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B R Levin

Publications and source records attributed to B R Levin.

At least 19 recordsLinked to original sources
PubMed2005

Phenotypic tolerance: antibiotic enrichment of noninherited resistance in bacterial populations.

When growing bacteria are exposed to bactericidal concentrations of antibiotics, the sensitivity of the bacteria to the antibiotic commonly decreases with time, and substantial fractions of the bacteria survive. Using Escherichia coli CAB1 and antibiotics of five different classes (ampicillin, ciprofloxacin, rifampin, streptomycin, and tetracycline), we examine the details of this phenomenon and, with the aid of mathematical models, develop and explore the properties and predictions of three hypotheses that can account for this phenomenon: (i) antibiotic decay, (ii) inherited resistance, and (iii) phenotypic tolerance. Our experiments cause us to reject the first two hypotheses and provide evidence that this phenomenon can be accounted for by the antibiotic-mediated enrichment of subpopulations physiologically tolerant to but genetically susceptible to these antibiotics, phenotypic tolerance. We demonstrate that tolerant subpopulations generated by exposure to one concentration of an antibiotic are also tolerant to higher concentrations of the same antibiotic and can be tolerant to antibiotics of the other four types. Using a mathematical model, we explore the effects of phenotypic tolerance to the microbiological outcome of antibiotic treatment and demonstrate, a priori, that it can have a profound effect on the rate of clearance of the bacteria and under some conditions can prevent clearance that would be achieved in the absence of tolerance.

Anti-Bacterial Agents↗
PubMed2002

Models for the spread of resistant pathogens.

I consider three mathematical models of the epidemiology of antibiotic treatment and the evolution of resistance. All of these models explore the relationship between the volume of antibiotic use and the frequency and rate of ascent (or descent) of resistance. The first model is in the population genetics tradition and assumes that in the absence of treatment the frequency of resistance wanes at a rate proportional to the fitness costs associated with resistance, but precipitously ascends to high frequencies in treated patients. The second two models are in the compartment, or SIR, model tradition of infectious disease epidemiology. The first of these considers the relationship between resistance and rates of antibiotic treatment in open communities. The second explores the factors contributing to the frequency of resistance in the closed settings of hospitals and nursing homes. While I give some consideration to the epidemiological and medical implications of the results of the analysis of the properties of these models, for the most part the models are the message. I end with a harangue about the utility of simple mathematics for these considerations and a plea to obtain realistic estimates of the parameters of these models and test the validity of the predictions generated from the analysis of these models.

Antibiotic Prophylaxis↗
PubMed2001

Minimizing potential resistance: a population dynamics view.

I examine the results of studies that used mathematical models of the epidemiology and population genetics of antibiotic treatment and resistance in open communities and in hospitals to explore the following issues: the relationship between antibiotic consumption and the frequency of antibiotic resistance in bacterial populations in communities and in hospitals; methods of controlling the growth, dissemination, and persistence of antibiotic resistance in these settings; the extent to which resistance can be controlled; and the speed with which the effects of control measures will be realized. In open communities, it will take years or even decades to see substantial reductions in the frequency of antibiotic resistance solely as a result of more prudent (reduced) use of antibiotics. However, if we can restrict the input of resistant bacteria into hospitals, through the application of infection control and other measures, it should be possible to reduce the frequency of resistance and even eliminate resistant bacteria from these institutions in short order.

Anti-Bacterial Agents↗
PubMed2001

Why we don't get sick: the within-host population dynamics of bacterial infections.

To pathogenic microparasites (viruses, bacteria, protozoa, or fungi), we and other mammals (living organisms at large) are little more than soft, thin-walled flasks of culture media. Almost every time we eat, brush our teeth, scrape our skin, have sex, get bitten by insects, and inhale, we are confronted with populations of microbes that are capable of colonizing the mucosa lining our orifices and alimentary tract and proliferating in fluids and cells within us. Nevertheless, we rarely get sick, much less succumb to these infections. The massive numbers of bacteria and other micro- and not-so-micro organisms that abound and replicate in our alimentary tract and cover our skin and the mucosa lining our orifices normally maintain their communities in seemingly peaceful coexistence with the somatic cells that define us. Why don't these microbes invade and proliferate in the culture media within the soft, thin-walled flask that envelops us? Why don't they cause disease and lead to our rapid demise?

Bacteria↗
PubMed2001

Epidemiology, evolution, and future of the HIV/AIDS pandemic.

We used mathematical models to address several questions concerning the epidemiologic and evolutionary future of HIV/AIDS in human populations. Our analysis suggests that 1) when HIV first enters a human population, and for many subsequent years, the epidemic is driven by early transmissions, possibly occurring before donors have seroconverted to HIV-positive status; 2) new HIV infections in a subpopulation (risk group) may decline or level off due to the saturation of the susceptible hosts rather than to evolution of the virus or to the efficacy of intervention, education, and public health measures; 3) evolution in humans for resistance to HIV infection or for the infection to engender a lower death rate will require thousands of years and will be achieved only after vast numbers of persons die of AIDS; 4) evolution is unlikely to increase the virulence of HIV; and 5) if HIV chemotherapy reduces the transmissibility of the virus, treating individual patients can reduce the frequency of HIV infections and AIDS deaths in the general population.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Bacteria are different: observations, interpretations, speculations, and opinions about the mechanisms of adaptive evolution in prokaryotes.

To some extent, the genetic theory of adaptive evolution in bacteria is a simple extension of that developed for sexually reproducing eukaryotes. In other, fundamental ways, the process of adaptive evolution in bacteria is quantitatively and qualitatively different from that of organisms for which recombination is an integral part of the reproduction process. In this speculative and opinionated discussion, we explore these differences. In particular, we consider (i) how, as a consequence of the low rates of recombination, "ordinary" chromosomal gene evolution in bacteria is different from that in organisms where recombination is frequent and (ii) the fundamental role of the horizontal transmission of genes and accessory genetic elements as sources of variation in bacteria. We conclude with speculations about the evolution of accessory elements and their role in the adaptive evolution of bacteria.

Bacteria↗
PubMed2000

The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions.

A simple mathematical model of bacterial transmission within a hospital was used to study the effects of measures to control nosocomial transmission of bacteria and reduce antimicrobial resistance in nosocomial pathogens. The model predicts that: (i) Use of an antibiotic for which resistance is not yet present in a hospital will be positively associated at the individual level (odds ratio) with carriage of bacteria resistant to other antibiotics, but negatively associated at the population level (prevalence). Thus inferences from individual risk factors can yield misleading conclusions about the effect of antibiotic use on resistance to another antibiotic. (ii) Nonspecific interventions that reduce transmission of all bacteria within a hospital will disproportionately reduce the prevalence of colonization with resistant bacteria. (iii) Changes in the prevalence of resistance after a successful intervention will occur on a time scale of weeks to months, considerably faster than in community-acquired infections. Moreover, resistance can decline rapidly in a hospital even if it does not carry a fitness cost. The predictions of the model are compared with those of other models and published data. The implications for resistance control and study design are discussed, along with the limitations and assumptions of the model.

Anti-Bacterial Agents↗
PubMed2000

Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria.

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

Adaptation, Biological↗
PubMed2000

Natural selection, infectious transfer and the existence conditions for bacterial plasmids.

Despite the near-ubiquity of plasmids in bacterial populations and the profound contribution of infectious gene transfer to the adaptation and evolution of bacteria, the mechanisms responsible for the maintenance of plasmids in bacterial populations are poorly understood. In this article, we address the question of how plasmids manage to persist over evolutionary time. Empirical studies suggest that plasmids are not infectiously transmitted at a rate high enough to be maintained as genetic parasites. In part i, we present a general mathematical proof that if this is the case, then plasmids will not be able to persist indefinitely solely by carrying genes that are beneficial or sometimes beneficial to their host bacteria. Instead, such genes should, in the long run, be incorporated into the bacterial chromosome. If the mobility of host-adaptive genes imposes a cost, that mobility will eventually be lost. In part ii, we illustrate a pair of mechanisms by which plasmids can be maintained indefinitely even when their rates of transmission are too low for them to be genetic parasites. First, plasmids may persist because they can transfer locally adapted genes to newly arriving strains bearing evolutionary innovations, and thereby preserve the local adaptations in the face of background selective sweeps. Second, plasmids may persist because of their ability to shuttle intermittently favored genes back and forth between various (noncompeting) bacterial strains, ecotypes, or even species.

Bacterial Physiological Phenomena↗
PubMed2000

Effects of antiviral usage on transmission dynamics of herpes simplex virus type 1 and on antiviral resistance: predictions of mathematical models.

Herpes simplex virus type 1 (HSV-1) causes recurrent herpes labialis (RHL), a common disease afflicting up to 40% of adults worldwide. Mathematical models are used to analyze the effect of antiviral treatment on the transmission of, and the prevalence of drug resistance in, HSV-1 in the United States. Three scenarios are analyzed: no antiviral use, the current level of use, and a substantial increase in nucleoside analogue use, such as might occur if topical penciclovir were available over-the-counter for the treatment of RHL. A basic model predicts that present level of nucleoside analogue use has a negligible effect on HSV-1 transmission and that even if use of topical penciclovir for (RHL) increased substantially, the overall prevalence of infectious HSV-1 is unlikely to be reduced by more than 5%. An expanded model, which allows for acquired resistance and includes immunocompromised hosts and other more realistic features, predicts that current antiviral use is unlikely to lead to any noticeable increase in resistance. If antiviral use increases, the resulting rise in resistance in the population will depend primarily on the probability that immunocompetent hosts will acquire permanent resistance upon treatment. This probability is known to be small, but its exact value remains uncertain. If acquired resistance occurs less than once per 2,500 treated episodes, then in the community at large, the frequency of HSV-1 resistance is predicted to increase slowly, if at all (remaining below 0.5% for >50 years), even with extensive nucleoside analogue use. If acquired resistance emerges in 1 of 625 treated episodes (the maximum of an approximate 95% confidence interval derived from the results of several studies of resistance in treated hosts), then the prevalence of infection with resistant HSV-1 could rise from about 0.2% to 1.5 to 3% within 50 years. The limitations of existing data on acquired resistance and the potential impact of acquired resistance if it occurs are discussed, and strategies are suggested for enhancing information on acquired resistance. The predictions of this model contrast with the more rapid increases in antimicrobial resistance anticipated by models and observed for other pathogenic bacteria and viruses. The reasons for these contrasting predictions are discussed.

Aging↗
PubMed2000

Concentration-dependent selection of small phenotypic differences in TEM beta-lactamase-mediated antibiotic resistance.

In this paper, the first robust experimental evidence of in vitro and in vivo concentration-dependent selection of low-level antibiotic-resistant genetic variants is described. The work is based on the study of an asymmetric competition assay with pairs of isogenic Escherichia coli strains, differing only (apart from a neutral chromosomal marker) in a single amino acid replacement in a plasmid-mediated TEM-1 beta-lactamase enzyme, which results in the new TEM-12 beta-lactamase. The mixture was challenged by different antibiotic concentrations, both in vitro and in the animal model, and the selective process of the variant population was carefully monitored. A mathematical model was constructed to test the hypothesis that measured growth and killing rates of the individual TEM variants at different antibiotic concentrations could be used to predict quantitatively the strength of selection for TEM-12 observed in competition experiments at these different concentrations.

Animals↗
PubMed1999

Population biology, evolution, and infectious disease: convergence and synthesis.

Traditionally, the interest of population and evolutionary biologists in infectious diseases has been almost exclusively in their role as agents of natural selection in higher organisms. Recently, this interest has expanded to include the genetic structure and evolution of microparasite populations, the mechanisms of pathogenesis and the immune response, and the population biology, ecology, and evolutionary consequences of medical and public health interventions. This article describes recent work in these areas, emphasizing the ways in which quantitative, population-biological approaches have been contributing to the understanding of infectious disease and the design and evaluation of interventions for their treatment and prevention.

Animals↗
PubMed1999

The biological cost of antibiotic resistance.

The frequency and rates of ascent and dissemination of antibiotic resistance in bacterial populations are anticipated to be directly related to the volume of antibiotic use and inversely related to the cost that resistance imposes on the fitness of bacteria. The data available from recent laboratory studies suggest that most, but not all, resistance-determining mutations and accessory elements engender some fitness cost, but those costs are likely to be ameliorated by subsequent evolution.

Adaptation, Physiological↗
PubMed1998

The population genetics of antibiotic resistance. II: Analytic theory for sustained populations of bacteria in a community of hosts.

The phenomenon of antibiotic resistance is of practical importance and theoretical interest. As a foundation for further studies by simulation, experiment, and observation, we here develop a mathematical model for the dynamics of resistance among the bacteria resident in a population of hosts. The model incorporates the effects of natural selection within untreated hosts, colonization by bacteria from the environment, and the rapid increase of resistance in hosts who receive antibiotics. We derive explicit formulas for the distribution of resistance among hosts and for the rise or fall of resistance when the frequency of treatment is changed.

Anti-Bacterial Agents↗
PubMed1998

Resistance to antimicrobial chemotherapy: a prescription for research and action.

The growing problem of resistance to antimicrobial chemotherapy was discussed by participants at the February 1995 workshop at Emory University on population biology, evolution, and control of infectious diseases. They discussed the nature and source of this problem and identified areas of research in which information is lacking for the development of programs to control of the emergence and spread of resistant bacteria. Particular attention was given to theoretical (mathematical modeling) and empirical studies of the within and between-host population biology (epidemiology) and the evolution of microbial resistance to chemotherapeutic agents. Suggestions were made about the kinds of models and data needed, and the procedures that could be employed to stem the ascent and dissemination of resistant bacteria. This article summarizes the observations and recommendations made at the 1995 meeting and in the correspondence between participants that followed. It concludes with an update on the theoretical and empirical research on the between- and within-host population biology and evolution of resistance to antimicrobial chemotherapy most of which has been done since that meeting.

Bacteria↗
PubMed1998

Population dynamics of tuberculosis treatment: mathematical models of the roles of non-compliance and bacterial heterogeneity in the evolution of drug resistance.

SETTING: Patient non-compliance and/or spatial heterogeneity in drug concentration or effectiveness may contribute to the emergence of drug resistance during multiple-drug chemotherapy of tuberculosis. OBJECTIVE: Using mathematical models of mycobacterial population dynamics under antimicrobial treatment, to assess the effects of non-compliance, heterogeneity and other factors on the success of treatment. DESIGN: A mathematical model is used to generate predictions about the ascent of drug resistance in treated hosts with non-compliance and/or a 'protected compartment' of bacteria where only one drug is active; simulations of a more realistic version of this model take into account random mutation, and different assumptions about the size of, and growth rate of bacteria in, the protected compartment. RESULTS: The existence of a protected compartment can increase the likelihood of resistance to the single drug active in that compartment, but only if bacteria resistant to that drug can grow in the protected compartment or if the host is non-adherent to the treatment regimen. However, the protected compartment may also slow the ascent of bacteria resistant to drugs not active in it (e.g. isoniazid) by providing a reservoir of non-selected mycobacteria. The model predicts that relative rates of killing are more important than mutation rates in determining the order in which resistant mutants ascend. Model predictions, in combination with data about drug resistance patterns, suggest that non-compliance, but not heterogeneity, is an important cause of treatment failure. CONCLUSION: Patterns of acquired drug resistance may be used to infer processes of selection during treatment; mathematical models can aid in generating predictions about the relative impacts of treatment parameters in the evolution of resistance, and eventually in suggesting improved treatment protocols.

Antitubercular Agents↗