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Biomedical subjects

Marc Lipsitch

Publications and source records attributed to Marc Lipsitch.

At least 19 recordsLinked to original sources
PubMed2007

Age- and serogroup-related differences in observed durations of nasopharyngeal carriage of penicillin-resistant pneumococci.

Using data from an ongoing Swedish intervention project, the observed durations of nasopharyngeal carriage of penicillin-nonsusceptible Streptococcus pneumoniae (PNSP) (MIC of penicillin G of >or=0.5 microg/ml) stratified by both pneumococcal serogroup and age of the carrier were compared. The means and 95% confidence intervals (CIs) were estimated by fitting a gamma distribution to the observed duration of carriage for each age and serogroup stratum. The mean observed duration of carriage for all cases was 37 days (95% CI, 35 to 38 days). Children below the age of 5 years carried PNSP for significantly longer periods (43 days; 95% CI, 41 to 45 days) compared with older individuals (25 days; 95% CI, 24 to 27 days). There were also differences within the group of cases below the age of 5 years, as the duration of carriage became significantly shorter for each increasing age step: <1, 1 to 2, and 3 to 4 years. In addition, patients <5 years of age carried serogroups 9 and 14 for significantly shorter periods than groups 6 and 23. Serogroup 9 was also carried for significantly shorter periods than group 19. For patients aged 5 years or older, no significant difference in carriage duration for different ages or serogroups could be noted. As young children have the longest duration of PNSP carriage, interventions aiming to reduce the prevalence in this group are of great importance. The results highlight the importance of taking both serogroup and age of the carriers into account when studying the dynamics of pneumococcal transmission in young children.

Adolescent↗
PubMed2006

Diversity and antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae carriage isolates in the post-heptavalent conjugate vaccine era.

BACKGROUND: In response to the selective pressure of pneumococcal conjugate vaccine, increased asymptomatic carriage of antibiotic-nonsusceptible nonvaccine serotypes (NVTs) has been observed. Possible mechanisms include de novo acquisition of resistance, serotype switching, introduction of new clones, and expansion of existing clones. METHODS: To investigate the process of increased antibiotic nonsusceptibility among replacing serotypes, we applied multilocus sequence typing to samples of 126 and 222 pneumococci collected in 2001 and 2004, respectively, from the nasopharynges of children <7 years of age in 16 Massachusetts communities. RESULTS: We found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of NVTs, particularly in serotypes 19A, 15A, and 35B. In 19A, several unrelated clones increased in frequency, whereas, in the other 2 serotypes, single resistant lineages were responsible for the increased prevalence of resistant strains. CONCLUSIONS: The decreased prevalence of antibiotic resistance with the introduction of heptavalent pneumococcal conjugate vaccine is likely to be partially eroded over time as vaccine-included serotypes are replaced by resistant clones of NVTs. The clinical significance of this will depend on the pathogenic potential of replacing clones to cause local (e.g., otitis media) or invasive disease.

Anti-Bacterial Agents↗
PubMed2006

Upgrading antibiotic use within a class: tradeoff between resistance and treatment success.

Increasing resistance to antibiotics creates the need for prudent antibiotic use. When resistance to various antibiotics within a class is driven by stepwise accumulation of mutations, a dilemma may exist in regard to replacing an antibiotic that is losing effectiveness due to resistance with a new drug within the same class. Such replacement may enhance treatment success in the short term but promote the spread of highly resistant strains. We used mathematical models to quantify the tradeoff between minimizing treatment failures (by switching early) and minimizing the proliferation of the highly resistant strain (by delaying the switch). Numerical simulations were applied to investigate the cumulative prevalence of the highly resistant strain (Resistance) and the cumulative number of treatment failures (Failure) that resulted from following different antibiotic use policies. Whereas never switching to the new drug always minimizes Resistance and maximizes Failure, immediate switching usually maximizes Resistance and minimizes Failure. Thus, in most circumstances, there is a strict tradeoff in which early use of the new drug enhances treatment effectiveness while hastening the rise of high-level resistance. This tradeoff is most acute when acquired resistance is rare and the highly resistant strain is readily transmissible. However, exceptions occur when use of the new drug frequently leads to acquired resistance and when the highly resistant strain has substantial "fitness cost"; these circumstances tend to favor an immediate switch. We discuss the implications of these considerations in regard to antibiotic choices for Streptococcus pneumoniae.

Anti-Bacterial Agents↗
PubMed2006

Beneficial and perverse effects of isoniazid preventive therapy for latent tuberculosis infection in HIV-tuberculosis coinfected populations.

In sub-Saharan Africa, where the emergence of HIV has caused dramatic increases in tuberculosis (TB) case notifications, new strategies for TB control are necessary. Isoniazid preventive therapy (IPT) for HIV-TB coinfected individuals reduces the reactivation of latent Mycobacterium tuberculosis infections and is being evaluated as a potential community-wide strategy for improving TB control. We developed a mathematical model of TB/HIV coepidemics to examine the impact of community-wide implementation of IPT for TB-HIV coinfected individuals on the dynamics of drug-sensitive and -resistant TB epidemics. We found that community-wide IPT will reduce the incidence of TB in the short-term but may also speed the emergence of drug-resistant TB. We conclude that community-wide IPT in areas of emerging HIV and drug-resistant TB should be coupled with diagnostic and treatment policies designed to identify and effectively treat the increasing proportion of patients with drug-resistant TB.

AIDS-Related Opportunistic Infections↗
PubMed2006

Incremental increase in fitness cost with increased beta -lactam resistance in pneumococci evaluated by competition in an infant rat nasal colonization model.

BACKGROUND: We evaluated the impact of resistant penicillin-binding protein (PBP) allele acquisition on the ability of penicillin-resistant (PEN-R) pneumococcal strains to compete with penicillin-susceptible (PEN-S) ancestors for upper-respiratory-tract (URT) colonization. METHODS: PEN-S serotype 2, 6B, and 9V strains were transformed into derivatives expressing an increasing number of PEN-R PBP forms (2X, 2X-1A, and 2X-1A-2B for serotype 2 and 2X, 2X-2B, and 2X-2B-1A for 6B and 9V). Infant rats were inoculated intranasally with a mix of a PEN-R and PEN-S strains. For consecutive days, samples were collected for assessment of the ratio of PEN-S to PEN-R cells colonizing the URT. The selective index (SI), defined as the change in the natural logarithm of the ratio of PEN-S to PEN-R strains from the inoculum to the nasal-wash samples, quantified differences in fitness. RESULTS: SIs significantly > 0 (indicating a cost of resistant allele acquisition) were observed 4-5 days after colonization in all but serotype 6B pbp2x transfomants. Additional replacements with low-affinity forms of pbp2b and pbp1a genes reduced further ability to compete in all strains. CONCLUSIONS: The cost of penicillin-resistance acquisition for the Streptococcus pneumoniae strain competing with its susceptible ancestor to colonize the URT increases with the number of resistant pbp alleles acquired.

Amino Acid Sequence↗
PubMed2006

Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo.

Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1-specific CTLs in vivo. We estimate that only 2% of productively infected CD4+ cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10(7)) per day but are not responsible for the majority of infected cell death.

Cell Survival↗
PubMed2006

The influence of hitchhiking and deleterious mutation upon asexual mutation rates.

The question of how natural selection affects asexual mutation rates has been considered since the 1930s, yet our understanding continues to deepen. The distribution of mutation rates observed in natural bacteria remains unexplained. It is well known that environmental constancy can favor minimal mutation rates. In contrast, environmental fluctuation (e.g., at period T) can create indirect selective pressure for stronger mutators: genes modifying mutation rate may "hitchhike" to greater frequency along with environmentally favored mutations they produce. This article extends a well-known model of Leigh to consider fitness genes with multiple mutable sites (call the number of such sites alpha). The phenotypic effect of such a gene is enabled if all sites are in a certain state and disabled otherwise. The effects of multiple deleterious loci are also included (call the number of such loci gamma). The analysis calculates the indirect selective effects experienced by a gene inducing various mutation rates for given values of alpha, gamma, and T. Finite-population simulations validate these results and let us examine the interaction of drift with hitchhiking selection. We close by commenting on the importance of other factors, such as spatiotemporal variation, and on the origin of variation in mutation rates.

Models, Genetic↗
PubMed2006

Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide.

Serotype-specific immunity to Streptococcus pneumoniae is conferred by antibodies to the capsular polysaccharides, which define the 90 known serotypes. Whether antibody to the species-common cell wall polysaccharide (C-Ps) is protective has been a matter of controversy. Here we show that C-Ps given intranasally with mucosal adjuvant increased the resistance of mice to experimental nasopharyngeal colonization by capsulated S. pneumoniae of serotype 6B. This immunity could be induced in mice congenitally lacking immunoglobulin but was dependent upon CD4+ T cells. Elimination of the charged amino group on the polymer backbone by N acetylation of C-Ps reduced the immunity, as did treatment of the mice with antibody to the cytokine interleukin-17A at the time of challenge, both consistent with the hypothesis of T-cell activation due to the zwitterionic motif of the polymer. C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy against S. pneumoniae.

Administration, Intranasal↗
PubMed2006

Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae.

The bactericidal activity of Streptococcus pneumoniae toward Staphylococcus aureus is mediated by hydrogen peroxide. Catalase eliminated this activity. Pneumococci grown anaerobically or genetically lacking pyruvate oxidase (SpxB) were not bactericidal, nor were nonpneumococcal streptococci. These results provide a possible mechanistic explanation for the interspecies interference observed in epidemiologic studies.

Antibiosis↗
PubMed2005

Mechanisms by which antibiotics promote dissemination of resistant pneumococci in human populations.

Mechanisms by which antimicrobials contribute to dissemination of pneumococcal resistance are incompletely characterized. A serial cross-sectional study of nasopharyngeal pneumococcal carriage in healthy, home-living children <or=6 years of age was conducted in four rural communities-two in Utah (1998-2003) and two in Idaho (2002-2003). Prevalence odds ratios for carriage of resistant pneumococci (OR(res)) and of susceptible pneumococci (OR(sus)) were estimated. Dynamic transmission models were developed to facilitate a mechanistic interpretation of OR(res) and OR(sus) and to compare the population impact of distinct antimicrobial classes. A total of 5,667 cultures were obtained; 25% of the cultures were positive, and 29% of isolates exhibited reduced susceptibility to penicillin. The adjusted OR(res) for recent individual and sibling cephalosporin use was 2.2 (95% confidence interval: 1.4, 3.4) and 1.8 (95% confidence interval: 1.0, 3.3), respectively. Neither individual nor sibling penicillin use was associated with increased OR(res). Rather, recent use of penicillins was associated with decreased carriage of susceptible pneumococci (OR(sus) = 0.2, 95% confidence interval: 0.1, 0.3). In simulations, both types of effects promoted dissemination of resistant pneumococci at the population level. Findings show that oral cephalosporins enhance the risk of acquiring resistant pneumococci. Penicillins accelerate clearance of susceptible strains. The effect of penicillins in increasing resistance is shared equally by treated and untreated members of the population.

Anti-Bacterial Agents↗
PubMed2005

Serum serotype-specific pneumococcal anticapsular immunoglobulin g concentrations after immunization with a 9-valent conjugate pneumococcal vaccine correlate with nasopharyngeal acquisition of pneumococcus.

BACKGROUND: Immunization with pneumococcal conjugate vaccines (PCVs) reduces nasopharyngeal colonization by Streptococcus pneumoniae. We attempted to correlate postvaccination serum serotype-specific pneumococcal anticapsular immunoglobulin (Ig) G concentrations with new acquisitions of vaccine-type (VT) serotypes and the VT-related serotype 6A. METHODS: A total of 132 day care center attendees aged 12-35 months received a 9-valent PCV (PnCRM9) and were followed for 2 years for new nasopharyngeal acquisitions of S. pneumoniae. A total of 132 control subjects received a meningococcus type C conjugate vaccine. Serum serotype-specific pneumococcal anticapsular IgG concentrations were determined at 1 month after complete immunization. RESULTS: A logistic regression model of the probability of having a new acquisition of S. pneumoniae (for serotypes 9V, 14, 19F, and 23F) as a function of the IgG concentration showed a negative coefficient, indicating that higher IgG concentrations led to a decreasing probability of having a new acquisition, and achieved statistical significance for serotypes 14 and 19F. Similarly, a new acquisition of serotype 6A was shown to be significantly inversely related to the anti-6B IgG concentration. An effect of the IgG concentration on duration of carriage was not demonstrated. CONCLUSION: The magnitude of herd protection against S. pneumoniae provided by a PCV may depend on the magnitude of IgG concentrations.

Antibodies, Bacterial↗
PubMed2005

Modeling community- and individual-level effects of child-care center attendance on pneumococcal carriage.

BACKGROUND: The prevalence of pneumococcal carriage varies widely across communities. This variation is not fully explained by risk factors at the individual level but may be explained by factors producing effects at both the individual and community levels, such as child-care center (CCC) attendance. METHODS: We developed a transmission model to evaluate whether the combined risks of attending CCCs and associating with playmates who attend CCCs account for a large proportion of the variability in the prevalence of pneumococcal carriage across communities. We based parameters for the model on data from a multicommunity study. RESULTS: According to our model, differences in the proportion of children who attend CCCs can account for a range of 4%-56% in the prevalence of pneumococcal carriage across communities. Our model, which was based on data collected from 16 Massachusetts communities, predicts that the odds of carriage associated with CCC attendance are 2-3 times the odds associated with no CCC attendance (individual-level effect). The model also predicts that the odds of carriage for nonattendees in a community with CCCs are up to 6 times the odds for children in a community without CCCs (community-level effect). In addition, the mean number of hours spent at CCCs by a single attendee appears to exert effects on pneumococcal carriage that are independent of either the proportion of CCC attendance in the community or the mean number of hours these attendees spend in child care. CONCLUSIONS: We used data from multiple communities to develop a transmission model that explains marked differences in pneumococcal carriage across communities by variations in CCC attendance. This model only accounts for CCC attendance among young children and does not include other known risk factors for pneumococcal carriage.

Carrier State↗
PubMed2005

CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization.

Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal immunization by live pneumococcal colonization or by a killed, nonencapsulated whole-cell vaccine protected antibody-deficient mice against colonization, suggesting independence of antibodies to any pneumococcal antigens. Protection by intranasal immunization with whole-cell vaccine was completely abrogated in T cell-deficient mice, and in mice that were congenitally deficient in CD4(+) T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of, CD8(+) T cells were fully protected. Protection in this model was observed beyond 2 months after immunization, arguing against innate or nonspecific immune mechanisms. Thus, we find that immunity to pneumococcal colonization can be induced in the absence of antibody, independent of the capsular type, and this protection requires the presence of CD4(+) T cells at the time of challenge.

Administration, Intranasal↗
PubMed2005

Are anticapsular antibodies the primary mechanism of protection against invasive pneumococcal disease?

BACKGROUND: Antibody to capsular polysaccharide has been the basis of several vaccines that offer protection against invasive disease from Streptococcus pneumoniae. The success of such vaccines has led to the inference that natural protection against invasive pneumococcal disease is largely conferred by anticapsular antibody. If this is so, one would expect that the decline in disease from different serotypes would vary significantly, and that the appearance of substantial concentrations of anticapsular antibodies would coincide temporally with the decline in age-specific incidence. METHODS AND FINDINGS: Using incidence data from the United States, we show that, on the contrary, the decline in incidence with age is quite similar for the seven most important serogroups, despite large differences in exposure in the population. Moreover, only modest increases in antibody concentration occur over the second and third years of life, a period in which serotype-specific incidence declines to less than 25% of its peak. We also present detailed data on the distribution of antibody concentrations in Israeli toddlers, which are consistent with the United States findings. The same conclusion is supported by new data on age-specific incidence in Finland, which is compared with published data on antibody acquisition in Finnish toddlers. CONCLUSION: We suggest some additional studies of the mechanisms of protection that could distinguish among potential alternative mechanisms, including acquired immunity to noncapsular antigens, maturation of nonspecific immune responses, or changes in anatomy or exposure.

Age Factors↗