Modelling dynamics of plasmid-gene mediated antimicrobial resistance in enteric bacteria using stochastic differential equations. - Related Documents




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410601.0000Modelling dynamics of plasmid-gene mediated antimicrobial resistance in enteric bacteria using stochastic differential equations. The ubiquitous commensal bacteria harbour genes of antimicrobial resistance (AMR), often on conjugative plasmids. Antimicrobial use in food animals subjects their enteric commensals to antimicrobial pressure. A fraction of enteric Escherichia coli in cattle exhibit plasmid-gene mediated AMR to a third-generation cephalosporin ceftiofur. We adapted stochastic differential equations with diffusion approximation (a compartmental stochastic mathematical model) to research the sources and roles of stochasticity in the resistance dynamics, both during parenteral antimicrobial therapy and in its absence. The results demonstrated that demographic stochasticity among enteric E. coli in the occurrence of relevant events was important for the AMR dynamics only when bacterial numbers were depressed during therapy. However, stochasticity in the parameters of enteric E. coli ecology, whether externally or intrinsically driven, contributed to a wider distribution of the resistant E. coli fraction, both during therapy and in its absence, with stochasticities in individual parameters interacting in their contribution.201323982723
962910.9997Costs of antibiotic resistance genes depend on host strain and environment and can influence community composition. Antibiotic resistance genes (ARGs) benefit host bacteria in environments containing corresponding antibiotics, but it is less clear how they are maintained in environments where antibiotic selection is weak or sporadic. In particular, few studies have measured if the direct effect of ARGs on host fitness is fixed or if it depends on the host strain, perhaps marking some ARG-host combinations as selective refuges that can maintain ARGs in the absence of antibiotic selection. We quantified the fitness effects of six ARGs in 11 diverse Escherichia spp. strains. Three ARGs (bla(TEM-116), cat and dfrA5, encoding resistance to β-lactams, chloramphenicol, and trimethoprim, respectively) imposed an overall cost, but all ARGs had an effect in at least one host strain, reflecting a significant strain interaction effect. A simulation predicts these interactions can cause the success of ARGs to depend on available host strains, and, to a lesser extent, can cause host strain success to depend on the ARGs present in a community. These results indicate the importance of considering ARG effects across different host strains, and especially the potential of refuge strains to allow resistance to persist in the absence of direct selection, in efforts to understand resistance dynamics.202438889784
965220.9997Transfer and Persistence of a Multi-Drug Resistance Plasmid in situ of the Infant Gut Microbiota in the Absence of Antibiotic Treatment. The microbial ecosystem residing in the human gut is believed to play an important role in horizontal exchange of virulence and antibiotic resistance genes that threatens human health. While the diversity of gut-microorganisms and their genetic content has been studied extensively, high-resolution insight into the plasticity, and selective forces shaping individual genomes is scarce. In a longitudinal study, we followed the dynamics of co-existing Escherichia coli lineages in an infant not receiving antibiotics. Using whole genome sequencing, we observed large genomic deletions, bacteriophage infections, as well as the loss and acquisition of plasmids in these lineages during their colonization of the human gut. In particular, we captured the exchange of multidrug resistance genes, and identified a clinically relevant conjugative plasmid mediating the transfer. This resistant transconjugant lineage was maintained for months, demonstrating that antibiotic resistance genes can disseminate and persist in the gut microbiome; even in absence of antibiotic selection. Furthermore, through in vivo competition assays, we suggest that the resistant transconjugant can persist through a fitness advantage in the mouse gut in spite of a fitness cost in vitro. Our findings highlight the dynamic nature of the human gut microbiota and provide the first genomic description of antibiotic resistance gene transfer between bacteria in the unperturbed human gut. These results exemplify that conjugative plasmids, harboring resistance determinants, can transfer and persists in the gut in the absence of antibiotic treatment.201729018426
382830.9997Interaction with a phage gene underlie costs of a β-lactamase. The fitness cost of an antibiotic resistance gene (ARG) can differ across host strains, creating refuges that allow the maintenance of an ARG in the absence of direct selection for its resistance phenotype. Despite the importance of such ARG-host interactions for predicting ARG dynamics, the basis of ARG fitness costs and their variability between hosts are not well understood. We determined the genetic basis of a host-dependent cost of a β-lactamase, bla(TEM-116*), that conferred a significant cost in one Escherichia coli strain but was close to neutral in 11 other Escherichia spp. strains. Selection of a bla(TEM-116*)-encoding plasmid in the strain in which it initially had a high cost resulted in rapid and parallel compensation for that cost through mutations in a P1-like phage gene, relA(P1). When the wild-type relA(P1) gene was added to a strain in which it was not present and in which bla(TEM-116*) was neutral, it caused the ARG to become costly. Thus, relA(P1) is both necessary and sufficient to explain bla(TEM-116*) costs in at least some host backgrounds. To our knowledge, these findings represent the first demonstrated case of the cost of an ARG being influenced by a genetic interaction with a phage gene. The interaction between a phage gene and a plasmid-borne ARG highlights the complexity of selective forces determining the maintenance and spread of ARGs and, by extension, encoding phage and plasmids in natural bacterial communities.IMPORTANCEAntibiotic resistance genes (ARGs) play a major role in the increasing problem of antibiotic resistance in clinically relevant bacteria. Selection of these genes occurs in the presence of antibiotics, but their eventual success also depends on the sometimes substantial costs they impose on host bacteria in antibiotic-free environments. We evolved an ARG that confers resistance to penicillin-type antibiotics in one host in which it did confer a cost and in one host in which it did not. We found that costs were rapidly and consistently reduced through parallel genetic changes in a gene encoded by a phage that was infecting the costly host. The unmutated version of this gene was sufficient to cause the ARG to confer a cost in a host in which it was originally neutral, demonstrating an antagonism between the two genetic elements and underlining the range and complexity of pressures determining ARG dynamics in natural populations.202438194254
381840.9997A study of the transfer of tetracycline resistance genes between Escherichia coli in the intestinal tract of a mouse and a chicken model. Experiments to demonstrate the transfer of genes within a natural environment are technically difficult because of the unknown numbers and strains of bacteria present, as well as difficulties designing adequate control experiments. The results of such studies should be viewed within the limits of the experimental design. Most experiments to date have been based on artificial models, which only give approximations of the real-life situation. The current study uses more natural models and provides information about tetracycline resistance as it occurs in wild-type bacteria within the environment of the normal intestinal tract of an animal. Tetracycline sensitive, nalidixic acid resistant Escherichia coli isolates of human origin were administered to mice and chicken animal models. They were monitored for acquisition of tetracycline resistance from indigenous or administered donor E. coli. Five sets of in vivo experiments demonstrated unequivocal transfer of tetracycline resistance to tetracycline sensitive recipients. The addition of tetracycline in the drinking water of the animals increased the probability of transfer between E. coli strains originating from the same animal species. The co-transfer of unselected antibiotic resistance in animal models was also demonstrated.200616930278
382650.9997Co-resistance: an opportunity for the bacteria and resistance genes. Co-resistance involves transfer of several genes into the same bacteria and/or the acquisition of mutations in different genetic loci affecting different antimicrobials whereas pleiotropic resistance implies the same genetic event affecting several antimicrobials. There is an increasing prevalence of isolates with co-resistance which are over-represented within the so-called high-risk clones. Compensatory events avoid fitness cost of co-resistance, even in the absence of antimicrobials. Nevertheless, they might be selected by different antimicrobials and a single agent might select co-resistant isolates. This process, named as co-selection, is not avoided with cycling or mixing strategies of antimicrobial use. Co-resistance and co-selection processes increase the opportunity for persistence of the bacteria and resistance genes and should be considered when designing strategies for decreasing antimicrobial resistance.201121840259
381960.9997Enhancement of bacterial competitive fitness by apramycin resistance plasmids from non-pathogenic Escherichia coli. The study of antibiotic resistance has in the past focused on organisms that are pathogenic to humans or animals. However, the development of resistance in commensal organisms is of concern because of possible transfer of resistance genes to zoonotic pathogens. Conjugative plasmids are genetic elements capable of such transfer and are traditionally thought to engender a fitness burden on host bacteria. In this study, conjugative apramycin resistance plasmids isolated from newborn calves were characterized. Calves were raised on a farm that had not used apramycin or related aminoglycoside antibiotics for at least 20 months prior to sampling. Of three apramycin resistance plasmids, one was capable of transfer at very high rates and two were found to confer fitness advantages on new Escherichia coli hosts. This is the first identification of natural plasmids isolated from commensal organisms that are able to confer a fitness advantage on a new host. This work indicates that reservoirs of antibiotic resistance genes in commensal organisms might not decrease if antibiotic usage is halted.200617148431
405470.9997Ecological impact of antibiotic use in animals on different complex microflora: environment. Different means of interaction between microecological systems in different animal hosts (including humans) and the environment may occur during the transfer of resistant bacteria and their resistance genes. Spread of resistance takes place in different ways with respect to clonal spread of resistance strains by the spread of wide host range plasmids and translocatable elements. Commensals in ecosystems have a special significance and a pronounced capacity for acquisition and transfer of resistance genes as with Enterococcus faecium and Escherichia coli in the gut flora or Pseudomonas spp. in aquatic environments. The route of transmission from animals to humans by meat products is well established. Other routes via water and food plants (vegetables) have been investigated less, although resistance genes transfer in aquatic environments as evidenced from sequence comparison of such genes (e.g. tetR, floR in Salmonella typhimurium DT104). Whether this is due to rare but important transfer events or whether there is a more frequent exchange in aquatic or terrestrial environments needs further elucidation.200010794954
403480.9997Environmental and clinical antibiotic resistomes, same only different. The history of antibiotic use in the clinic is one of initial efficacy followed inevitably by the emergence of resistance. Often this resistance is the result of the capture and mobilization of genes that have their origins in environmental reservoirs. Both antibiotic production and resistance are ancient and widely distributed among microbes in the environment. This deep reservoir of resistance offers the opportunity for gene flow into susceptible disease-causing bacteria. Not all resistance genes are equally successfully mobilized, and some dominate in the clinic. The differences and similarities in resistance mechanisms and associated genes among environments reveal a complex interplay between gene capture and mobilization that requires study of gene diversity and gene product function to fully understand the breadth and depth of resistance and the risk to human health.201931330416
410790.9997Modeling the infection dynamics of bacteriophages in enteric Escherichia coli: estimating the contribution of transduction to antimicrobial gene spread. Animal-associated bacterial communities are infected by bacteriophages, although the dynamics of these infections are poorly understood. Transduction by bacteriophages may contribute to transfer of antimicrobial resistance genes, but the relative importance of transduction among other gene transfer mechanisms is unknown. We therefore developed a candidate deterministic mathematical model of the infection dynamics of enteric coliphages in commensal Escherichia coli in the large intestine of cattle. We assumed the phages were associated with the intestine and were predominantly temperate. Model simulations demonstrated how, given the bacterial ecology and infection dynamics, most (>90%) commensal enteric E. coli bacteria may become lysogens of enteric coliphages during intestinal transit. Using the model and the most liberal assumptions about transduction efficiency and resistance gene frequency, we approximated the upper numerical limits ("worst-case scenario") of gene transfer through specialized and generalized transduction in E. coli by enteric coliphages when the transduced genetic segment is picked at random. The estimates were consistent with a relatively small contribution of transduction to lateral gene spread; for example, generalized transduction delivered the chromosomal resistance gene to up to 8 E. coli bacteria/hour within the population of 1.47 × 10(8) E. coli bacteria/liter luminal contents. In comparison, the plasmidic blaCMY-2 gene carried by ~2% of enteric E. coli was transferred by conjugation at a rate at least 1.4 × 10(3) times greater than our generalized transduction estimate. The estimated numbers of transductants varied nonlinearly depending on the ecology of bacteria available for phages to infect, that is, on the assumed rates of turnover and replication of enteric E. coli.201424814786
3830100.9997Resistance Gene Carriage Predicts Growth of Natural and Clinical Escherichia coli Isolates in the Absence of Antibiotics. Bacterial pathogens that carry antibiotic resistance alleles sometimes pay a cost in the form of impaired growth in antibiotic-free conditions. This cost of resistance is expected to be a key parameter for understanding how resistance spreads and persists in pathogen populations. Analysis of individual resistance alleles from laboratory evolution and natural isolates has shown they are typically costly, but these costs are highly variable and influenced by genetic variation at other loci. It therefore remains unclear how strongly resistance is linked to impaired antibiotic-free growth in bacteria from natural and clinical scenarios, where resistance alleles are likely to coincide with other types of genetic variation. To investigate this, we measured the growth of 92 natural and clinical Escherichia coli isolates across three antibiotic-free environments. We then tested whether variation of antibiotic-free growth among isolates was predicted by their resistance to 10 antibiotics, while accounting for the phylogenetic structure of the data. We found that isolates with similar resistance profiles had similar antibiotic-free growth profiles, but it was not simply that higher average resistance was associated with impaired growth. Next, we used whole-genome sequences to identify antibiotic resistance genes and found that isolates carrying a greater number of resistance gene types grew relatively poorly in antibiotic-free conditions, even when the resistance genes they carried were different. This suggests that the resistance of bacterial pathogens is linked to growth costs in nature, but it is the total genetic burden and multivariate resistance phenotype that predict these costs, rather than individual alleles or mean resistance across antibiotics.IMPORTANCE Managing the spread of antibiotic resistance in bacterial pathogens is a major challenge for global public health. Central to this challenge is understanding whether resistance is linked to impaired bacterial growth in the absence of antibiotics, because this determines whether resistance declines when bacteria are no longer exposed to antibiotics. We studied 92 isolates of the key bacterial pathogen Escherichia coli; these isolates varied in both their antibiotic resistance genes and other parts of the genome. Taking this approach, rather than focusing on individual genetic changes associated with resistance as in much previous work, revealed that growth without antibiotics was linked to the number of specialized resistance genes carried and the combination of antibiotics to which isolates were resistant but was not linked to average antibiotic resistance. This approach provides new insights into the genetic factors driving the long-term persistence of antibiotic-resistant bacteria, which is important for future efforts to predict and manage resistance.201930530714
4108110.9997Evaluating targets for control of plasmid-mediated antimicrobial resistance in enteric commensals of beef cattle: a modelling approach. Enteric commensal bacteria of food animals may serve as a reservoir of genes encoding antimicrobial resistance (AMR). The genes are often plasmidic. Different aspects of bacterial ecology can be targeted by interventions to control plasmid-mediated AMR. The field efficacy of interventions remains unclear. We developed a deterministic mathematical model of commensal Escherichia coli in its animate and non-animate habitats within a beef feedlot's pen, with some E. coli having plasmid-mediated resistance to the cephalosporin ceftiofur. We evaluated relative potential efficacy of within- or outside-host biological interventions delivered throughout rearing depending on the targeted parameter of bacterial ecology. Most instrumental in reducing the fraction of resistant enteric E. coli at steer slaughter age were interventions acting on the enteric E. coli and capable of either 'plasmid curing' E. coli, or lowering maximum E. coli numbers or the rate of plasmid transfer in this habitat. Also efficient was to increase the regular replacement of enteric E. coli. Lowering replication rate of resistant E. coli alone was not an efficient intervention target.201323339899
4044120.9997Antibiotic resistance in food-related bacteria--a result of interfering with the global web of bacterial genetics. A series of antibiotic resistance genes have been sequenced and found to be identical or nearly identical in various ecological environments. Similarly, genetic vectors responsible for assembly and mobility of antibiotic resistance genes, such as transposons, integrons and R plasmids of similar or identical type are also widespread in various niches of the environment. Many zoonotic bacteria carry antibiotic resistance genes directly from different food-producing environments to the human being. These circumstances may have a major impact on the degree for success in treating infectious diseases in man. Several recent examples demonstrate that use of antibiotics in all parts of the food production chain contributes to the increasing level of antibiotic resistance among the food-borne pathogenic bacteria. Modern industrialized food production adds extra emphasis on lowering the use of antibiotics in all parts of agriculture, husbandry and fish farming because these food products are distributed to very large numbers of humans compared to more traditional smaller scale niche production.200212222637
4303130.9997Enrichment of antibiotic resistance genes within bacteriophage populations in saliva samples from individuals undergoing oral antibiotic treatments. Spread of antibiotic resistance is a significant challenge for our modern health care system, and even more so in developing countries with higher prevalence of both infections and resistant bacteria. Faulty usage of antibiotics has been pinpointed as a driving factor in spread of resistant bacteria through selective pressure. However, horizontal gene transfer mediated through bacteriophages may also play an important role in this spread. In a cohort of Tanzanian patients suffering from bacterial infections, we demonstrate significant differences in the oral microbial diversity between infected and non-infected individuals, as well as before and after oral antibiotics treatment. Further, the resistome carried both by bacteria and bacteriophages vary significantly, with bla (CTX-M1) resistance genes being mobilized and enriched within phage populations. This may impact how we consider spread of resistance in a biological context, as well in terms of treatment regimes.202236425042
4033140.9997Evolution and ecology of antibiotic resistance genes. A new perspective on the topic of antibiotic resistance is beginning to emerge based on a broader evolutionary and ecological understanding rather than from the traditional boundaries of clinical research of antibiotic-resistant bacterial pathogens. Phylogenetic insights into the evolution and diversity of several antibiotic resistance genes suggest that at least some of these genes have a long evolutionary history of diversification that began well before the 'antibiotic era'. Besides, there is no indication that lateral gene transfer from antibiotic-producing bacteria has played any significant role in shaping the pool of antibiotic resistance genes in clinically relevant and commensal bacteria. Most likely, the primary antibiotic resistance gene pool originated and diversified within the environmental bacterial communities, from which the genes were mobilized and penetrated into taxonomically and ecologically distant bacterial populations, including pathogens. Dissemination and penetration of antibiotic resistance genes from antibiotic producers were less significant and essentially limited to other high G+C bacteria. Besides direct selection by antibiotics, there is a number of other factors that may contribute to dissemination and maintenance of antibiotic resistance genes in bacterial populations.200717490428
4651150.9997Long-term shifts in patterns of antibiotic resistance in enteric bacteria. Several mechanisms are responsible for the ability of microorganisms to tolerate antibiotics, and the incidence of resistance to these compounds within bacterial species has increased since the commercial use of antibiotics became widespread. To establish the extent of and changes in the diversity of antibiotic resistance patterns in natural populations, we determined the MICs of five antibiotics for collections of enteric bacteria isolated from diverse hosts and geographic locations and during periods before and after commercial application of antibiotics began. All of the pre-antibiotic era strains were susceptible to high levels of these antibiotics, whereas 20% of strains from contemporary populations of Escherichia coli and Salmonella enterica displayed high-level resistance to at least one of the antibiotics. In addition to the increase in the frequency of high-level resistance, background levels, conferred by genes providing nonspecific low-level resistance to multiple antibiotics, were significantly higher among contemporary strains. Changes in the incidence and levels of antibiotic resistance are not confined to particular segments of the bacterial population and reflect responses to the increased exposure of bacteria to antimicrobial compounds over the past several decades.200011097921
9258160.9997Plasmid Viability Depends on the Ecological Setting of Hosts within a Multiplasmid Community. Plasmids are extrachromosomal genetic elements, some of which disperse horizontally between different strains and species of bacteria. They are a major factor in the dissemination of virulence factors and antibiotic resistance. Understanding the ecology of plasmids has a notable anthropocentric value, and therefore, the interactions between bacterial hosts and individual plasmids have been studied in detail. However, bacterial systems often carry multiple genetically distinct plasmids, but dynamics within these multiplasmid communities have remained unstudied. Here, we set to investigate the survival of 11 mobilizable or conjugative plasmids under five different conditions where the hosts had a differing ecological status in comparison to other bacteria in the system. The key incentive was to determine whether plasmid dynamics are reproducible and whether there are tradeoffs in plasmid fitness that stem from the ecological situation of their initial hosts. Growth rates and maximum population densities increased in all communities and treatments over the 42-day evolution experiment, although plasmid contents at the end varied notably. Large multiresistance-conferring plasmids were unfit when the community also contained smaller plasmids with fewer resistance genes. This suggests that restraining the use of a few antibiotics can make bacterial communities sensitive to others. In general, the presence or absence of antibiotic selection and plasmid-free hosts (of various fitnesses) has a notable influence on which plasmids survive. These tradeoffs in different settings can help explain, for example, why some resistance plasmids have an advantage during a rapid proliferation of antibiotic-sensitive pathogens whereas others dominate in alternative situations. IMPORTANCE Conjugative and mobilizable plasmids are ubiquitous in bacterial systems. Several different plasmids can compete within a single bacterial community. We here show that the ecological setting of the host bacteria has a notable effect on the survival of individual plasmids. Selection for opportunistic genes such as antibiotic resistance genes and the presence of plasmid-free hosts can determine which plasmids survive in the system. Host bacteria appear to adapt specifically to a situation where there are multiple plasmids present instead of alleviating the plasmid-associated fitness costs of individual plasmids. Plasmids providing antibiotic resistance survived under all conditions even if there was a constant migration of higher-fitness plasmid-free hosts and no selection via antibiotics. This study is one of the first to observe the behavior of multiple genetically different plasmids as a part of a single system.202235416702
3827170.9997The fitness cost of horizontally transferred and mutational antimicrobial resistance in Escherichia coli. Antimicrobial resistance (AMR) in bacteria implies a tradeoff between the benefit of resistance under antimicrobial selection pressure and the incurred fitness cost in the absence of antimicrobials. The fitness cost of a resistance determinant is expected to depend on its genetic support, such as a chromosomal mutation or a plasmid acquisition, and on its impact on cell metabolism, such as an alteration in an essential metabolic pathway or the production of a new enzyme. To provide a global picture of the factors that influence AMR fitness cost, we conducted a systematic review and meta-analysis focused on a single species, Escherichia coli. By combining results from 46 high-quality studies in a multilevel meta-analysis framework, we find that the fitness cost of AMR is smaller when provided by horizontally transferable genes such as those encoding beta-lactamases, compared to mutations in core genes such as those involved in fluoroquinolone and rifampicin resistance. We observe that the accumulation of acquired AMR genes imposes a much smaller burden on the host cell than the accumulation of AMR mutations, and we provide quantitative estimates of the additional cost of a new gene or mutation. These findings highlight that gene acquisition is more efficient than the accumulation of mutations to evolve multidrug resistance, which can contribute to the observed dominance of horizontally transferred genes in the current AMR epidemic.202337455716
3831180.9997The distribution of fitness effects of plasmid pOXA-48 in clinical enterobacteria. Antimicrobial resistance (AMR) in bacteria is a major public health problem. The main route for AMR acquisition in clinically important bacteria is the horizontal transfer of plasmids carrying resistance genes. AMR plasmids allow bacteria to survive antibiotics, but they also entail physiological alterations in the host cell. Multiple studies over the last few years have indicated that these alterations can translate into a fitness cost when antibiotics are absent. However, due to technical limitations, most of these studies are based on analysing new associations between plasmids and bacteria generated in vitro, and we know very little about the effects of plasmids in their native bacterial hosts. In this study, we used a CRISPR-Cas9-tool to selectively cure plasmids from clinical enterobacteria to overcome this limitation. Using this approach, we were able to study the fitness effects of the carbapenem resistance plasmid pOXA-48 in 35 pOXA-48-carrying isolates recovered from hospitalized patients. Our results revealed that pOXA-48 produces variable effects across the collection of wild-type enterobacterial strains naturally carrying the plasmid, ranging from fitness costs to fitness benefits. Importantly, the plasmid was only associated with a significant fitness reduction in four out of 35 clones, and produced no significant changes in fitness in the great majority of isolates. Our results suggest that plasmids produce neutral fitness effects in most native bacterial hosts, helping to explain the great prevalence of plasmids in natural microbial communities.202337505800
4148190.9997Plasmids in the environment. Bacterial plasmids existed in bacteria before the antibiotic era but their presence was brought into prominence by the use of antibiotics which selected for antibiotic resistant strains. Subsequently, the range of genes carried on plasmids was shown to extend far beyond those coding for antibiotic resistance. Any consideration of plasmids in the environment, therefore, must include all plasmids whether or not they are genetically linked with antibiotic resistance. Antibiotic resistant bacteria may be found in the environment either by contamination with excreta from man and animals in which the strains were selected, or by their selection within the environment by antibiotics synthesized in situ or reaching the environment in an undegraded form in sewage from man and animals, or from industry. Other agents, also contaminating the environment, exert a selective pressure such as heavy metals in industrial effluents which select for metal resistance. This paper reviews the incidences and role of plasmids in various habitats including natural waters, soil, pastures, farm wastes, and human sewage from both hospitalised and other populations. Aspects of plasmid ecology, their biological role, and the transmissibility of genetic material between bacteria within the environment are considered. Two recent studies in Bristol, UK, are reported. The first was a genetic study on Escherichia coli isolates from calf slurry. Various DNA probes were used to determine the extent of gene exchange between the various serotypes within the natural environment. The second was a preliminary study to determine the stability of a recombinant plasmid, in a wild strain of Escherichia coli of pig origin, after its release into a semi-contained farm situation. It is now recognized that plasmids are widely distributed in bacterial populations in terrestrial and aquatic environments. Many have been detected by their carriage of genes coding for antibiotic or heavy metal resistance. Others, mainly cryptic in nature, have been demonstrated by plasmid profile studies on isolates from various habitats. Plasmids were shown to be present in a relatively few bacteria deposited in culture collections prior to the antibiotic era. Subsequently, the increased prevalence of R plasmids in bacteria in most ecosystems were due mainly to the selective pressure imposed by the use of antibiotics. This pressure may have been exerted either in the environment in which the strains were found or elsewhere, the environment subsequently being contaminated by antibiotic resistant bacteria.(ABSTRACT TRUNCATED AT 400 WORDS)19883074480