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Biomedical subjects

B R Levin

Publications and source records attributed to B R Levin.

At least 37 records · Page 2Linked to original sources
PubMed1997

Evaluating treatment protocols to prevent antibiotic resistance.

The spread of bacteria resistant to antimicrobial agents calls for population-wide treatment strategies to delay or reverse the trend toward antibiotic resistance. Here we propose new criteria for the evaluation of the population-wide effects of treatment protocols for directly transmitted bacterial infections and discuss different usage patterns for single and multiple antibiotic therapy. A mathematical model suggests that the long-term benefit of single drug treatment from introduction of the antibiotic until a high frequency of resistance precludes its use is almost independent of the pattern of antibiotic use. When more than one antibiotic is employed, sequential use of different antibiotics in the population ("cycling") is always inferior to treatment strategies where, at any given time, equal fractions of the population receive different antibiotics. However, treatment of all patients with a combination of antibiotics is in most cases the optimal treatment strategy.

Anti-Bacterial Agents↗
PubMed1997

Adaptation to the fitness costs of antibiotic resistance in Escherichia coli.

Policies aimed at alleviating the growing problem of drug-resistant pathogens by restricting antimicrobial usage implicitly assume that resistance reduces the Darwinian fitness of pathogens in the absence of drugs. While fitness costs have been demonstrated for bacteria and viruses resistant to some chemotherapeutic agents, these costs are anticipated to decline during subsequent evolution. This has recently been observed in pathogens as diverse as HIV and Escherichia coli. Here we present evidence that these gentic adaptations to the costs of resistance can virtually preclude resistant lineages from reverting to sensitivity. We show that second site mutations which compensate for the substantial (14 and 18% per generation) fitness costs of streptomycin resistant (rpsL) mutations in E. coli create a genetic background in which streptomycin sensitive, rpsL+ alleles have a 4-30% per generation selective disadvantage relative to adapted, resistant strains. We also present evidence that similar compensatory mutations have been fixed in long-term streptomycin-resistant laboratory strains of E. coli and may account for the persistence of rpsL streptomycin resistance in populations maintained for more than 10,000 generations in the absence of the antibiotic. We discuss the public health implications of these and other experimental results that question whether the more prudent use of antimicrobial chemotherapy will lead to declines in the incidence of drug-resistant pathogenic microbes.

Adaptation, Physiological↗
PubMed1997

The within-host population dynamics of antibacterial chemotherapy: conditions for the evolution of resistance.

For tuberculosis and number of other bacterial infections, treatment with a single antimicrobial drug frequently fails due to the ascent of mutants resistant to that drug. To minimize the likelihood of this occurrence, multiple drugs with independent resistance mechanisms are used simultaneously. None the less, multiply resistant bacteria sometimes emerge even when patients are simultaneously treated with two or more drugs, and the ascent of these multiply-resistant mutants may result in treatment failure in the patient and spread of these resistant bacteria to other hosts. We consider two mathematical models of antibacterial chemotherapy which can account for the ascent of multiple antibiotic resistance within hosts treated with multiple antibiotics. In both, multiple resistance evolves because of selection favouring mutants resistant to fewer than all of the chemotherapeutic agents employed, intermediates. In one model, this occurs because of temporal fluctuations in the concentrations of the antibiotics in the course of normal treatment and/or because of non-adherence to the treatment regime. In the other, intermediates are favoured and multiple resistance evolves because of tissue and somatic cell heterogeneity. In the effective concentrations of the antibiotics and physiological variation in the sensitivity of subpopulations of bacteria to different antibiotics. We discuss the limitations (and assets) of this model and approach and the implications for the design of antibiotic treatment regimes. Finally, we consider how the assumptions behind this model and the predictions made from its analysis could be tested experimentally.

Animals↗
PubMed1997

The population genetics of antibiotic resistance.

Mathematical models are used to ascertain the relationship between the incidence of antibiotic treatment and the frequency of resistant bacteria in the commensal flora of human hosts, as well as the rates at which these frequencies would decline following a cessation of antibiotic use. Recent studies of the population biology of plasmid-encoded and chromosomal antibiotic resistance are reviewed for estimates of the parameters of these models and to evaluate other factors contributing to the fate of antibiotic-resistant bacteria in human hosts. The implications of these theoretical and empirical results to the future of antibacterial chemotherapy are discussed.

Anti-Bacterial Agents↗
PubMed1997

The population dynamics of antimicrobial chemotherapy.

We present and analyze a series of mathematical models for the emergence of resistance during antibiotic treatment of an infected host. The models consider the population dynamics of antibiotic-sensitive and -resistant bacteria during the course of treatment and addresses the following problems: (i) the probability of obtaining a resistant mutant during the course of treatment as a function of antibiotic exposure; (ii) the conditions under which high, infrequent doses of an antibiotic are predicted to succeed in preventing the emergence of resistance; (iii) the conditions for the success of multiple drug treatment in suppressing the emergence of resistance and the relationship between antibiotic synergism and suppression of resistance; and (iv) the conditions under which nonadherence to the prescribed treatment regimen is predicted to result in treatment failure due to resistance. We analyze the predictions of the model for interpreting and extrapolating existing experimental studies of treatment efficacy and for optimizing treatment protocols to prevent the emergence of resistance.

Anti-Bacterial Agents↗
PubMed1996

Cholera: nice bacteria and bad viruses.

The genes coding for cholera toxin are borne on, and can be infectiously transmitted by, a filamentous bacteriophage, raising intriguing questions about the mechanisms and evolution of bacterial pathogenesis, and the taxonomy, epidemiology and control of cholera and other bacterial diseases.

Animals↗
PubMed1996

The intrinsic rate of increase of HIV/AIDS: epidemiological and evolutionary implications.

A method derived from demographic theory is presented for modeling the epidemiology of an infectious disease. For long-term infections, this method better accounts for host variation in survival and transmission rates than classical compartment models. Examples of the applications of this method focus on a single long-term infectious disease, HIV/AIDS. The method is employed to examine (1) how changes in transmission rates during different stages of infection affect the rate of spread of HIV/AIDS both in wholly susceptible populations and in populations where the number of potential hosts is limited, (2) the way the relative frequencies of the different stages of infection vary over time, (3) how the rate at which the epidemic is growing (or diminishing) affects the fraction of HIV-infected individuals who manifest the symptoms of AIDS, (4) the effect of treatment on the rate of spread of HIV, and (5) the potential effects of natural selection on the virulence of HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1996

T-cell homeostasis, competition, and drift: AIDS as HIV-accelerated senescence of the immune repertoire.

The observation that the density of CD8+ T-lymphocytes increases as the density of CD4+ T-cells declines in adult HIV-1/AIDS patients, together with evidence that the total density of T-cells is regulated (homeostasis) has led to the suggestion that competition between lineages, and classes of T-cells contributes to the pathology of HIV. We use a mathematical model of the interactions between populations of T-cells, HIV, and other parasites to explore the effects of T-cell homeostasis and competition on the progression to AIDS. We demonstrate that as a consequence of parasite-mediated T-cell replication, of competition within and between different T-cell clones, and random processes (T-cell drift), some CD4+ lineages will be represented by relatively few cells, dearths, and some lineages may be lost, leaving holes in the immune repertoire. By killing CD4+ T-lymphocytes, HIV accelerates the rate at which these dearths and holes accumulate and leads to an early breakdown of the immune control of HIV and other parasites, AIDS. When this model allows for intense, but not complete, competition between the CD4+ and CD8+ T-cell populations, it can account for most of the features of an HIV-1 infection in adults, including the gradual decline in CD4+ T-cell densities and concomitant increase in HIV density, as well as the variability in time from infection to AIDS and the decline in the time from infection to AIDS in older patients.

AIDS-Related Opportunistic Infections↗
PubMed1994

Short-sighted evolution and the virulence of pathogenic microorganisms.

For some microorganisms, virulence may be an inadvertent consequence of mutation and selection in the parasite population, occurring within a host during the course of an infection. This type of virulence is short-sighted, in that it engenders no advantage to the pathogen beyond the afflicted host. Bacterial meningitis, poliomyelitis and AIDS are three candidates for this model of the evolution of virulence.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Erythrocytic glutathione in cystic fibrosis. A possible marker of pulmonary dysfunction.

To evaluate the role of red blood cell (RBC) antioxidants as clinical markers of oxidative exposure, we measured RBC glutathione (GSH) concentrations in 32 adult patients with cystic fibrosis (CF), and 8 healthy age-matched control subjects. We chose patients with CF because this disease is characterized by severe bronchial inflammation and marked oxidant-antioxidant imbalance. Although the GSH concentration of the two study groups was not significantly different, the RBC GSH concentration of patients with CF had a greater variability (p = 0.01) and was also inversely and significantly correlated to tests of pulmonary function (p < 0.05). These data indicate a large and significant interindividual variability of erythrocytic antioxidants in patients with CF, with a compensatory, but probably inadequate, increase in patients with more severe respiratory deterioration. Red blood cell GSH concentration may thus provide a biologic marker for disease severity and a rationale for antioxidant manipulation in these patients.

Adult↗
PubMed1993

Sensitivity of naturally occurring coliphages to type I and type II restriction and modification.

Protection against lethal infections by bacteriophage may seem the most likely role of restriction-modification (R-M) systems in bacteria and the reason for their evolution. There are, however, phenomena which question this phage-mediated selection hypothesis for the maintenance of extant R-M systems. Most prominent among these are the mechanisms phage have to avoid or otherwise limit the effects of the restriction endonucleases produced by their host bacteria. To evaluate the importance of these antirestriction mechanisms in Escherichia coli, we have examined the sensitivity of coliphage from natural and laboratory sources to a series of type I and II R-M systems. The results of our study indicate that, in vivo, restriction endonucleases have no effect on a substantial fraction of naturally occurring coliphage. The absence of restriction sites appears to be the most common reason why these phage are unaffected by type II restriction endonucleases, but other antirestriction mechanisms also operate. On the other hand, the frequency of naturally occurring coliphage sensitive to restriction appears sufficiently great for phage-mediated selection to be a viable hypothesis for the maintenance of R-M in E. coli and its accessory elements.

Biological Evolution↗
PubMed1990

Selection and evolution of virulence in bacteria: an ecumenical excursion and modest suggestion.

Why do parasites kill their hosts? During this past decade, research in three different areas; evolutionary ecology, medical microbiology, and population genetics has provided theory and data that address this and related questions of selection and the evolution and maintenance of parasite virulence. A general theory of parasite-host coevolution and the conditions for selection to favour parasite virulence has been put forth. Considerable advances have been made in elucidating the mechanisms of pathogenicity and inheritance of virulence in bacteria. The population genetic structure and the relationship between pathogenic and non-pathogenic forms has been determined for a number of species of bacteria. We critically review these developments and their implications for questions of selection and the evolution and maintenance of virulence in bacteria. We postulate how selection may operate on specific types of bacterial virulence and present a general protocol to experimentally test hypotheses concerning selection and the evolution of virulence in bacteria.

Animals↗
PubMed1990

Fluctuation analysis: the probability distribution of the number of mutants under different conditions.

In the 47 years since fluctuation analysis was introduced by Luria and Delbrück, it has been widely used to calculate mutation rates. Up to now, in spite of the importance of such calculations, the probability distribution of the number of mutants that will appear in a fluctuation experiment has been known only under the restrictive, and possibly unrealistic, assumptions: (1) that the mutation rate is exactly proportional to the growth rate and (2) that all mutants grow at a rate that is a constant multiple of the growth rate of the original cells. In this paper, we approach the distribution of the number of mutants from a new point of view that will enable researchers to calculate the distribution to be expected using assumptions that they believe to be closer to biological reality. The new idea is to classify mutations according to the number of observable mutants that derive from the mutation when the culture is selectively plated. This approach also simplifies the calculations in situations where two, or many, kinds of mutation may occur in a single culture.

Bacteria↗
PubMed1990

Estimating the rate of plasmid transfer: an end-point method.

We describe a method for determining the rate parameter of conjugative plasmid transfer that is based on single estimates of donor, recipient and transconjugant densities and the growth rate in exponential phase of the mating culture. The formula for estimating the plasmid transfer rate, gamma, was derived from a mathematical model describing cell growth and plasmid transfer in batch culture. Computer simulations were used to explore the sensitivity of this method to the realities of bacterial life, such as growth rate differences, plasmid segregation and transitory derepression of pilus synthesis. As predicted by the theory, mating experiments with the plasmid R1 in Escherichia coli K12 demonstrated that the estimate gamma is unaffected by cell density, donor:recipient ratio and mating time. Unlike previous techniques, our method allows us to investigate the effect of environmental factors on plasmid transfer rates when these factors also influence population growth rates. To illustrate this, we examined the effect of temperature on the rate of plasmid transfer.

Computer Simulation↗
PubMed1989

Distribution of the P-associated-pilus (pap) region among Escherichia coli from natural sources: evidence for horizontal gene transfer.

Variation in chromosomal DNA in Escherichia coli was studied with probes specific for the P-associated-pilus (pap) region. The presence of DNA homologous to pap was determined by dot blots. Variation in the number of copies of pap and in the organization of internal and flanking sequences was determined by Southern blot hybridization. The 229 strains studied were also classified by O:K:H serotyping and multilocus enzyme electrophoresis. There was considerable heterogeneity in the presence of pap and distribution of pap-homologous DNA in these E. coli strains from natural sources. In general, there was less variation in pap among strains of the same specific O:K:H serotype and enzyme electrophoretic type than among random isolates. There were, however, E. coli strains identified as members of the same clone by O:K:H serotyping and enzyme electrophoresis that were pap positive and pap negative or had different Southern blot patterns for the pap probes (pap type). There were also isolates of the same pap type that differed in two of three O:K:H serotype antigens and the majority of enzymes that determined their enzyme electrophoretic type. These latter two observations were interpreted as evidence for the horizontal (infectious) transfer of the pap-homologous sequences among clones of E. coli.

Bacterial Adhesion↗
PubMed1988

Frequency-dependent selection in bacterial populations.

There are many situations in which the direction and intensity of natural selection in bacterial populations will depend on the relative frequencies of genotypes. In some cases, this selection will favour rare genotypes and result in the maintenance of genetic variability; this is termed stabilizing frequency-dependent selection. In other cases, selection will only favour genotypes when they are common. Rare types cannot invade and genetic variability will not be maintained; this is known as disruptive frequency-dependent selection. Phage-mediated selection for bacteria with novel restriction-modification systems is frequency-dependent and stabilizing. In mass culture, selection for the production of toxins and allelopathic agents is likely to be frequency-dependent but disruptive. This also occurs in selection favouring genes and transposable elements that cause mutations. Here I review the results of theoretical and experimental studies of stabilizing and disruptive frequency-dependent selection in bacterial populations, and speculate on the importance of this kind of selection in the adaptation and evolution of these organisms and their accessory elements (plasmid, phage and transposons).

Bacteria↗