Eili Y. Klein

Hospitalizations and Deaths Caused by Methicillin-Resistant Staphylococcus aureus, United States, 1999–2005

MRSA should be a national priority for disease control.

A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970-2010

Mathematical models of mosquito-borne pathogen transmission originated in the early twentieth century to provide insights into how to most effectively combat malaria. The foundations of the Ross–Macdonald theory were established by 1970. Since then, there has been a growing interest in reducing the public health burden of mosquito-borne pathogens and an expanding use of models to guide their control. To assess how theory has changed to confront evolving public health challenges, we compiled a bibliography of 325 publications from 1970 through 2010 that included at least one mathematical model of mosquito-borne pathogen transmission and then used a 79-part questionnaire to classify each of 388 associated models according to its biological assumptions. As a composite measure to interpret the multidimensional results of our survey, we assigned a numerical value to each model that measured its similarity to 15 core assumptions of the Ross–Macdonald model. Although the analysis illustrated a growing acknowledgement of geographical, ecological and epidemiological complexities in modelling transmission, most models during the past 40 years closely resemble the Ross–Macdonald model. Modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity and temporal variation in the transmission process.

Community-associated methicillin-resistant Staphylococcus aureus in outpatients, United States, 1999-2006.

These patients likely play a role in transmission of these organisms into hospitals.

The Changing Epidemiology of Methicillin-Resistant Staphylococcus aureus in the United States: A National Observational Study

Methicillin-resistant Staphylococcus aureus (MRSA) can cause major illness and death and impose serious economic costs on patients and hospitals. Community-associated MRSA (CA-MRSA) is a growing problem in US hospitals, which are already dealing with high levels of hospital-associated MRSA (HA-MRSA), but little is known about how patient age and seasonal differences in the incidence of these 2 forms of MRSA affect the epidemic. By using national data on hospitalizations and antibiotic resistance, we estimated the magnitude and trends in annual S. aureus and MRSA hospitalization rates from 2005-2009 by patient age, infection type, and resistance phenotype (CA-MRSA vs. HA-MRSA). Although no statistically significant increase in the hospitalization rate was seen over the study period, the total number of infections increased. In 2009, there were an estimated 463,017 (95% confidence interval: 441,595, 484,439) MRSA-related hospitalizations at a rate of 11.74 (95% confidence interval: 11.20, 12.28) per 1,000 hospitalizations. We observed significant differences in infection type by age, with HA-MRSA-related hospitalizations being more common in older individuals. We also noted significant seasonality in incidence, particularly in children, with CA-MRSA peaking in the late summer and HA-MRSA peaking in the winter, which may be caused by seasonal shifts in antibiotic prescribing patterns.

Seasonality and Temporal Correlation between Community Antibiotic Use and Resistance in the United States

BACKGROUND Therapeutic antibiotic use in humans is a significant driver of antibiotic resistance. The seasonal effect of antibiotic use on antibiotic resistance has been poorly quantified because of lack of large-scale, spatially disaggregated time-series data on antibiotic use and resistance. METHODS We used time-series analysis (Box-Jenkins) on US antibiotic usage from IMS Health and on antibiotic resistance from The Surveillance Network from 1999-2007 to estimate the effect of aminopenicillin, fluoroquinolone, trimethoprim/sulfamethoxazole, and tetracycline usage on resistance of Escherichia coli to drugs within these classes. We also quantified the effect of fluoroquinolone and macrolide/lincosamide usage on resistance of methicillin-resistant Staphylococcus aureus (MRSA) to ciprofloxacin and clindamycin (which has a similar mode of action to macrolides), respectively. RESULTS Prevalence of resistant Escherichia coli was significantly correlated with lagged (by 1 month) antibiotic prescriptions for aminopenicillins (0.22, P = .03) and fluoroquinolones (0.24, P = .02), which are highly prescribed, but was uncorrelated to antibiotic classes with lower prescription levels. Fluoroquinolone prescriptions were also significantly correlated with a 1-month lag with the prevalence of ciprofloxacin-resistant MRSA (0.23, P = .03). CONCLUSIONS Large-scale usage of antibiotics can generate seasonal patterns of resistance that fluctuate on a short time scale with changes in antibiotic retail sales, suggesting that use of antibiotics in the winter could have a significant effect on resistance. In addition, the strong correlation between community use of antibiotics and resistance isolated in the hospital indicates that restrictions imposed at the hospital level are unlikely to be effective unless coordinated with campaigns to reduce unnecessary antibiotic use at the community level.

Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread.

The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread.

Recasting the theory of mosquito-borne pathogen transmission dynamics and control

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world. Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle. That framework, especially Macdonalds formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases. A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross–Macdonald assumption of homogeneous transmission in a well-mixed population. Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory. Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement. Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold. Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

Trends in Resistance to Carbapenems and Third-Generation Cephalosporins among Clinical Isolates of Klebsiella pneumoniae in the United States, 1999–2010

OBJECTIVE Multidrug-resistant Enterobacteriaceae pose a serious infection control challenge and have emerged as a public health threat. We examined national trends in the proportion of Klebsiella pneumoniae isolates resistant to carbapenems (CRKP) and third-generation cephalosporins (G3CRKP). DESIGN AND SETTING Retrospective analysis of approximately 500,000 K. pneumoniae isolates cultured between January 1999 and July 2010 at 287 clinical laboratories throughout the United States. METHODS Isolates were defined as CRKP if they were nonsusceptible to 1 or more carbapenems and were defined as G3CRKP if they were nonsusceptible to ceftazidime, ceftriaxone, or related antibiotics. A multivariable analysis examined trends in the proportion of resistant isolates, adjusting for age, sex, isolate source, patient location, and geographic region. RESULTS The crude proportion of CRKP increased from less than 0.1% to 4.5% between 2002 and 2010; the frequency of G3CRKP increased from 5.3% to 11.5% between 1999 and 2010. G3CRKP and CRKP were more common among elderly patients (those greater than 65 years of age); the adjusted odds ratio (aOR) relative to pediatric patients (those less than 18 years of age) was 1.2 for G3CRKP (95% confidence interval [CI], 1.2-1.3) and 3.3 for CRKP (95% CI, 2.6-4.2). G3CRKP and CRKP were also more common among patients from the northeastern United States (aOR, 2.9 [95% CI, 2.8-3.0] and 9.0 [95% CI, 7.9-10.4]) than among those from the western United States. The prevalence of outpatient CRKP isolates increased after 2006, reaching 1.9% of isolates in our sample in 2010 (95% CI, 1.6%-2.1%). CONCLUSIONS The frequency of G3CRKP and CRKP is increasing in all regions of the United States, and resistance is emerging among isolates recovered in the outpatient setting. This underscores the need for enhanced laboratory capacity and coordinated surveillance strategies to contain the further spread of these emerging pathogens.

Clinically immune hosts as a refuge for drug-sensitive malaria parasites

BackgroundMutations in Plasmodium falciparum that confer resistance to first-line antimalarial drugs have spread throughout the world from a few independent foci, all located in areas that were likely characterized by low or unstable malaria transmission. One of the striking differences between areas of low or unstable malaria transmission and hyperendemic areas is the difference in the size of the population of immune individuals. However, epidemiological models of malaria transmission have generally ignored the role of immune individuals in transmission, assuming that they do not affect the fitness of the parasite. This model reconsiders the role of immunity in the dynamics of malaria transmission and its impact on the evolution of antimalarial drug resistance under the assumption that immune individuals are infectious.MethodsThe model is constructed as a two-stage susceptible-infected-susceptible (SIS) model of malaria transmission that assumes that individuals build up clinical immunity over a period of years. This immunity reduces the frequency and severity of clinical symptoms, and thus their use of drugs. It also reduces an individuals level of infectiousness, but does not impact the likelihood of becoming infected.ResultsSimulations found that with the introduction of resistance into a population, clinical immunity can significantly alter the fitness of the resistant parasite, and thereby impact the ability of the resistant parasite to spread from an initial host by reducing the effective reproductive number of the resistant parasite as transmission intensity increases. At high transmission levels, despite a higher basic reproductive number, R0, the effective reproductive number of the resistant parasite may fall below the reproductive number of the sensitive parasite.ConclusionThese results suggest that high-levels of clinical immunity create a natural ecological refuge for drug-sensitive parasites. This provides an epidemiological rationale for historical patterns of resistance emergence and suggests that future outbreaks of resistance are more likely to occur in low- or unstable-transmission settings. This finding has implications for the design of drug policies and the formulation of malaria control strategies, especially those that lower malaria transmission intensity.

The burden of vancomycin-resistant enterococcal infections in US hospitals, 2003 to 2004 ☆

Despite significant concern in the health care community regarding vancomycin-resistant enterococci (VRE), there are no estimates of the total number of VRE infections that occur each year in US hospitals. Using data from a national survey of hospital discharges and a national antimicrobial resistance surveillance system, we estimated the annual number of US hospitalization with VRE bloodstream, urinary tract, and wound or intra-abdominal infections. Because of the inexact nature of hospital discharge diagnosis coding, we made both a conservative and liberal estimate of hospitalization with VRE infection by using a variety of data sources. For the years 2003 and 2004, we conservatively estimated that there were 20777 and 20931 VRE infections, respectively; for those same years, the liberal estimates were 78330 and 85586, respectively. Because there are such a large number of hospital discharges for which an infection is coded without an organism code, it is likely that the conservative estimate is an underestimate of the true burden. These estimates highlight the importance of controlling VRE and the need to develop improved methods for tracking the burden of such infections.