In vitro activity of rifaximin against clinical isolates of Escherichia coli and other enteropathogenic bacteria isolated from travellers returning to the UK

doi:10.1016/j.ijantimicag.2014.01.026

International Journal of Antimicrobial Agents

Volume 43, Issue 5, May 2014, Pages 431-437

https://doi.org/10.1016/j.ijantimicag.2014.01.026 Get rights and content

Abstract

Rifaximin is licensed in the EU and USA for treating travellers’ diarrhoea caused by non-invasive bacteria. Selection for resistance mechanisms of public health significance might occur if these are linked to rifamycin resistance. Rifaximin MICs were determined by agar dilution for 90 isolates each of Escherichia coli, Shigella spp., nontyphoidal Salmonella enterica, typhoidal S. enterica and Campylobacter spp., an additional 60 E. coli with CTX-M ESBLs isolated from patients with travellers’ diarrhoea, and 30 non-diarrhoeal carbapenemase-producing E. coli. Comparators were rifampicin, ciprofloxacin, azithromycin, trimethoprim/sulfamethoxazole and doxycycline. Isolates with rifaximin MICs>32 mg/L were screened for arr genes, and critical rpoB regions were sequenced. Rifaximin was active at ≤32 mg/L against 436/450 (96.9%) diverse Enterobacteriaceae, whereas 81/90 (90%) Campylobacter spp. were resistant to rifaximin at ≥128 mg/L. Rifaximin MICs were ≥128 mg/L for two Shigella and five MDR E. coli producing NDM (n = 3), OXA-48 (n = 1) or CTX-M-15 (n = 1). Two of the five MDR E. coli had plasmids harbouring arr-2 together with bla_NDM, and two (one each with bla_NDM and bla_CTX-M-15) had His526Asn substitutions in RpoB. The rifamycin resistance mechanism remained undefined in one MDR E. coli isolate (with bla_OXA-48) and the two Shigella isolates. Rifaximin showed good in vitro activity against diverse Enterobacteriaceae but was largely inactive against Campylobacter spp. Rifaximin has potential to co-select MDR E. coli in the gut flora, but much stronger associations were seen between ESBL and/or carbapenemase production and resistance to alternative treatments for travellers’ diarrhoea, notably ciprofloxacin and azithromycin.

Introduction

Diarrhoea is the most common illness reported in international travellers, with bacterial pathogens (including enteropathogenic Escherichia coli, Salmonella enterica, Campylobacter spp. and Shigella spp.) responsible for most cases. Although travellers’ diarrhoea is usually self-limiting, ciprofloxacin or azithromycin may be used to reduce the duration and severity. In contrast to these two agents, rifaximin, a semisynthetic rifamycin licensed for the treatment of travellers’ diarrhoea caused by non-invasive bacterial pathogens in the EU and USA, has minimal absorption from the gut (<1% of oral dose) and offers an alternative with fewer systemic effects [1]. Nevertheless, travel is also a risk factor for colonisation or infection by strains of E. coli with extended-spectrum β-lactamases (ESBLs) and carbapenemases [1]. If these organisms are rifaximin-resistant there is a theoretical potential for rifaximin to select for them in the gut flora.

Rifamycins inhibit RNA synthesis by binding to the β-subunit of DNA-dependent mRNA polymerase. Resistance can entail target modification arising from mutations within four highly conserved regions of rpoB, the chromosomal gene that encodes the β-subunit of the mRNA polymerase [2], [3]. Alternatively, resistance can arise via acquisition of plasmid-mediated arr genes, which encode ADP-ribosyltransferases that inactivate rifamycins [4]. As a third mechanism, reduced cellular accumulation owing to efflux can also underlie rifamycin resistance [3].

Studies to date on the rifaximin susceptibility of enteropathogens from travellers’ diarrhoea have focused on US travellers whose travel patterns tend to differ from their UK counterparts, with more travel to Latin America and less to South Asia. Little is known about the rifaximin susceptibility of enteropathogens from UK travellers, and rifamycins are not routinely tested against these organisms.

Against this background, the in vitro activity of rifaximin and comparator agents was assessed against 450 enteropathogens isolated from travellers returning to the UK as well as against 90 clinical multidrug-resistant (MDR) isolates of E. coli that produced ESBLs and/or carbapenemases. Acquired resistance mechanisms were sought in isolates with high rifaximin and/or rifampicin minimum inhibitory concentrations (MICs).

Section snippets

Bacterial isolates

In total, 450 test isolates were selected arbitrarily based on patient history of foreign travel among reference submissions sent between 2004 and 2011 to Public Health England's (PHE) Gastrointestinal Bacteria Reference Unit (London, UK). These comprised 90 isolates each of E. coli, Shigella spp., nontyphoidal S. enterica, typhoidal S. enterica and Campylobacter spp. (23 Campylobacter coli and 67 Campylobacter jejuni). The most frequent travel destination reported was South Asia (200

Susceptibility to rifamycins

The MIC of both rifamycins for E. coli ATCC 25922 was 16 mg/L. Amongst the panel of Enterobacteriaceae isolated from travellers returning to the UK with diarrhoea, the rifaximin MICs were unimodal, with peaks at between 4 mg/L and 32 mg/L according to the species group (highest for typhoidal salmonellae and lowest for non-typhoidal salmonellae; Table 2); MIC distributions of rifampicin for these groups similarly clustered from 8 to 32 mg/L. Similarly, the MIC distributions of both rifaximin and

Discussion

Diarrhoea is the most common illness reported in international travellers, particularly those to low-income countries. High levels of resistance are seen to the antibiotics traditionally used to treat travellers’ diarrhoea, principally doxycycline and co-trimoxazole, with increasing resistance to the current first-line agents (azithromycin and ciprofloxacin) among enteropathogens isolated from travellers returning to Spain and the USA [11], [12].

Studies to date indicate that rifaximin has good

Funding

This work was supported by Norgine Pharmaceuticals Ltd.

Competing interests

KLH and SM have received conference support from Norgine Pharmaceuticals Ltd.; KLH, DML and NW have received speakers’ or advisory board honoraria from Norgine Pharmaceuticals; DML consults for numerous pharmaceutical and diagnostic companies, including Meiji Seika, Achaogen, Astellas, AstraZeneca, Bayer, Basilea, bioMérieux, Cubist, Discuva, GSK, Kalidex, Merck, Pfizer, Roche and Tetraphase, holds grants from Basilea, Cubist, Meiji Seika and Merck, has received lecture honoraria or travel

Ethical approval

Not required.

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Cited by (27)

Antibiotic susceptibility among non-clinical Escherichia coli as a marker of antibiotic pressure in Peru (2009–2019): one health approach
2022, Heliyon
Citation Excerpt :
The high number of isolates exhibiting intermediate resistance levels to a series of unrelated antibiotics might be related to the presence of subinhibitory antibiotic concentrations favoring the selection of non-specific low-level resistance mechanisms, such as overexpression of efflux pumps or other adaptative responses, or to external factors, such as the presence of environmental contaminants (e.g: heavy metals, chemicals, solvents), which might favor similar scenarios [107, 108, 109]. In this sense, a study analyzing the mechanisms of rifaximin resistance in 74 commensal and 136 diarrheogenic isolates from a periurban area of Lima showed an unusual scenario, with 100% of the isolates having a minimal inhibitory concentration (MIC) ≥32 mg/L [75], when studies on E. coli with a very diverse geographical origin only showed the presence of a few E. coli isolates presenting a maximum MIC of ≥32 mg/L [40, 110, 111, 112]. This atypical resistance pattern was related to the presence of overexpressed efflux pumps in 95.2% of the isolates, with only 9 out of 200 (4.5%) isolates having MICs ≥32 mg/L after the use of an efflux pump inhibitor [75].
Antimicrobial resistance is an increasing health problem worldwide with serious implications in global health. The overuse and misuse of antimicrobials has resulted in the spread of antimicrobial-resistant microorganisms in humans, animals and the environment. Surveillance of antimicrobial resistance provides important information contributing to understanding dissemination within these environments. These data are often unavailable in low- and middle-income countries, such as Peru. This review aimed to determine the levels of antimicrobial resistance in non-clinical Escherichia coli beyond the clinical setting in Peru.
We searched 2009–2019 literature in PUBMED, Google Scholar and local repositories.
Thirty manuscripts including human, food, environmental, livestock, pets and/or wild animals’ samples were found. The analysis showed high resistance levels to a variety of antimicrobial agents, with >90% of resistance for streptomycin and non-extended-spectrum cephalosporin in livestock and food. High levels of rifamycin resistance were also found in non-clinical samples from humans. In pets, resistance levels of 70–>90% were detected for quinolones tetracycline and non-extended spectrum cephalosporins. The results suggest higher levels of antimicrobial resistance in captive than in free-ranging wild-animals. Finally, among environmental samples, 50–70% of resistance to non-extended-spectrum cephalosporin and streptomycin was found.
High levels of resistance, especially related to old antibacterial agents, such as streptomycin, 1st and 2nd generation cephalosporins, tetracyclines or first-generation quinolones were detected. Antimicrobial use and control measures are needed with a One Health approach to identify the main drivers of antimicrobial resistance due to interconnected human, animal and environmental habitats.
Doxycycline as an antimalarial: Impact on travellers’ diarrhoea and doxycycline resistance among various stool bacteria – Prospective study and literature review
2022, Travel Medicine and Infectious Disease
Citation Excerpt :
EUCAST has not established the breakpoint MICs for doxycycline. We selected >4, since it is used by CLSI [16] and several other studies [29,36,48,69]. Had we applied ≥16 as a breakpoint MIC value, the co-resistance rate would have been 83.3% (75/90), yielding the co-resistance rates of 90.9% for doxycycline users (10/11) and 82.3% for non-users (65/70).
Antibiotics predispose travellers to acquire multidrug-resistant bacteria, such as extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE). Although widely used in antimalarial prophylaxis, doxycycline has scarcely been studied in this respect.
We explored the impact of doxycycline on rates of traveller's diarrhoea (TD), ESBL-PE acquisition and, particularly, doxycycline co-resistance among travel-acquired ESBL-PE in a sample of 412 visitors to low- and middle-income countries.
We reviewed the literature on traveller studies of doxycycline/tetracycline resistance among stool pathogens and the impact of doxycycline on TD rates, ESBL-PE acquisition, and doxycycline/tetracycline resistance.
The TD rates were similar for doxycycline users (32/46; 69.6%) and non-users (256/366; 69.9%). Of the 90 travel-acquired ESBL-PE isolates, 84.4% were co-resistant to doxycycline: 100% (11/11) among users and 82.3% (65/79) among non-users.
The literature on doxycycline's effect on TD was not conclusive nor did it support a recent decline in doxycycline resistance. Although doxycycline did not increase ESBL-PE acquisition, doxycycline-resistance among stool pathogens proved more frequent for users than non-users.
Our prospective data and the literature review together suggest the following: 1) doxycycline does not prevent TD; 2) doxycycline use favours acquisition of doxy/tetracycline-co-resistant intestinal bacteria; 3) although doxycycline does not predispose to travel-related ESBL-PE acquisition per se, it selects ESBL-PE strains co-resistant to doxycycline; 4) doxycycline resistance rates are high among stool bacteria in general with no evidence of any tendency to decrease.
Bacterial travellers’ diarrhoea: A narrative review of literature published over the past 10 years
2022, Travel Medicine and Infectious Disease
Citation Excerpt :
In the case of EAEC and ETEC, rates of resistance to rifaximin appear to be lower than those observed for other antibiotics and there is no indication that rifaximin minimum inhibitory concentrations (MICs) increase among recovered isolates [7,108], although data on resistance rates are limited [7]. Furthermore, rifaximin should not be used to treat Campylobacter-associated TD due to its high level of resistance and evidence of clinical failure [116,122,159] and is unsuitable for the treatment of invasive disease [7]. Since the aetiology of TD remains undetermined in 40–50% of cases [160], physicians should exercise caution when prescribing rifaximin in regions where Campylobacter or invasive pathogens are prevalent.
Travellers’ diarrhoea (TD) is the most frequent illness experienced by international travellers to lower-income countries with bacterial agents considered to account for 80–90% of cases. In this review, we summarise evidence published on bacterial TD over the past 10 years, focusing on the epidemiology and aetiology of TD. Diarrhoeagenic Escherichia coli (DEC) continue to be the most commonly implicated bacteria in TD, although Enteropathogenic E. coli (EPEC) and Enteroaggregative E. coli (EAEC) now appear to be predominant where Enterotoxigenic E. coli (ETEC) was previously considered most prevalent globally. Where fluroquinolone resistance had primarily been documented for Campylobacter in Southeast Asia, widespread resistance has been observed in most regions of the world for multiple enteropathogens, including Shigella, Salmonella, ETEC and EAEC. Implementation of novel molecular methods for pathogen detection has led to identification of bacterial pathogens, including Clostridium difficile (with and without the use of prior antibiotics), Arcobacter species and Bacteroides fragilis, as aetiological agents in TD. The widespread resistance to first-line antibiotics in multiple bacterial enteropathogens warrants continued surveillance and re-evaluation of current treatment practices. Further investigations are required to determine the prevalence and geographical distribution of bacterial enteropathogens that have been more recently implicated in TD.
Susceptibility to rifaximin and other antimicrobials of bacteria isolated in patients with acute gastrointestinal infections in Southeast Mexico
2017, Revista de Gastroenterologia de Mexico
Bacterias enteropatógenas aisladas en la Ciudad de México han mostrado una alta tasa de resistencia a diversos antibióticos, con excepción de la rifaximina (RIF). La RIF es un antibiótico no absorbible que alcanza altas concentraciones fecales (≈ 8,000 μg/g). La susceptibilidad a los antimicrobianos puede variar en distintas regiones geográficas.
Investigar la susceptibilidad a rifaximina y otros antimicrobianos de bacterias enteropatógenas aisladas de pacientes con diarrea aguda en el sureste de México.
Se analizaron 614 cepas de bacterias aisladas de pacientes con diarrea aguda de 4 ciudades del sureste del México. Se realizó antibiograma con: ampicilina (AMP), trimetoprim/sulfametoxazol (T-S), neomicina (NEO), furazolidona (FUR), ciprofloxacino (CIP), cloranfenicol (CLO) y fosfomicina (FOS) por difusión en agar a las concentraciones estándar recomendadas por CLSI y ASM y RIF en 4 concentraciones por microdilución.
La mayoría de las bacterias fueron Escherichia coli (55%) en todas sus variantes patógenas, Shigella (16.8%), Salmonella (15.3%), Aeromonas (7.8%) y menos de 5% Campylobacter, Yersinia, Vibrio y Plesiomonas. La susceptibilidad global acumulada a RIF fue del 69.1, el 90.8, el 98.9 y el 100% a las concentraciones de 100, 200, 400 y 800 μg/ml, respectivamente. La susceptibilidad global a los otros antibióticos fue: FOS 82.8%, CLO 76.8%, CIP 73.9%, FUR 64%, T-S 58.7%, NEO 55.8% y AMP 23.8%. La susceptibilidad a RIF 400 y 800 μg fue significativamente mayor que con los otros antimicrobianos (p < 0.001).
Se encontraron datos similares a los de un estudio previo realizado en la Ciudad de México: susceptibilidad a RIF en > 98% de las cepas bacterianas y alta frecuencia de resistencia a varios antimicrobianos comunes.
Enteropathogenic bacteria isolated in Mexico City have shown a high rate of resistance to different antibiotics, with the exception of rifaximin (RIF). RIF is a nonabsorbable antibiotic that reaches high fecal concentrations (≈ 8,000 μg/g). Susceptibility to antimicrobials can vary in different geographic regions.
To study the susceptibility to rifaximin and other antimicrobials of enteropathogenic bacteria isolated in patients with acute diarrhea in the southeastern region of Mexico.
A total of 614 strains of bacteria isolated from patients with acute diarrhea from 4 cities in Southeast Mexico were analyzed. An antibiogram with the following antibiotics was created: ampicillin (AMP), trimethoprim/sulfamethoxazole (T-S), neomycin (NEO), furazolidone (FUR), ciprofloxacin (CIP), chloramphenicol (CHL), and fosfomycin (FOS), assessed through the agar diffusion method at the standard concentrations recommended by the Clinical and Laboratory Standards Institute (CLSI) and the American Society for Microbiology (ASM), and RIF, assessed through microdilution at 4 concentrations.
The bacteria were Escherichia coli (55%), as the majority, in all its pathogenic variants, Shigella (16.8%), Salmonella (15.3%), Aeromonas (7.8%), and less than 5% Campylobacter, Yersinia, Vibrio, and Plesiomonas. The accumulated overall susceptibility to RIF was 69.1, 90.8, 98.9, and 100% at concentrations of 100, 200, 400, and 800 μg/ml, respectively. Overall susceptibility to other antibiotics was FOS 82.8%, CHL 76.8%, CIP 73.9%, FUR 64%, T-S 58.7%, NEO 55.8%, and AMP 23.8%. Susceptibility to RIF at 400 and 800 μg was significantly greater than with the other antimicrobials (P<.001).
The data of the present study were similar to those of a previous study carried out in Mexico City: susceptibility to RIF in > 98% of the bacterial strains and a high frequency of resistance to several common antimicrobials.
Natural plant products inhibits growth and alters the swarming motility, biofilm formation, and expression of virulence genes in enteroaggregative and enterohemorrhagic Escherichia coli
2016, Food Microbiology
Citation Excerpt :
The results of this study showed that citral also showed antimicrobial activity against pathogenic E. coli strains. The potent activity of rifaximin against all E. coli strains was reported by Hopkins et al. (2014), and confirmed in this study. Almost all of the treatments reduced swarming motility of the E. coli strains; however, and contrary to our expectations, carvacrol promoted swarming in EHEC O157:H7 and EAEC 042, but not in EAEC 0104:H4.
The purpose of this study was to determine the effects of plant products on the growth, swarming motility, biofilm formation and virulence gene expression in enterohemorrhagic Escherichia coli O157:H7 and enteroaggregative E. coli strain 042 and a strain of O104:H4 serotype.
Extracts of Lippia graveolens and Haematoxylon brassiletto, and carvacrol, brazilin were tested by an antimicrobial microdilution method using citral and rifaximin as controls. All products showed bactericidal activity with minimal bactericidal concentrations ranging from 0.08 to 8.1 mg/ml. Swarming motility was determined in soft LB agar. Most compounds reduced swarming motility by 7%–100%; except carvacrol which promoted motility in two strains. Biofilm formation studies were done in microtiter plates. Rifaximin inhibited growth and reduced biofilm formation, but various concentrations of other compounds actually induced biofilm formation. Real time PCR showed that most compounds decreased stx2 expression. The expression of pic and rpoS in E. coli 042 were suppressed but in E. coli O104:H4 they varied depending on compounds.
In conclusion, these extracts affect E. coli growth, swarming motility and virulence gene expression. Although these compounds were bactericidal for pathogenic E. coli, sublethal concentrations had varied effects on phenotypic and genotypic traits, and some increased virulence gene expression.
Systematic review of loperamide: No proof of antibiotics being superior to loperamide in treatment of mild/moderate travellers' diarrhoea
2016, Travel Medicine and Infectious Disease
Looking at the worldwide emergency of antimicrobial resistance, international travellers appear to have a central role in spreading the bacteria across the globe. Travellers' diarrhoea (TD) is the most common disease encountered by visitors to the (sub)tropics. Both TD and its treatment with antibiotics have proved significant independent risk factors of colonization by resistant intestinal bacteria while travelling. Travellers should therefore be given preventive advice regarding TD and cautioned about taking antibiotics: mild or moderate TD does not require antibiotics. Logical alternatives are medications with effects on gastrointestinal function, such as loperamide. The present review explores literature on loperamide in treating TD. Adhering to manufacturer's dosage recommendations, loperamide offers a safe and effective alternative for relieving mild and moderate symptoms. Moreover, loperamide taken singly does no predispose to contracting MDR bacteria. Most importantly, we found no proof that would show antibiotics to be significantly more effective than loperamide in treating mild/moderate TD.

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^☆: These data were first presented at the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 31 March–2 April 2012, London, UK [abstracts P1829 and P1293].

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International Journal of Antimicrobial Agents

Abstract

Introduction

Section snippets

Bacterial isolates

Susceptibility to rifamycins

Discussion

Funding

Competing interests

Ethical approval

References (23)

Resistance to rifampicin: at the crossroads between ecological, genomic and medical concerns

Int J Antimicrob Agents

Therapy of travelers’ diarrhea with rifaximin on various continents

Am J Gastroenterol

The role of international travel in the worldwide spread of multiresistant Enterobacteriaceae

J Antimicrob Chemother

Fitness and molecular mechanisms of resistance to rifaximin in in vitro selected Escherichia coli mutants

Microb Drug Resist

Rifamycin antibiotic resistance by ADP-ribosylation: structure and diversity of Arr

Proc Natl Acad Sci USA

Variation in the genetic environments of bla_CTX-M-15 in Escherichia coli from the faeces of travellers returning to the United Kingdom

J Antimicrob Chemother

Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. Document M07-A9

Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement. Document M100-S23

Phylogenetic diversity of Escherichia coli strains producing NDM-type carbapenemases

J Antimicrob Chemother

for rapid detection of genes encoding CTX-M extended-spectrum β-lactamases

J Antimicrob Chemother

Detection of plasmid-mediated AmpC β-lactamase genes in clinical isolates by using multiplex PCR

J Clin Microbiol

Cited by (27)

Antibiotic susceptibility among non-clinical Escherichia coli as a marker of antibiotic pressure in Peru (2009–2019): one health approach

Doxycycline as an antimalarial: Impact on travellers’ diarrhoea and doxycycline resistance among various stool bacteria – Prospective study and literature review

Bacterial travellers’ diarrhoea: A narrative review of literature published over the past 10 years

Susceptibility to rifaximin and other antimicrobials of bacteria isolated in patients with acute gastrointestinal infections in Southeast Mexico

Natural plant products inhibits growth and alters the swarming motility, biofilm formation, and expression of virulence genes in enteroaggregative and enterohemorrhagic Escherichia coli

Systematic review of loperamide: No proof of antibiotics being superior to loperamide in treatment of mild/moderate travellers' diarrhoea

In vitro activity of rifaximin against clinical isolates of Escherichia coli and other enteropathogenic bacteria isolated from travellers returning to the UK☆

Abstract

Introduction

Section snippets

Bacterial isolates

Susceptibility to rifamycins

Discussion

Funding

Competing interests

Ethical approval

Int J Antimicrob Agents

Am J Gastroenterol

The role of international travel in the worldwide spread of multiresistant Enterobacteriaceae

J Antimicrob Chemother

Fitness and molecular mechanisms of resistance to rifaximin in in vitro selected Escherichia coli mutants

Microb Drug Resist

Rifamycin antibiotic resistance by ADP-ribosylation: structure and diversity of Arr

Proc Natl Acad Sci USA

Variation in the genetic environments of blaCTX-M-15 in Escherichia coli from the faeces of travellers returning to the United Kingdom

J Antimicrob Chemother

Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. Document M07-A9

Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement. Document M100-S23

Phylogenetic diversity of Escherichia coli strains producing NDM-type carbapenemases

J Antimicrob Chemother

for rapid detection of genes encoding CTX-M extended-spectrum β-lactamases

J Antimicrob Chemother

Detection of plasmid-mediated AmpC β-lactamase genes in clinical isolates by using multiplex PCR

J Clin Microbiol

Variation in the genetic environments of bla_CTX-M-15 in Escherichia coli from the faeces of travellers returning to the United Kingdom