria are not well known, and killing resistant pathogens alone may not be good enough to prevent the transfer of the resistance gene. Non-prudent use of antimicrobials in dairy farms increases selection pressure, which could result in the emergence, persistence, and horizontal transfer of antimicrobial-resistant determinants from resistant to non-resistant bacteria. Bacteria exchange resistance genes through mobile genetic elements such as plasmids, bacteriophages, pathogenicity islands, and these genes may ultimately enter bacteria pathogenic to humans or commensal or opportunistic bacterial pathogens. The prudent use of antimicrobials in dairy farms requires identification of the pathogen causing

*Animal Reproduction in Veterinary Medicine*

raw waste milk or pasteurized waste milk from antibiotic-treated cows to calves increases pressure on gut microbes such as *E. coli* to became antimicrobial-resistant [43–45]. Aust et al. [43] showed that the proportion of antimicrobial-resistant *E. coli,* especially cephalosporin-resistant *E. coli* isolates, was significantly higher in calves fed waste milk or pasteurized waste milk from antimicrobial treated cows than calves fed bulk tank milk from non-antibiotic treated cows. However, pasteurized waste milk from cows not treated with antimicrobials is acceptable to be feed to young calves [43] but it is not known if pasteurization prevents the transfer of antimicrobial-resistant genes to microbes in the calve's gut. Some studies also showed that feeding pasteurized waste milk from antimicrobial treated cows to calves increased the presence of phenotypic resistance to ampicillin, cephalothin, ceftiofur, and florfenicol in fecal *E. coli* compared with milk replacer-fed calves [45]. However, the presence of resistance to sulfonamides, tetracyclines, and aminoglycosides was common in dairy calves regardless of the source of milk, suggesting other driving factors for resistance development [45]. It has been suggested that antimicrobial residues present in waste milk have a non-specific effect at a lower taxonomical level [44]. Collectively, these non-prudent antimicrobials usage practices in dairy farms expose a large number of animals in dairy farms to antimicrobials and also increases the use of antimicrobials in dairy farms, which in turn creates intense pressure on microbes in animals' body especially commensal and opportunistic microbes in the gastrointestinal tract and farm environments. Some of these commensal bacteria in the animal body are serious human pathogens (e.g., *E. coli* 0157:H7). *Staphylococcus aureus* is one of the pathogens with a known ability to develop antimicrobial resistance and established *S. aureus* infections are persistent and difficult to clear. The failure to control these infections leads to the presence of reservoirs in the dairy herd, which ultimately leads to the spread of the

infection and the culling of the chronically infected cows [46, 47].

resistome from dairy farms to human, animal, and environment.

Monitoring antimicrobial resistance patterns of bacterial isolates from cases of mastitis is important for treatment decisions and proper design of mitigation measures. It also helps to determine emergence, persistence, and potential risk of the spread of antimicrobial-resistant bacteria and resistome to human, animal, and environment [48, 49]. The prudent use of antimicrobials in dairy farms reduce emergence, persistence, and spread of antimicrobial-resistant bacteria and

**1.2 Transmission of antimicrobial-resistant bacteria from dairy farms to human**

Most studies showed that there is no widespread, emerging resistance among mastitis pathogens [2–4] in dairy farms. However, dairy farms may serve as a source of antimicrobial-resistant human pathogenic bacteria. Extensive use of thirdgeneration cephalosporins (3GCs) in dairy cattle for the prevention and treatment of mastitis [3, 25, 28] and other diseases of dairy cattle [31, 32] can result in the carriage of extended-spectrum beta-lactamase producing *Enterobacteriaceae* (ESBL Ent) [50, 51]. Third- and fourth-generation cephalosporins are commonly used for the treatment of invasive Gram-negative bacterial infections in humans [52–54]. In 2017, there were an estimated 197,400 cases of ESBL Ent among hospitalized patients and 9100 estimated deaths in the US alone [55]. Among *Enterobacteriaceae, Escherichia coli* (*E. coli*) is the most common bacteria that reside in the gut as normal microflora or opportunist pathogen of animals and humans. However, certain pathogenic strains can cause diseases such as mastitis in cattle, neonatal calf diarrhea in calves and hemorrhagic enteritis, and more life-threatening conditions such as hemolytic uremic syndrome and urinary tract infections in humans. New strains of multi-drug resistant foodborne pathogens that produce extended-spectrum

**186**

mastitis, determining the susceptibility/resistance of the pathogen, and proper dose, duration, and frequency of treatment to ensure effective concentrations of the antibiotic to eliminate the pathogen.
