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M Lipsitch

Publications and source records attributed to M Lipsitch.

At least 19 recordsLinked to original sources
PubMed2001

Understanding the spread of antibiotic resistant pathogens in hospitals: mathematical models as tools for control.

As microorganisms become more resistant to antimicrobial agents, effective infection control measures will become increasingly important. However, despite multiple studies on infection prevention, few data exist on the quantitative effects of the individual aspects of infection control strategies. The combination of epidemiologic surveillance, molecular genotyping, observational studies on compliance, and mathematical modeling may improve our ability to determine the quantitative effects of individual infection control measures. This may help to design more effective infection control programs. In this study, we review several of the models that have been published and speculate on the usefulness of mathematical modeling for improving the prevention of infection.

Anti-Bacterial Agents↗
PubMed2001

Interpreting results from trials of pneumococcal conjugate vaccines: a statistical test for detecting vaccine-induced increases in carriage of nonvaccine serotypes.

Conjugate vaccines against Streptococcus pneumoniae (pneumococcus) protect against nasopharyngeal carriage of serotypes included in the vaccine. However, in several clinical trials, vaccinees have shown increased carriage of nonvaccine serotypes of pneumococcus. These increases may be due to serotype replacement, if vaccine-induced protection against carriage of vaccine serotypes increases susceptibility to carriage of nonvaccine serotypes. Alternatively, observed increases may be an artifact of "unmasking," in which nonvaccine serotypes are more readily detected among vaccinees than among controls because vaccine serotypes are not present. In this paper, a statistical test for distinguishing serotype replacement from unmasking is described. The test attempts to reject a null model of unmasking alone; serotype replacement is inferred if the observed increase in detectable nonvaccine serotype carriage among vaccinees is significantly greater than that expected under the null model. Significance is assessed using the Bayesian "posterior predictive p value" as modified by Robins et al. (J Am Stat Assoc 2000;95:1143-56). Analysis of data from a South African trial suggests that replacement may have occurred in the study, but results do not reach the conventional level of significance in rejecting the null hypothesis of unmasking (p = 0.074). The author performs sensitivity analyses for the prior and for unmeasured confounding by differences in susceptibility to pneumococcus carriage. The implications of the findings and the assumptions and limitations of this technique are then discussed.

Bayes Theorem↗
PubMed2001

Measuring and interpreting associations between antibiotic use and penicillin resistance in Streptococcus pneumoniae.

Studies of the relationship between antibiotic use and resistance in pneumococci have produced conflicting results, reflecting differences in study design, setting, and measures of association used. Mathematical models of pneumococcal transmission dynamics provide a framework for interpreting and reconciling these studies. The model predicts, and the review of published studies confirms, that treatment often has little effect in increasing an individual's absolute risk of carrying/being infected by penicillin-resistant Streptococcus pneumoniae (PRSP). However, treatment substantially increases a patient's risk of carriage of/infection by PRSP relative to that of penicillin-susceptible S. pneumoniae (PSSP). The appropriate measure of association depends on the question of interest. Antibiotic use can substantially increase the prevalence of risk in the community as a whole, even when there is a small or nonexistent effect of treatment on the absolute risk that a treated individual will carry a resistant organism. Recommendations for the design and analysis of future studies of antibiotic treatment and pneumococcal resistance are proposed.

Animals↗
PubMed2001

The rise and fall of antimicrobial resistance.

Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent and rate of increase of the problem varies widely with different pathogen-drug combinations. The rate of increase of resistance depends primarily on the availability of resistant variants and the intensity of selection imposed by antimicrobial treatment (appropriately measured). Declines in resistance following antimicrobial control measures are typically faster in hospital-acquired infections than in community-acquired ones, probably owing to the dependence in the latter case on the fitness cost of resistance. Open questions and approaches for testing the hypotheses proposed here are outlined.

Bacteria↗
PubMed2001

Visualizing pneumococcal infections in the lungs of live mice using bioluminescent Streptococcus pneumoniae transformed with a novel gram-positive lux transposon.

Animal studies with Streptococcus pneumoniae have provided valuable models for drug development. In order to monitor long-term pneumococcal infections noninvasively in living mice, a novel gram-positive lux transposon cassette, Tn4001 luxABCDE Km(r), that allows random integration of lux genes onto the bacterial chromosome was constructed. The cassette was designed so that the luxABCDE and kanamycin resistance genes were linked to form a single promoterless operon. Bioluminescence and kanamycin resistance only occur in a bacterial cell if this operon has transposed downstream of a promoter on the bacterium's chromosome. S. pneumoniae D39 was transformed with plasmid pAUL-A Tn4001 luxABCDE Km(r), and a number of highly bioluminescent colonies were recovered. Genomic DNA from the brightest D39 strain was used to transform a number of clinical S. pneumoniae isolates, and several of these strains were tested in animal models, including a pneumococcal lung infection model. Strong bioluminescent signals were seen in the lungs of the animals containing these pneumococci, allowing the course and antibiotic treatment of the infections to be readily monitored in real time in the living animals. Recovery of the bacteria from the animals showed that the bioluminescent signal corresponded to the number of CFU and that the lux construct was highly stable even after several days in vivo. We believe that this lux transposon will greatly expand the ability to evaluate drug efficacy against gram-positive bacteria in living animals using bioluminescence.

Amoxicillin↗
PubMed2001

Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci.

A whole-cell killed unencapsulated pneumococcal vaccine given by the intranasal route with cholera toxin as an adjuvant was tested in two animal models. This vaccination was highly effective in preventing nasopharyngeal colonization with an encapsulated serotype 6B strain in mice and also conferred protection against illness and death in rats inoculated intrathoracically with a highly encapsulated serotype 3 strain. When the serotype 3 challenge strain was incubated in the sera of immunized rats, it was no longer virulent in an infant-rat sepsis model, indicating that the intranasal immunization elicited protective systemic antibodies. These studies suggest that killed whole-cell unencapsulated pneumococci given intranasally with an adjuvant may provide multitypic protection against capsulated pneumococci.

Adjuvants, Immunologic↗
PubMed2000

Competition among Streptococcus pneumoniae for intranasal colonization in a mouse model.

Widespread use of conjugate vaccines against Streptococcus pneumoniae, by reducing carriage of S. pneumoniae serotypes included in the vaccine, may result in an increase in nasopharyngeal carriage of - and disease from - nonvaccine serotypes of the same species. Mathematical models predict that the extent of such replacement will depend positively on the degree to which carriage of vaccine-type S. pneumoniae inhibits acquisition of nonvaccine-type pneumococci, and may depend negatively on the inhibition of vaccine-type pneumococci by nonvaccine-type pneumococci. We used a mouse model of intranasal carriage of pneumococci to test whether such inhibition occurs between different pneumococcal strains. Mice carrying a streptomycin-resistant derivative of S. pneumoniae BG9163 (serotype 6B) as a resident strain showed reduced levels of colonization when challenged intranasally by optochin-resistant derivatives of the same strain and of a serotype 23F pneumococcus, BG8826. Inhibition could be overcome by increasing the dose of the challenge strain. Carriage of optochin-resistant BG9163 did not inhibit acquisition of the streptomycin-resistant variant. Colonization by a challenge strain did not significantly affect the level of colonization with the resident strain. These results provide evidence that is consistent with several hitherto untested assumptions of mathematical models of serotype replacement and suggest that a biological mechanism exists that could account for serotype replacement that is observed in clinical trials. The findings provide a basis for further studies of in vivo interactions between strains of S. pneumoniae.

Animals↗
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

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↗
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↗
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

Dual roles for DNA sequence identity and the mismatch repair system in the regulation of mitotic crossing-over in yeast.

Sequence divergence acts as a potent barrier to homologous recombination; much of this barrier derives from an antirecombination activity exerted by mismatch repair proteins. An inverted repeat assay system with recombination substrates ranging in identity from 74% to 100% has been used to define the relationship between sequence divergence and the rate of mitotic crossing-over in yeast. To elucidate the role of the mismatch repair machinery in regulating recombination between mismatched substrates, we performed experiments in both wild-type and mismatch repair defective strains. We find that a single mismatch is sufficient to inhibit recombination between otherwise identical sequences, and that this inhibition is dependent on the mismatch repair system. Additional mismatches have a cumulative negative effect on the recombination rate. With sequence divergence of up to approximately 10%, the inhibitory effect of mismatches results mainly from antirecombination activity of the mismatch repair system. With greater levels of divergence, recombination is inefficient even in the absence of mismatch repair activity. In both wild-type and mismatch repair defective strains, an approximate log-linear relationship is observed between the recombination rate and the level of sequence divergence.

Crossing Over, Genetic↗