Antibiotic Resistance in Campylobacter: Mechanisms, Resistance Emergence, Therapy, and Future Perspective

Abstract

The global public health challenge posed by antibiotic-resistant Campylobacter strains is increasingly pressing. Originally treatable with antibiotics, these infections now face a clinical management dilemma due to resistance mechanisms such as antibiotic-inactivating enzymes, target alterations, and drug extrusion. This resistance emerges from a polyclonal pathogen population, co-infections, and antibiotic misuse in food animals. The agriculture industry’s excessive antibiotic use for growth promotion and infection prevention contributes to the spread of resistant bacteria. Particularly concerning are resistant Campylobacter strains, mainly C. jejuni and C. coli, linked to human pandemics via livestock-associated resistant bacteria, including tetracycline-resistant strains common in poultry. Agricultural antibiotic overuse significantly drives antimicrobial resistance in these species. Horizontal gene transfer further exacerbates this issue by creating “superbugs” resistant to multiple antibiotics. It is crucial to investigate how farming practices and biosecurity impact Campylobacter antimicrobial resistance, affecting both animal and human health. This chapter focuses on the primary mechanisms of Campylobacter antibiotic resistance and their transfer and persistence across species.

1. Introduction

Campylobacter is a bacterial genus that includes several Gram-negative species. One of the most common species that cause human illnesses in developed countries is Campylobacter jejuni, which can lead to gastroenteritis. The global prevalence of campylobacteriosis has increased over the years, and one of the contributing factors is their ability to develop antibiotic resistance [1].

The history of Campylobacter antibiotic resistance dates to the 1980s when researchers noticed decreasing susceptibilities of Campylobacter strains toward tetracyclines, macrolides, and fluoroquinolones. Since then, multiple studies have reported a rise in the prevalence of antimicrobial-resistant Campylobacter jejuni strains worldwide. The development and spread of antibiotic-resistant Campylobacter species are mainly linked with their extensive usage in veterinary medicine for growth promotion and disease prevention purposes [2].

The acquisition of antibiotic resistance mechanisms among bacteria occurs through horizontal gene transfer events such as conjugation or transduction. Additionally, spontaneous mutations can lead to genetic changes that confer drug resistance. A major concern regarding multidrug-resistant (MDR) Campylobacter infections is the limited treatment options available due to an increasing rate of resistance caused by efflux pumps and alterations in DNA gyrase enzymes [3].

Macrolides are one class of antibiotics commonly used for treating campylobacteriosis primarily because they penetrate well into the intestinal epithelium where most infections occur. However, common macrolide antibiotics including erythromycin and azithromycin are no longer effective against MDR-Campylobacter jejuni isolates that exhibit higher minimum inhibitory concentrations (MICs). This has led to increased use of fluoroquinolones, which are broad-spectrum antibiotics with high bioavailability and good tissue penetration capabilities. However, the emergence of fluoroquinolone-resistant Campylobacter species has been reported worldwide, with a significant negative impact on appropriate treatment options for MDR-Campylobacter infections [4].

The emergence of antibiotic resistance in Campylobacter is a concerning issue as it can have detrimental effects on public health. Antibiotic resistance can lead to treatment failure, prolonged illness, and an increased risk of complications. Moreover, it can also lead to the spread of resistant strains within communities and even between countries. Resistance to antibiotics in Campylobacter is mainly attributed to the misuse and overuse of antibiotics in both human healthcare and animal agriculture. Several classes of antibiotics have been used to treat Campylobacter infections, including macrolides (erythromycin), fluoroquinolones (ciprofloxacin), and tetracyclines (tetracycline). The misuse of these antibiotics has led to the selection pressure for resistant strains, with some studies reporting resistance rates as high as 90% [5].

In conclusion, the rapid emergence and spread of antibiotic-resistant Campylobacter strains are a major public health concern globally.

The limited treatment options available due to the increasing rate of resistance caused by efflux pumps and alterations in DNA gyrase enzymes pose a significant challenge for managing infections caused by multi-drug resistant bacteria, emphasizing the need for novel therapeutic strategies and stringent antibiotic stewardship programs to combat these evolving threats.

2. Campylobacter treatment history

Campylobacter is a bacterial pathogen that can cause gastroenteritis, an acute illness characterized by diarrhea, abdominal pain, fever, and sometimes vomiting. Campylobacter infection is typically self-limiting, which means it will resolve on its own within a few days without specific treatment [6]. However, in severe cases or for individuals with weakened immune systems, antibiotic treatment may be necessary. Traditionally, fluoroquinolones have been widely used for empirical treatment of Campylobacter infection, while third-generation cephalosporins and macrolides have been alternative treatment options [7]. The treatment history for Campylobacter infections dates back to the early twentieth century, when antibiotics were first introduced. Initially, antibiotics such as tetracycline and erythromycin were effective in treating Campylobacter infections. However, over time, Campylobacter developed resistance to these antibiotics, leading to the need for new treatment strategies.

However, the emergence of antibiotic-resistant Campylobacter strains has become a global burden and threatens the effectiveness of these treatments. In recent years, the proportion of antibiotic-resistant Campylobacter strains has been on the rise, with some countries reporting extremely high levels of resistance [8] to commonly used antibiotics such as tetracyclines, quinolones, and macrolides.

This has led to increased difficulties in finding effective treatment options for Campylobacter infection, particularly in severe cases. The overuse and misuse of antibiotics in both human medicine and food animal production have contributed to the emergence and spread of antibiotic-resistant Campylobacter strains [8].

3. Antibiotic resistance mechanisms continuously emerge in campylobacter spp

One of the major challenges in the treatment and control of Campylobacter infections is antibiotic resistance. The emergence of new antibiotic resistance mechanisms in Campylobacter poses a significant threat to public health [9]. Several studies have reported that the use of antibiotics in animal husbandry and agriculture contributes to the development and spread of antibiotic resistance in Campylobacter. Additionally, the presence of antibiotic-resistant Campylobacter strains in poultry products is a significant concern as chicken meat is one of the main sources of human Campylobacter infections. Using sequencing tools, it has been identified that Campylobacter genomes have various resistance genes, including multidrug-resistant efflux complex CmeABC [10] and its regulatory gene cmeR, the MacAB efflux locus, tetO locus, and a large number of other antibiotic resistance genes. Furthermore, research indicates that new antibiotic resistance mechanisms continue to emerge in Campylobacter [11]. These mechanisms include mutations in existing genes and the acquisition of resistance genes through horizontal gene transfer.

3.1 Antibiotic resistance mechanisms of campylobacter spp. to fluoroquinolone

Point mutations in the DNA gyrase A (GyrA) region that determines quinolone resistance (QR) are the primary mechanism by which Campylobacter develops resistance to fluoroquinolone. Campylobacter fluoroquinolone resistance (CFR) has not been linked to DNA gyrase B mutations [12]. In Gram-negative bacteria, the topoisomerase IV (parC/parE) genes are similarly involved in (CFR); however, Campylobacter lacks these genes. The lack of evidence linking parC/parE mutations to Campylobacter resistance to fluoroquinolone antimicrobials [13] is not surprising as a result. A single point mutation in the quinolone resistance (QR) of gyrA is sufficient to significantly reduce Campylobacter’s susceptibility to fluoroquinolone antimicrobials, in contrast to fluoroquinolone resistance in other enteric organisms (such as Salmonella and Escherichia coli), in which acquisition of high-level fluoroquinolone resistance requires stepwise accumulation of point mutations in gyrA and parC [14]. The C257T alteration in the gyrA gene, which results in the T86I substitution in the gyrase and provides high-level resistance to fluoroquinolone, is the mutation that is most frequently seen in Campylobacter isolates that are fluoroquinolone resistant [14]. T86K, A70T, and D90N are other variants that have been linked to resistance but are less frequent and do not impart as much fluoroquinolone resistance as the T86I mutation [12, 13, 14]. The multidrug efflux pump, CmeABC, Figure 1 also contributes to fluoroquinolone resistance in addition to GyrA mutations by lowering the concentration of the drugs in Campylobacter cells [14, 16]. As a result, the gyrA mutations and CmeABC cooperate to mediate FQ resistance. Campylobacter has no known plasmid-mediated quinolone-resistance determinants like qnr, all of the known FQ resistance determinants in Campylobacter are chromosomally encoded.

Figure 1.

CmeABC expression by DNA gyrase [15].

3.2 Antibiotic resistance mechanisms of campylobacter spp. to macrolides

Macrolides are often the first choice for antibiotic treatment but high levels of macrolide resistance in Campylobacter spp., have been reported, which limits their efficacy [17].

The most common mechanism of macrolide resistance among Campylobacter spp. involves mutations within the 23S rRNA gene that impede drug binding to the ribosome. Other mechanisms include efflux pumps that actively remove the drug from bacterial cells and enzymatic modification of the drug by erythromycin esterase enzymes.

Resistance between Campylobacter differs reports found that Campylobacter coli strains have been found to be more resistant than Campylobacter jejuni strains to macrolide antimicrobials such as azithromycin, erythromycin, and clindamycin.

Studies indicate the mphA gene present on mobile genetic elements and encoding a phosphotransferase that inactivates macrolides, has been found to be commonly associated with macrolide resistance among Campylobacter spp. [18]. Furthermore, its expression may be induced by tyrosine use in swine [19]. Studies have indicated a high prevalence of macrolide-resistant Campylobacter spp., which is of concern given the widespread use of macrolides in veterinary medicine. The emergence and spread of antibiotic resistance are often linked to inappropriate or excessive antibiotic usage both in humans and animals. Furthermore, studies have suggested that factors such as veterinary use of fluoroquinolones and macrolides influence the number of resistant isolates found in humans. In addition, it has been observed that prior to animal usage, there was little to no emergence of quinolone resistance. Multiplex PCR testing could provide more opportunities for accurate diagnosis and therefore targeted antimicrobial therapy. Therefore, increased surveillance efforts are needed to better understand the mechanisms involved in these emerging resistances so appropriate measures can be taken before ineffective treatment leads to further downstream effects such as prolonged illness or severe complications like Guillain-Barré syndrome. It is vital for public health workers to outweigh risks versus benefits when making decisions related.

4. ESBL production in campylobacter spp.

One concerning development is the emergence of extended-spectrum beta-lactamase production in Campylobacter spp., which confers antibiotic resistance to these pathogens. Sources of ESBL Production: ESBL-producing strains of Enterobacteriaceae, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, have been primarily associated with hospital-acquired infections due to their resistance to many clinically relevant antibiotics. However, recent studies indicate that ESBL production is also occurring in other bacterial genera including Campylobacter spp. One potential source of ESBL genes is waste from hospitals, pharmaceutical companies, and livestock producers that contain antimicrobial substances that have been circulating in our environment for several years or more. These substances exert selective pressure on the microbiome present within this waste by promoting survival and propagation over time among those bacteria possessing genetic mechanisms enabling them to acquire resistance through horizontal gene transfer. Transmission Dynamics: Although it has yet to be determined whether transmissible forms of ESBL genes exist solely within environmental reservoir.

A report [20] indicates the prevalence of ESBL in Campylobacter isolated from poultry and swine samples in the United States. The results showed that 34% of Campylobacter isolates from poultry and 12% of Campylobacter isolates from swine were positive for ESBL production. The study also found a high rate of resistance to other antibiotics in ESBL-positive Campylobacter isolates, indicating that the emergence of ESBL in Campylobacter is associated with multidrug resistance. The presence of ESBL in Campylobacter poses a significant threat to human health as it limits the effectiveness of antibiotics in treating infections caused by this pathogen. Therefore, it is crucial to monitor the prevalence of ESBL in Campylobacter and to develop strategies to control its spread in both animal and human populations.

5. Future combat of campylobacter antibiotic resistance

To combat Campylobacter antibiotic resistance, several necessary actions can be taken. Firstly, it is crucial to implement stricter regulations and guidelines on the use of antibiotics in agriculture.

This includes controlling the use of antibiotics such as fluoroquinolones in animal feed and water. In addition, alternative methods such as probiotics and vaccination may be explored to reduce the use of antibiotics in animal production. Secondly, appropriate antibiotic stewardship in human medicine should be encouraged to minimize unnecessary antibiotic use and reduce the risk of developing resistant strains. Thirdly, a robust surveillance system to monitor both the incidence and prevalence of antibiotic-resistant Campylobacter should be established. This can help to inform appropriate treatment strategies and identify emerging resistance patterns. Lastly, there should be an increased focus on research and development to develop new antibiotics or alternative therapies for Campylobacter infection.

These actions can be taken by collaborations between governments, public health authorities, the agricultural industry, and healthcare professionals. Overall, implementing a comprehensive and multi-pronged approach to combat Campylobacter antibiotic resistance is essential. In addition, public education and awareness campaigns can also play a vital role in reducing the overuse of antibiotics by promoting responsible use and highlighting the risks associated with antibiotic resistance. Furthermore, the use of phages to control Campylobacter in poultry and other animals could be a promising alternative to antibiotics. TYPLEX ® Chelate, a synthetic complex of L-tyrosine and Fe has been shown to have a unique action on Campylobacter, suggesting the potential for alternative strategies in controlling this pathogen.

6. Conclusion

Campylobacter antibiotic resistance is a significant public health threat that requires urgent action. The implementation of stricter regulations on the use of antibiotics in agriculture, appropriate antibiotic stewardship in human medicine, the establishment of a robust surveillance system, and increased research and development efforts for new antibiotics or alternative therapies are all essential components of a comprehensive strategy to combat this issue. Moreover, public education and awareness campaigns should be conducted to promote responsible antibiotic use, while exploring alternative methods like probiotics or phages as options for controlling Campylobacter. Campylobacter is a highly prevalent bacteria that causes gastrointestinal infections and is associated with Guillain-Barré syndrome.