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Marc Lipsitch

Publications and source records attributed to Marc Lipsitch.

At least 37 records · Page 2Linked to original sources
PubMed2005

Capsule homology does not increase the frequency of transformation of linked penicillin binding proteins PBP 1a and PBP 2x in Streptococcus pneumoniae.

Penicillin resistance is mainly confined to a limited number of Streptococcus pneumoniae serotypes. Given linkage between the capsular biosynthesis locus and two penicillin binding proteins, we tested whether capsule homology increases transformation rates of penicillin resistance. Transformation rates in homologous donor-recipient pairs were no higher than expected, falsifying this hypothesis.

Anti-Bacterial Agents↗
PubMed2005

Antibodies to conserved pneumococcal antigens correlate with, but are not required for, protection against pneumococcal colonization induced by prior exposure in a mouse model.

In mice following intranasal exposure to Streptococcus pneumoniae, protection against pneumococcal colonization was independent of antibody but dependent on CD4(+) T cells. Nonetheless, concentrations of antibodies to three conserved pneumococcal antigens correlated with protection against colonization. Concentrations of antibodies to conserved pneumococcal antigens may be correlates of protection without being effectors of protection.

Animals↗
PubMed2004

Transmissibility of 1918 pandemic influenza.

The 1918 influenza pandemic killed 20-40 million people worldwide, and is seen as a worst-case scenario for pandemic planning. Like other pandemic influenza strains, the 1918 A/H1N1 strain spread extremely rapidly. A measure of transmissibility and of the stringency of control measures required to stop an epidemic is the reproductive number, which is the number of secondary cases produced by each primary case. Here we obtained an estimate of the reproductive number for 1918 influenza by fitting a deterministic SEIR (susceptible-exposed-infectious-recovered) model to pneumonia and influenza death epidemic curves from 45 US cities: the median value is less than three. The estimated proportion of the population with A/H1N1 immunity before September 1918 implies a median basic reproductive number of less than four. These results strongly suggest that the reproductive number for 1918 pandemic influenza is not large relative to many other infectious diseases. In theory, a similar novel influenza subtype could be controlled. But because influenza is frequently transmitted before a specific diagnosis is possible and there is a dearth of global antiviral and vaccine stores, aggressive transmission reducing measures will probably be required.

Cities↗
PubMed2004

Weather-based prediction of Plasmodium falciparum malaria in epidemic-prone regions of Ethiopia II. Weather-based prediction systems perform comparably to early detection systems in identifying times for interventions.

BACKGROUND: Timely and accurate information about the onset of malaria epidemics is essential for effective control activities in epidemic-prone regions. Early warning methods that provide earlier alerts (usually by the use of weather variables) may permit control measures to interrupt transmission earlier in the epidemic, perhaps at the expense of some level of accuracy. METHODS: Expected case numbers were modeled using a Poisson regression with lagged weather factors in a 4th-degree polynomial distributed lag model. For each week, the numbers of malaria cases were predicted using coefficients obtained using all years except that for which the prediction was being made. The effectiveness of alerts generated by the prediction system was compared against that of alerts based on observed cases. The usefulness of the prediction system was evaluated in cold and hot districts. RESULTS: The system predicts the overall pattern of cases well, yet underestimates the height of the largest peaks. Relative to alerts triggered by observed cases, the alerts triggered by the predicted number of cases performed slightly worse, within 5% of the detection system. The prediction-based alerts were able to prevent 10-25% more cases at a given sensitivity in cold districts than in hot ones. CONCLUSIONS: The prediction of malaria cases using lagged weather performed well in identifying periods of increased malaria cases. Weather-derived predictions identified epidemics with reasonable accuracy and better timeliness than early detection systems; therefore, the prediction of malarial epidemics using weather is a plausible alternative to early detection systems.

Algorithms↗
PubMed2004

Weather-based prediction of Plasmodium falciparum malaria in epidemic-prone regions of Ethiopia I. Patterns of lagged weather effects reflect biological mechanisms.

BACKGROUND: Malaria epidemics due to Plasmodium falciparum are reported frequently in the East African highlands with high case fatality rates. There have been formal attempts to predict epidemics by the use of climatic variables that are predictors of transmission potential. However, little consensus has emerged about the relative importance and predictive value of different factors. Understanding the reasons for variation is crucial to determining specific and important indicators for epidemic prediction. The impact of temperature on the duration of a mosquito's life cycle and the sporogonic phase of the parasite could explain the inconsistent findings. METHODS: Daily average number of cases was modeled using a robust Poisson regression with rainfall, minimum temperature and maximum temperatures as explanatory variables in a polynomial distributed lag model in 10 districts of Ethiopia. To improve reliability and generalizability within similar climatic conditions, we grouped the districts into two climatic zones, hot and cold. RESULTS: In cold districts, rainfall was associated with a delayed increase in malaria cases, while the association in the hot districts occurred at relatively shorter lags. In cold districts, minimum temperature was associated with malaria cases with a delayed effect. In hot districts, the effect of minimum temperature was non-significant at most lags, and much of its contribution was relatively immediate. CONCLUSIONS: The interaction between climatic factors and their biological influence on mosquito and parasite life cycle is a key factor in the association between weather and malaria. These factors should be considered in the development of malaria early warning system.

Animals↗
PubMed2004

Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals.

Hospital-acquired infections caused by antibiotic-resistant bacteria pose a grave and growing threat to public health. Antimicrobial cycling, in which two or more antibiotic classes are alternated on a time scale of months to years, seems to be a leading candidate in the search for treatment strategies that can slow the evolution and spread of antibiotic resistance in hospitals. We develop a mathematical model of antimicrobial cycling in a hospital setting and use this model to explore the efficacy of cycling programs. We find that cycling is unlikely to reduce either the evolution or the spread of antibiotic resistance. Alternative drug-use strategies such as mixing, in which each treated patient receives one of several drug classes used simultaneously in the hospital, are predicted to be more effective. A simple ecological explanation underlies these results. Heterogeneous antibiotic use slows the spread of resistance. However, at the scale relevant to bacterial populations, mixing imposes greater heterogeneity than does cycling. As a consequence, cycling is unlikely to be effective and may even hinder resistance control. These results may explain the limited success reported thus far from clinical trials of antimicrobial cycling.

Anti-Bacterial Agents↗
PubMed2004

Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units.

Hospitals use many strategies to control nosocomial transmission of vancomycin-resistant enterococci (VRE). Strategies include "passive surveillance," with isolation of patients with known previous or current VRE colonization or infection, and "active surveillance," which uses admission cultures, with subsequent isolation of patients who are found to be colonized with VRE. We created a mathematical model of VRE transmission in an intensive care unit (ICU) using data from an existing active surveillance program; we used the model to generate the estimated benefits associated with active surveillance. Simulations predicted that active surveillance in a 10-bed ICU would result in a 39% reduction in the annual incidence of VRE colonization when compared with no surveillance. Initial isolation of all patients, with withdrawal of isolation if the results of surveillance cultures are negative, was predicted to result in a 65% reduction. Passive surveillance was minimally effective. Using the best available data, active surveillance is projected to be effective for reducing VRE transmission in ICU settings.

Anti-Bacterial Agents↗
PubMed2004

The analysis of hospital infection data using hidden Markov models.

Surveillance data for communicable nosocomial pathogens usually consist of short time series of low-numbered counts of infected patients. These often show overdispersion and autocorrelation. To date, almost all analyses of such data have ignored the communicable nature of the organisms and have used methods appropriate only for independent outcomes. Inferences that depend on such analyses cannot be considered reliable when patient-to-patient transmission is important. We propose a new method for analysing these data based on a mechanistic model of the epidemic process. Since important nosocomial pathogens are often carried asymptomatically with overt infection developing in only a proportion of patients, the epidemic process is usually only partially observed by routine surveillance data. We therefore develop a 'structured' hidden Markov model where the underlying Markov chain is generated by a simple transmission model. We apply both structured and standard (unstructured) hidden Markov models to time series for three important pathogens. We find that both methods can offer marked improvements over currently used approaches when nosocomial spread is important. Compared to the standard hidden Markov model, the new approach is more parsimonious, is more biologically plausible, and allows key epidemiological parameters to be estimated.

Cross Infection↗
PubMed2004

Age-specific immunoglobulin g (IgG) and IgA to pneumococcal protein antigens in a population in coastal kenya.

Streptococcus pneumoniae is the primary etiological agent of community-acquired pneumonia and a major cause of meningitis and bacteremia. Three conserved pneumococcal proteins-pneumolysin, pneumococcal surface adhesin A (PsaA), and pneumococcal surface protein A (PspA)-are currently being investigated as vaccine candidates. Such protein-based vaccines, if proven effective, could provide a cheaper alternative to conjugate vaccine formulae. Few data from sub-Saharan Africa exist concerning the development of natural antibody to these antigens, however. To investigate the age-specific development of antiprotein immunoglobulin G (IgG) and IgA antibody responses, the sera of 220 persons 2 weeks to 84 years of age from coastal Kenya were assayed using enzyme-linked immunosorbent assays. IgG and IgA antibody responses to each antigen were observed in all age groups. Serum concentrations of IgG and IgA antibody responses to PspA and PdB (a recombinant toxoid derivative of pneumolysin), but not to PsaA, increased significantly with age (P < 0.001). No decline was observed in the sera of the elderly. Anti-protein IgG concentrations were only weakly correlated (0.30 < r < 0.56; P < 0.0001), as were IgA concentrations (0.24 < r < 0.54; P < 0.0001).

Adhesins, Bacterial↗
PubMed2004

Single-step capsular transformation and acquisition of penicillin resistance in Streptococcus pneumoniae.

The capsule (cps) locus of Streptococcus pneumoniae is flanked by the pbp2x and pbp1a genes, coding for penicillin-binding proteins, enzymes involved in cell wall synthesis that are targets for beta-lactams. This linkage suggested to us that selection for beta-lactam resistance might coselect for capsular transformants. The recombination event would then involve PBP genes, as well as the cps operon, and would change both the serotype and the resistance profile of the strain. We transformed beta-lactam-susceptible strain TIGR4 by using whole genomic DNA extracted from multidrug-resistant strain GA71, a serotype 19F variant of pneumococcal clone Spain(23F)-1, and selected beta-lactam-resistant transformants. Smooth colonies appearing on selective plates were subcultured, serotyped by the Quellung reaction, and genotyped to confirm the presence of the GA71 pbp2x-cps19-pbp1a locus in the TIGR4 genetic background by restriction fragment length polymorphism analysis of the whole locus and its flanking regions. The results showed that a new serotype, combined with resistance to beta-lactams, could emerge in a susceptible strain via a single transformation event. Quantitative analysis showed that transfer of the cps locus had occurred at an elevated rate in beta-lactam-selected transformants. This suggests that in natural settings selection by host immunity and selection by antibiotics may be interrelated because of "hitchhiking" effects due to linkage of resistance determinants and the capsule locus.

Bacterial Capsules↗
PubMed2004

Alert threshold algorithms and malaria epidemic detection.

We describe a method for comparing the ability of different alert threshold algorithms to detect malaria epidemics and use it with a dataset consisting of weekly malaria cases collected from health facilities in 10 districts of Ethiopia from 1990 to 2000. Four types of alert threshold algorithms are compared: weekly percentile, weekly mean with standard deviation (simple, moving average, and log-transformed case numbers), slide positivity proportion, and slope of weekly cases on log scale. To compare dissimilar alert types on a single scale, a curve was plotted for each type of alert, which showed potentially prevented cases versus number of alerts triggered over 10 years. Simple weekly percentile cutoffs appear to be as good as more complex algorithms for detecting malaria epidemics in Ethiopia. The comparative method developed here may be useful for testing other proposed alert thresholds and for application in other populations.

Algorithms↗
PubMed2003

Transmission dynamics and control of severe acute respiratory syndrome.

Severe acute respiratory syndrome (SARS) is a recently described illness of humans that has spread widely over the past 6 months. With the use of detailed epidemiologic data from Singapore and epidemic curves from other settings, we estimated the reproductive number for SARS in the absence of interventions and in the presence of control efforts. We estimate that a single infectious case of SARS will infect about three secondary cases in a population that has not yet instituted control measures. Public-health efforts to reduce transmission are expected to have a substantial impact on reducing the size of the epidemic.

Contact Tracing↗
PubMed2003

Geographic diversity and temporal trends of antimicrobial resistance in Streptococcus pneumoniae in the United States.

Resistance of Streptococcus pneumoniae to antibiotics is increasing throughout the United States, with substantial variation among geographic regions. We show that patterns of geographic variation are best explained by the intensity of selection for resistance, which is reflected by differences between the proportions of resistance within individual serotypes, rather than by differences between the frequencies of particular serotypes. Using a mathematical transmission model, we analyzed temporal trends in the proportions of singly and dually resistant organisms and found that pneumococcal strains resistant to both penicillin and erythromycin are increasing faster than strains singly resistant to either. Using the model, we predict that by 1 July 2004, in the absence of a vaccine, 41% of pneumococci at the Centers for Disease Control and Prevention (CDC)'s Active Bacterial Core surveillance (ABCs) sites, taken together, will be dually resistant, with 5% resistant to penicillin only and 5% to erythromycin only.

Drug Resistance↗
PubMed2003

Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection.

Streptococcus pneumoniae is one of the leading causes of invasive bacterial disease worldwide. Fragments of the cell wall and the cytolytic toxin pneumolysin have been shown to contribute substantially to inflammatory damage, although the interactions between pneumococcal components and host-cell structures have not been elucidated completely. Results of a previous study indicated that cell-wall components of pneumococci are recognized by Toll-like receptor (TLR)2 but suggested that pneumolysin induces inflammatory events independently of this receptor. In this study we tested the hypothesis that pneumolysin interacts with surface proteins of the TLR family other than TLR2. We found that pneumolysin stimulates tumor necrosis factor-alpha and IL-6 release in wild-type macrophages but not in macrophages from mice with a targeted deletion of the cytoplasmic TLR-adapter molecule myeloid differentiation factor 88, suggesting the involvement of the TLRs in pneumolysin recognition. Purified pneumolysin synergistically activated macrophage responses together with preparations of pneumococcal cell walls or staphylococcal peptidoglycan, which are known to activate TLR2. Furthermore, when compared with wild-type macrophages, macrophages from mice that carry a spontaneous mutation in TLR4 (P712H) were hyporesponsive to both pneumolysin alone and the combination of pneumolysin with pneumococcal cell walls. Finally, these TLR4-mutant mice were significantly more susceptible to lethal infection after intranasal colonization with pneumolysin-positive pneumococci than were control mice. We conclude that the interaction of pneumolysin with TLR4 is critically involved in the innate immune response to pneumococcus.

Animals↗
PubMed2003

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures.

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.

Alleles↗