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author:("oxman, Betsy")
1.  Prevalence of and Risk Factors for Multidrug-Resistant Acinetobacter baumannii Colonization Among High-Risk Nursing Home Residents 
To characterize the epidemiology of multidrug-resistant (MDR) Acinetobacter baumannii colonization in high-risk nursing home (NH) residents.
Nested case-control study within a multicenter prospective intervention trial.
Four NHs in Southeast Michigan.
Case patients and control subjects were NH residents with an indwelling device (urinary catheter and/or feeding tube) selected from the control arm of the Targeted Infection Prevention study. Cases were residents colonized with MDR (resistant to ≥3 classes of antibiotics) A. baumannii; controls were never colonized with MDR A. baumannii.
For active surveillance cultures, specimens from the nares, oropharynx, groin, perianal area, wounds, and device insertion site(s) were collected upon study enrollment, day 14, and monthly thereafter. A. baumannii strains and their susceptibilities were identified using standard microbiologic methods.
Of 168 NH residents, 25 (15%) were colonized with MDR A. baumannii. Compared with the 143 controls, cases were more functionally disabled (Physical Self-Maintenance Score >24; odds ratio, 5.1 [95% CI, 1.8–14.9]; P < .004), colonized with Proteus mirabilis (5.8 [1.9–17.9]; P < .003), and diabetic (3.4 [1.2–9.9]; P < .03). Most cases (22 [88%]) were colonized with multiple antibiotic-resistant organisms and 16 (64%) exhibited co-colonization with at least one other resistant gram-negative bacteria.
Functional disability, P. mirabilis colonization, and diabetes mellitus are important risk factors for colonization with MDR A. baumannii in high-risk NH residents. A. baumannii exhibits widespread antibiotic resistance and a preference to colonize with other antibiotic-resistant organisms, meriting enhanced attention and improved infection control practices in these residents.
PMCID: PMC4626246  PMID: 26072936
2.  Whole-genome sequencing of uropathogenic Escherichia coli reveals long evolutionary history of diversity and virulence 
Uropathogenic Escherichia coli (UPEC) are phenotypically and genotypically very diverse. This diversity makes it challenging to understand the evolution of UPEC adaptations responsible for causing urinary tract infections (UTI). To gain insight into the relationship between evolutionary divergence and adaptive paths to uropathogenicity, we sequenced at deep coverage (190×) the genomes of 19 E. coli strains from urinary tract infection patients from the same geographic area. Our sample consisted of 14 UPEC isolates and 5 non-UTI-causing (commensal) rectal E. coli isolates. After identifying strain variants using de novo assembly-based methods, we clustered the strains based on pairwise sequence differences using a neighbor-joining algorithm. We examined evolutionary signals on the whole-genome phylogeny and contrasted these signals with those found on gene trees constructed based on specific uropathogenic virulence factors.
The whole-genome phylogeny showed that the divergence between UPEC and commensal E. coli strains without known UPEC virulence factors happened over 32 million generations ago. Pairwise diversity between any two strains was also high, suggesting multiple genetic origins of uropathogenic strains in a small geographic region. Constrasting the whole-genome phylogeny with three gene trees constructed from common uropathogenic virulence factors, we detected no selective advantage of these virulence genes over other genomic regions. These results suggest that UPEC acquired uropathogenicity long time ago and used it opportunistically to cause extraintestinal infections.
PMCID: PMC4530057  PMID: 26112070
uropathogen; next-generation sequencing; phylogeny
3.  Cranberry juice capsules and urinary tract infection post surgery: Results of a randomized trial 
The risk of urinary tract infection (UTI) among women undergoing elective gynecologic surgery where a catheter is placed is high: 10 to 64% following catheter removal. We conducted the first randomized, double-blind, placebo-controlled trial of the therapeutic efficacy of cranberry juice capsules in preventing UTI post surgery.
Study Design
We recruited patients from a single hospital between August 2011 and January 2013. Eligible participants were undergoing elective gynecologic surgery that did not involve a fistula repair or vaginal mesh removal. 160 patients were randomized and received two cranberry juice capsules two times a day, equivalent to two 8-ounce servings of cranberry juice, for 6 weeks after surgery, or matching placebo. The primary endpoint was the proportion of participants who experienced clinically-diagnosed and treated UTI with or without positive urine culture. Kaplan-Meier plots and logrank tests compared the two treatment groups.
The occurrence of UTI was significantly lower in the cranberry treatment group compared to the placebo group (15/80 (19%) versus 30/80 (38%); OR=0.38; 95% CI: 0.19, 0.79; p=0.008). After adjustment for known confounders, including frequency of intermittent self-catheterization in the post- operative period, the protective effects of cranberry remained (OR=0.42; 95% CI: 0.18, 0.94). There were no treatment differences in the incidence of adverse events; including gastrointestinal upset (56% vs. 61% for cranberry vs. placebo).
Among women undergoing elective benign gynecologic surgery involving urinary catheterization, use of cranberry extract tablets during the postoperative period reduced the rate of UTI by half.
PMCID: PMC4519382  PMID: 25882919
catheter associated urinary tract infection; cranberry extract; clinical trial
4.  Use of the Microbiome in the Practice of Epidemiology: A Primer on -Omic Technologies 
The term microbiome refers to the collective genome of the microbes living in and on our bodies, but it has colloquially come to mean the bacteria, viruses, archaea, and fungi that make up the microbiota (previously known as microflora). We can identify the microbes present in the human body (membership) and their relative abundance using genomics, characterize their genetic potential (or gene pool) using metagenomics, and describe their ongoing functions using transcriptomics, proteomics, and metabolomics. Epidemiologists can make a major contribution to this emerging field by performing well-designed, well-conducted, and appropriately powered studies and by including measures of microbiota in current and future cohort studies to characterize natural variation in microbiota composition and function, identify important confounders and effect modifiers, and generate and test hypotheses about the role of microbiota in health and disease. In this review, we provide an overview of the rapidly growing literature on the microbiome, describe which aspects of the microbiome can be measured and how, and discuss the challenges of including the microbiome as either an exposure or an outcome in epidemiologic studies.
PMCID: PMC4498138  PMID: 26025238
bioinformatics; diversity; genomics; microbiome; microbiota
5.  Effects of Selection Pressure and Genetic Association on the Relationship between Antibiotic Resistance and Virulence in Escherichia coli 
Antimicrobial Agents and Chemotherapy  2015;59(11):6733-6740.
Antibiotic selection pressure and genetic associations may lead to the cooccurrence of resistance and virulence in individual pathogens. However, there is a lack of rigorous epidemiological evidence that demonstrates the cooccurrence of resistance and virulence at the population level. Using samples from a population-based case-control study in 25 villages in rural Ecuador, we characterized resistance to 12 antibiotics among pathogenic (n = 86) and commensal (n = 761) Escherichia coli isolates, classified by the presence or absence of known diarrheagenic virulence factor genes. The prevalences of resistance to single and multiple antibiotics were significantly higher for pathogenic isolates than for commensal isolates. Using a generalized estimating equation, antibiotic resistance was independently associated with virulence factor carriage, case status, and antibiotic use (for these respective factors: odds ratio [OR] = 3.0, with a 95% confidence interval [CI] of 1.7 to 5.1; OR = 2.0, with a 95% CI of 1.3 to 3.0; and OR = 1.5, with a 95% CI of 0.9 to 2.5). Virulence factor carriage was more strongly related to antibiotic resistance than antibiotic use for all antibiotics examined, with the exception of fluoroquinolones, gentamicin, and cefotaxime. This study provides epidemiological evidence that antibiotic resistance and virulence factor carriage are linked in E. coli populations in a community setting. Further, these data suggest that while the cooccurrence of resistance and virulence in E. coli is partially due to antibiotic selection pressure, it is also genetically determined. These findings should be considered in developing strategies for treating infections and controlling for antibiotic resistance.
PMCID: PMC4604409  PMID: 26282415
6.  Antibiotic Resistance in Animal and Environmental Samples Associated with Small-Scale Poultry Farming in Northwestern Ecuador 
mSphere  2016;1(1):e00021-15.
In developing countries, small-scale poultry farming employing antibiotics as growth promoters is being advanced as an inexpensive source of protein and income. Here, we present the results of a large ecoepidemiological study examining patterns of antibiotic resistance (AR) in E. coli isolates from small-scale poultry production environments versus domestic environments in rural Ecuador, where such backyard poultry operations have become established over the past decade. Our previous research in the region suggests that introduction of AR bacteria through travel and commerce may be an important source of AR in villages of this region. This report extends the prior analysis by examining small-scale production chicken farming as a potential source of resistant strains. Our results suggest that AR strains associated with poultry production likely originate from sources outside the study area and that these outside sources might be a better place to target control efforts than local management practices.
The effects of animal agriculture on the spread of antibiotic resistance (AR) are cross-cutting and thus require a multidisciplinary perspective. Here we use ecological, epidemiological, and ethnographic methods to examine populations of Escherichia coli circulating in the production poultry farming environment versus the domestic environment in rural Ecuador, where small-scale poultry production employing nontherapeutic antibiotics is increasingly common. We sampled 262 “production birds” (commercially raised broiler chickens and laying hens) and 455 “household birds” (raised for domestic use) and household and coop environmental samples from 17 villages between 2010 and 2013. We analyzed data on zones of inhibition from Kirby-Bauer tests, rather than established clinical breakpoints for AR, to distinguish between populations of organisms. We saw significantly higher levels of AR in bacteria from production versus household birds; resistance to either amoxicillin-clavulanate, cephalothin, cefotaxime, and gentamicin was found in 52.8% of production bird isolates and 16% of household ones. A strain jointly resistant to the 4 drugs was exclusive to a subset of isolates from production birds (7.6%) and coop surfaces (6.5%) and was associated with a particular purchase site. The prevalence of AR in production birds declined with bird age (P < 0.01 for all antibiotics tested except tetracycline, sulfisoxazole, and trimethoprim-sulfamethoxazole). Farming status did not impact AR in domestic environments at the household or village level. Our results suggest that AR associated with small-scale poultry farming is present in the immediate production environment and likely originates from sources outside the study area. These outside sources might be a better place to target control efforts than local management practices.
IMPORTANCE In developing countries, small-scale poultry farming employing antibiotics as growth promoters is being advanced as an inexpensive source of protein and income. Here, we present the results of a large ecoepidemiological study examining patterns of antibiotic resistance (AR) in E. coli isolates from small-scale poultry production environments versus domestic environments in rural Ecuador, where such backyard poultry operations have become established over the past decade. Our previous research in the region suggests that introduction of AR bacteria through travel and commerce may be an important source of AR in villages of this region. This report extends the prior analysis by examining small-scale production chicken farming as a potential source of resistant strains. Our results suggest that AR strains associated with poultry production likely originate from sources outside the study area and that these outside sources might be a better place to target control efforts than local management practices.
PMCID: PMC4863614  PMID: 27303705
antibiotic resistance; epidemiology; microbial ecology
7.  The role of respiratory viruses in the etiology of bacterial pneumonia 
Pneumonia is the leading cause of death among children less than 5 years old worldwide. A wide range of viral, bacterial and fungal agents can cause pneumonia: although viruses are the most common etiologic agent, the severity of clinical symptoms associated with bacterial pneumonia and increasing antibiotic resistance makes bacterial pneumonia a major public health concern. Bacterial pneumonia can follow upper respiratory viral infection and complicate lower respiratory viral infection. Secondary bacterial pneumonia is a major cause of influenza-related deaths. In this review, we evaluate the following hypotheses: (i) respiratory viruses influence the etiology of pneumonia by altering bacterial community structure in the upper respiratory tract (URT) and (ii) respiratory viruses promote or inhibit colonization of the lower respiratory tract (LRT) by certain bacterial species residing in the URT. We conducted a systematic review of the literature to examine temporal associations between respiratory viruses and bacteria and a targeted review to identify potential mechanisms of interactions. We conclude that viruses both alter the bacterial community in the URT and promote bacterial colonization of the LRT. However, it is uncertain whether changes in the URT bacterial community play a substantial role in pneumonia etiology. The exception is Streptococcus pneumoniae where a strong link between viral co-infection, increased carriage and pneumococcal pneumonia has been established.
PMCID: PMC4801059  PMID: 26884414
co-infection; ecology; pneumonia; influenza; Streptococcus pneumoniae
8.  The role of influenza in the epidemiology of pneumonia 
Scientific Reports  2015;5:15314.
Interactions arising from sequential viral and bacterial infections play important roles in the epidemiological outcome of many respiratory pathogens. Influenza virus has been implicated in the pathogenesis of several respiratory bacterial pathogens commonly associated with pneumonia. Though clinical evidence supporting this interaction is unambiguous, its population-level effects—magnitude, epidemiological impact and variation during pandemic and seasonal outbreaks—remain unclear. To address these unknowns, we used longitudinal influenza and pneumonia incidence data, at different spatial resolutions and across different epidemiological periods, to infer the nature, timing and the intensity of influenza-pneumonia interaction. We used a mechanistic transmission model within a likelihood-based inference framework to carry out formal hypothesis testing. Irrespective of the source of data examined, we found that influenza infection increases the risk of pneumonia by ~100-fold. We found no support for enhanced transmission or severity impact of the interaction. For model-validation, we challenged our fitted model to make out-of-sample pneumonia predictions during pandemic and non-pandemic periods. The consistency in our inference tests carried out on several distinct datasets, and the predictive skill of our model increase confidence in our overall conclusion that influenza infection substantially enhances the risk of pneumonia, though only for a short period.
PMCID: PMC4614252  PMID: 26486591
9.  Oral Health in a Sample of Pregnant Women from Northern Appalachia (2011–2015) 
Background. Chronic poor oral health has a high prevalence in Appalachia, a large region in the eastern USA. The Center for Oral Health Research in Appalachia (COHRA) has been enrolling pregnant women and their babies since 2011 in the COHRA2 study of genetic, microbial, and environmental factors involved in oral health in Northern Appalachia. Methods. The COHRA2 protocol is presented in detail, including inclusion criteria (healthy, adult, pregnant, US Caucasian, English speaking, and nonimmunocompromised women), recruiting (two sites: Pittsburgh, Pennsylvania, and West Virginia, USA), assessments (demographic, medical, dental, psychosocial/behavioral, and oral microbial samples and DNA), timelines (longitudinal from pregnancy to young childhood), quality control, and retention rates. Results. Preliminary oral health and demographic data are presented in 727 pregnant women, half from the greater Pittsburgh region and half from West Virginia. Despite similar tooth brushing and flossing habits, COHRA2 women in West Virginia have significantly worse oral health than the Pittsburgh sample. Women from Pittsburgh are older and more educated and have less unemployment than the West Virginia sample. Conclusions. We observed different prevalence of oral health and demographic variables between pregnant women from West Virginia (primarily rural) and Pittsburgh (primarily urban). These observations suggest site-specific differences within Northern Appalachia that warrant future studies.
PMCID: PMC4451284  PMID: 26089906
10.  L-Arginine Destabilizes Oral Multi-Species Biofilm Communities Developed in Human Saliva 
PLoS ONE  2015;10(5):e0121835.
The amino acid L-arginine inhibits bacterial coaggregation, is involved in cell-cell signaling, and alters bacterial metabolism in a broad range of species present in the human oral cavity. Given the range of effects of L-arginine on bacteria, we hypothesized that L-arginine might alter multi-species oral biofilm development and cause developed multi-species biofilms to disassemble. Because of these potential biofilm-destabilizing effects, we also hypothesized that L-arginine might enhance the efficacy of antimicrobials that normally cannot rapidly penetrate biofilms. A static microplate biofilm system and a controlled-flow microfluidic system were used to develop multi-species oral biofilms derived from pooled unfiltered cell-containing saliva (CCS) in pooled filter-sterilized cell-free saliva (CFS) at 37oC. The addition of pH neutral L-arginine monohydrochloride (LAHCl) to CFS was found to exert negligible antimicrobial effects but significantly altered biofilm architecture in a concentration-dependent manner. Under controlled flow, the biovolume of biofilms (μm3/μm2) developed in saliva containing 100-500 mM LAHCl were up to two orders of magnitude less than when developed without LAHCI. Culture-independent community analysis demonstrated that 500 mM LAHCl substantially altered biofilm species composition: the proportion of Streptococcus and Veillonella species increased and the proportion of Gram-negative bacteria such as Neisseria and Aggregatibacter species was reduced. Adding LAHCl to pre-formed biofilms also reduced biovolume, presumably by altering cell-cell interactions and causing cell detachment. Furthermore, supplementing 0.01% cetylpyridinium chloride (CPC), an antimicrobial commonly used for the treatment of dental plaque, with 500 mM LAHCl resulted in greater penetration of CPC into the biofilms and significantly greater killing compared to a non-supplemented 0.01% CPC solution. Collectively, this work demonstrates that LAHCl moderates multi-species oral biofilm development and community composition and enhances the activity of CPC. The incorporation of LAHCl into oral healthcare products may be useful for enhanced biofilm control.
PMCID: PMC4422691  PMID: 25946040
11.  Selected Vaginal Bacteria and Risk of Preterm Birth: An Ecological Perspective 
The Journal of Infectious Diseases  2013;209(7):1087-1094.
We examined the community ecology of vaginal microbial samples taken from pregnant women with previous preterm birth experience to investigate whether targeted pathogenic and commensal bacteria are related to risk of preterm birth in the current pregnancy. We found a significant correlation between the community structure of selected bacteria and birth outcome, but the correlation differed among self-reported racial/ethnic groups. Using a community ordination analysis, we observed infrequent co-occurrence of Mycoplasma and bacteria vaginosis associated bacteria 3 (BVAB3) among black and Hispanic participants. In addition, we found that the vaginal bacteria responded differently in different racial/ethnic groups to modifications of maternal behavioral (ie, douching and smoking) and biological traits (ie, body mass index [BMI]). Even after accounting for these maternal behaviors and traits, the selected vaginal bacteria was significantly associated with preterm birth among black and Hispanic participants. By contrast, white participants did not exhibit significant correlation between microbial community and birth outcome. Findings from this study affirm the necessity of considering women's race/ethnicity when evaluating the correlation between vaginal bacteria and preterm birth. The study also illustrates the importance of studying the vaginal microbiota from an ecological perspective, and demonstrates the power of ecological community analysis to improve understanding of infectious disease.
PMCID: PMC3952673  PMID: 24273044
preterm birth; vaginal; microbial community; community analysis
12.  Association of blaOXA-23 and bap with the persistence of Acinetobacter baumannii within a major healthcare system 
Objectives: Acinetobacter baumannii is an emerging opportunistic nosocomial pathogen. Two factors that may enhance persistence in healthcare settings are antimicrobial resistance and biofilm-forming ability. The aim of this work was to determine whether A. baumannii isolates that persist in healthcare settings (endemic), can be differentiated from sporadic isolates based upon their ability to resist antibiotics and their biofilm-forming capability.
Methods: Two hundred and ninety A. baumannii isolates were isolated over 17 months in the Detroit Medical Center (DMC). The isolates were genotyped using repetitive extragenic palindromic-PCR (REP-PCR). REP-types appearing greater than 10 times during active surveillance were considered endemic. The in vitro biofilm-forming ability and antibiotic resistance profile of each isolate were evaluated. Isolates were tested for the presence of two genetic markers—one implicated in biofilm formation (bap) and the other in antibiotic resistance (blaOXA-23).
Results: Of the 290 isolates evaluated, 84% carried bap and 36% carried blaOXA-23. Five unique REP-PCR banding-types were detected >10 times (endemic) and constituted 58% of the 290 isolates. These five endemic REP-PCR types were 5.1 times more likely than sporadic isolates to carry both bap and blaOXA-23. Furthermore, endemic isolates were resistant to 3 more antibiotic classes, on average, than sporadic isolates and four of the five endemic REP-PCR types formed denser biofilms in vitro than sporadic isolates.
Conclusions: Endemic A. baumannii isolates are more likely than sporadic isolates to possess factors that increase virulence and enhance survival within a large healthcare system.
PMCID: PMC4357298  PMID: 25814985
molecular epidemiology; REP-PCR; bap; OXA-23; antibiotic resistance; biofilms
13.  Exploring The Effect Of Dentition, Dental Decay and Familiality On Oral Health Using Metabolomics 
As a proof of principle, we used an untargeted global metabolic profiling of saliva to understand the biochemical processes associated with dental decay, dentition (primary and secondary tooth eruption) and familiality in a sample of 25 sibling pairs. Pairs were selected to represent four different combinations of dentition and tooth health: 1) both siblings with primary teeth and no decay (n=5); 2) both siblings with primary teeth and discordant for dental decay (n=6); 3) both siblings with primary teeth and dental decay (n=4); and 4) one sibling with primary teeth the other with mixed dentition and both with no dental decay (n=10). There was a strong effect of sibship on the metabolite profiles identified; this may reflect the effects of common genes, environment and behaviors, and shared oral microbial communities. Nested in the familial effects were associations of metabolite profile with dentition and with dental decay. Using three different analyses (Euclidean distance, hierarchical clustering and PCA using selected biochemicals) metabolite profiles of saliva from children with decayed teeth were more similar than the metabolite profiles of saliva from children with healthy (sound) teeth. Larger studies that include host behaviors, environmental factors, oral microbiota composition and structure, and host genetic predisposition are required to identify biomarkers for decay, and to estimate the relative contribution of host factors and oral microbes on risk of dental decay.
PMCID: PMC3943654  PMID: 24080168
metabolomics; dental caries; familiality
14.  Mycoplasma, Bacterial Vaginosis Associated Bacteria BVAB3, Race, and Risk of Preterm Birth in a High Risk Cohort 
Genital tract infection accounts for ~ 25–40% of all pre-term births. We sought to assess the relationship between preterm birth and selected vaginal bacterial taxa associated with preterm birth either directly or through their association with bacterial vaginosis (BV).
Vaginal fluid for Gram stain was collected between 17 and 22 weeks gestation as part of a randomized trial of ultrasound-indicated cerclage for preterm birth prevention in women at high risk for recurrent spontaneous preterm birth. Bacterial DNA was extracted from the Gram stain slides and analyzed using quantitative PCR.
Among the 499 participants, Mycoplasma was positively correlated with increased risk of preterm (RR = 1.83; 95% CI: 1.52,2.22) as was Mobiluncus (RR=1.36; 95% CI: 1.07, 1.73) and Atopobium (RR=1.44; 95% CI: 1.1, 1.87). However, there were strong interactions between race/ethnic group and the presence of these and other individual taxa on risk of preterm birth. By contrast, BVAB3 was consistently associated with a reduction in risk of preterm birth for all racial/ethnic groups (0.55; 95%CI: 0.39, 0.78).
BV is characterized by a reduction of Lactobacillus, and lactic acid producing bacteria and the presence of Mobiluncus; we found these factors and presence of Mycoplasma to be associated with increased risk of preterm birth. By contrast, the presence of a recently identified organism sufficient to cause BV, BVAB3, decreased risk of preterm birth. These findings give insight into why treating BV has mixed impact on risk of preterm birth.
PMCID: PMC3943817  PMID: 24096128
16.  Efflux-mediated resistance identified among norfloxacin resistant clinical strains of group B Streptococcus from South Korea 
Epidemiology and Health  2014;36:e2014022.
Group B Streptococcus (GBS), a common bowel commensal, is a major cause of neonatal sepsis and an emerging cause of infection in immune-compromised adult populations. Fluoroquinolones are used to treat GBS infections in those allergic to beta-lactams, but GBS are increasingly resistant to fluoroquinolones. Fluoroquinolone resistance has been previously attributed to quinolone resistance determining regions (QRDRs) mutations. We demonstrate that some of fluoroquinolone resistance is due to efflux-mediated resistance.
We tested 20 GBS strains resistant only to norfloxacin with no mutations in the QRDRs, for the efflux phenotype using norfloxacin and ethidium bromide as substrates in the presence of the efflux inhibitor reserpine. Also tested were 68 GBS strains resistant only to norfloxacin not screened for QRDRs, and 58 GBS strains resistant to ciprofloxacin, levofloxacin or moxifloxacin. Isolates were randomly selected from 221 pregnant women (35-37 weeks of gestation) asymptomatically carrying GBS, and 838 patients with GBS infection identified in South Korea between 2006 and 2008. The VITEK II automatic system (Biomerieux, Durham, NC, USA) was used to determine fluoroquinolone resistance.
The reserpine associated efflux phenotype was found in more than half of GBS strains resistant only to norfloxacin with no QRDR mutations, and half where QRDR mutations were unknown. No evidence of the efflux phenotype was detected in GBS strains that were resistant to moxifloxacin or levofloxacin or both. The reserpine sensitive efflux phenotype resulted in moderate increases in norfloxacin minimum inhibitory concentration (average=3.6 fold, range=>1-16 fold).
A substantial portion of GBS strains resistant to norfloxacin have an efflux phenotype.
PMCID: PMC4258715  PMID: 25322878
Fluoroquinolones; Norfloxacin; Ciprofloxacin; Levofloxacin; Moxifloxacin; Mutations; Efflux; Minimum inhibitory concentration
17.  Identifying the interaction between influenza and pneumococcal pneumonia using incidence data 
Science translational medicine  2013;5(191):191ra84.
The association between influenza virus and the bacterium Streptococcus pneumoniae (pneumococcus) has been proposed as a polymicrobial system, whereby transmission and pathogenicity of one pathogen (bacterium) are affected by interactions with the other (virus). However, studies focusing on different scales of resolution have painted an inconsistent picture: individual-scale animal experiments have unequivocally demonstrated an association, while epidemiological support in human populations is, at best, inconclusive. Here, we integrate weekly incidence reports and a mechanistic transmission model within a likelihood-based inference framework to characterize the nature, timing and magnitude of this interaction. We find support for a strong but short-lived interaction, with influenza infection increasing susceptibility to pneumococcal pneumonia ~100-fold. We infer modest population-level impacts arising from strong processes at the level of an individual, thereby resolving the dichotomy in seemingly inconsistent observations across scales. An accurate characterization of the influenza-pneumococcal interaction can form a basis for more effective clinical care and public health measures for pneumococcal pneumonia.
PMCID: PMC4178309  PMID: 23803706
18.  Time and dose-dependent risk of pneumococcal pneumonia following influenza: a model for within-host interaction between influenza and Streptococcus pneumoniae 
A significant fraction of seasonal and in particular pandemic influenza deaths are attributed to secondary bacterial infections. In animal models, influenza virus predisposes hosts to severe infection with both Streptococcus pneumoniae and Staphylococcus aureus. Despite its importance, the mechanistic nature of the interaction between influenza and pneumococci, its dependence on the timing and sequence of infections as well as the clinical and epidemiological consequences remain unclear. We explore an immune-mediated model of the viral–bacterial interaction that quantifies the timing and the intensity of the interaction. Taking advantage of the wealth of knowledge gained from animal models, and the quantitative understanding of the kinetics of pathogen-specific immunological dynamics, we formulate a mathematical model for immune-mediated interaction between influenza virus and S. pneumoniae in the lungs. We use the model to examine the pathogenic effect of inoculum size and timing of pneumococcal invasion relative to influenza infection, as well as the efficacy of antivirals in preventing severe pneumococcal disease. We find that our model is able to capture the key features of the interaction observed in animal experiments. The model predicts that introduction of pneumococcal bacteria during a 4–6 day window following influenza infection results in invasive pneumonia at significantly lower inoculum size than in hosts not infected with influenza. Furthermore, we find that antiviral treatment administered later than 4 days after influenza infection was not able to prevent invasive pneumococcal disease. This work provides a quantitative framework to study interactions between influenza and pneumococci and has the potential to accurately quantify the interactions. Such quantitative understanding can form a basis for effective clinical care, public health policies and pandemic preparedness.
PMCID: PMC3730679  PMID: 23825111
influenza–pneumococcal interaction; within-host model; influenza; pneumococcus; mathematical model
19.  Vaginal and Oral Microbes, Host Genotype and Preterm Birth 
Medical hypotheses  2009;73(6):963-975.
Preterm birth (PTB) is a leading cause of infant mortality and morbidity in the U.S. and across the globe. Infection and associated inflammation are important initiators for PTB pathways; an estimated 40% of PTBs are attributed to amniochorionic-decidual or systemic inflammation. Historically, intrauterine infections have been implicated in PTB; recent evidence suggests that infections remote from the fetal site may also be causative. There is strong epidemiological evidence that bacterial vaginosis and periodontitis -- two syndromes characterized by perturbations in the normal vaginal and oral bacterial microflora respectively-- are linked to infection-associated PTB. Oral and vaginal environments are similar in their bacterial microbiology; identical bacterial species have been independently isolated in periodontitis and bacterial vaginosis. Periodontitis and bacterial vaginosis also share many behavioral and sociodemographic risk factors suggesting a possible common pathophysiology. Genetic polymorphisms in host inflammatory responses to infection are shared between bacterial vaginosis, periodontitis and PTB, suggesting common mechanisms through which host genotype modify the effect of abnormal bacterial colonization on preterm birth. We review the state of knowledge regarding the risk of PTB attributable to perturbations in bacterial flora in oral and vaginal sites and the role of host genetics in modifying the risk of infection-related PTB. We posit that bacterial species that are common in perturbed vaginal and oral sites are associated with PTB through their interaction with the host immune system.
PMCID: PMC4026093  PMID: 19942083
Prematurity; infection; genotype
20.  Alternative Approaches to Conventional Treatment of Acute Uncomplicated Urinary Tract Infection in Women 
The increasing resistance of uropathogens to antibiotics, and recognition of generally self-limiting nature of uncomplicated urinary tract infection (UTI) suggests that it is time to reconsider empirical treatment of UTI using antibiotics. Identifying new and effective strategies to prevent recurrences and alterative treatment strategies are a high priority. We review the recent literature regarding the effects of functional food products, probiotics, vaccines, and alternative treatments on treating and preventing UTI.
PMCID: PMC3622145  PMID: 23378124
functional foods; probiotics; vaccines; anti-inflammatories
21.  Healthcare Workers’ Hand Microbiome May Mediate Carriage of Hospital Pathogens 
Pathogens  2013;3(1):1-13.
One function of skin microbiota is to resist colonization and infection by external microorganisms. We sought to detect whether the structure of the hand microbiota of 34 healthcare workers (HCW) in a surgical intensive care unit mediates or modifies the relationship between demographic and behavioral factors and potential pathogen carriage on hands after accounting for pathogen exposure. We used a taxonomic screen (16S rRNA) to characterize the bacterial community, and qPCR to detect presence of Staphylococcus aureus, Enterococcus spp., methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans on their dominant hands. Hands were sampled weekly over a 3-week period. Age, hand hygiene, and work shift were significantly associated with potential pathogen carriage and the associations were pathogen dependent. Additionally, the overall hand microbiota structure was associated with the carriage of potential pathogens. Hand microbiota community structure may act as a biomarker of pathogen carriage, and modifying that structure may potentially limit pathogen carriage among HCW.
PMCID: PMC4235731  PMID: 25437604
skin; hand; microbiome; microbiota; hand hygiene; healthcare; pathogen
22.  Impact of Technical Sources of Variation on the Hand Microbiome Dynamics of Healthcare Workers 
PLoS ONE  2014;9(2):e88999.
We assessed the dynamics of hand microbial community structure of 34 healthcare workers from a single surgical intensive care unit over a short (3 week) time period, whilst taking into account the technical sources of variability introduced by specimen collection, DNA extraction, and sequencing. Sample collection took place at 3 different time points. Only the sampling collection method appeared to have a significant impact on the observed hand microbial community structure among the healthcare workers. Analysis of samples collected using glove-juice showed a slightly more similar microbial composition within individual hand samples over time than between the hands of different individuals over time. This was not true for samples collected using a swab, where samples from a single individual were no more similar to each other over time than those among other individuals over time, suggesting they were essentially independent. DNA extraction techniques (lysozyme only versus enzyme cocktail) and sequencing (replicate set 1 versus 2) using Ion Torrent Personal Genome Machine, were not influential to the microbial community structures. Glove-juice sample collection may likely be the method of choice in hand hygiene studies in the healthcare setting.
PMCID: PMC3925205  PMID: 24551205
23.  Implications of the Human Microbiome Project for Epidemiology 
American Journal of Epidemiology  2013;177(3):197-201.
The structure and function of microorganisms that live in and on us, the human microbiota, are a tremendous resource. Microbiota may help to explain individual variability in health outcomes and be a source of new biomarkers for environmental exposures and of novel prognostic and diagnostic indicators. The increase in availability of low-cost, high-throughput techniques makes it relatively straightforward to include microbiota assessments in epidemiologic studies. With the recent joint publications of the findings of the Human Microbiome Consortium and related studies, the consequent surge of interest in microbiome research, and remarkable media attention, the time is ripe for epidemiologists to contribute their expertise to and translate results of microbiota research for population health.
PMCID: PMC3626050  PMID: 23296358
Human Microbiome Project; microbiome; microbiota
24.  Risk Factors Associated with Group B Streptococcus Resistant to Clindamycin and Erythromycin in Pregnant Korean Women 
Infection & Chemotherapy  2013;45(3):299-307.
The prevalence of group B streptococcus (GBS) among pregnant women and neonates in the Republic of Korea has increased. In addition, rates of resistance to antibiotics recommended for pregnant women allergic to penicillin, such as clindamycin and erythromycin, have increased. The aim of this study was to evaluate subject characteristics associated with GBS resistance to clindamycin and erythromycin.
Materials and Methods
A total of 418 clinical isolates from pregnant women in Korea were screened for antibiotic resistance from January 2006 to December 2011. Sociodemographic information, medical and obstetric history, and details of events during the previous 2 weeks were recorded using a standardized questionnaire.
The resistance rates were 39.5% for clindamycin and 23.0% for erythromycin. In multiple logistic regression analysis, the subject characteristic significantly associated with resistance to both antibiotics was a history of symptomatic sore throat in the 2 weeks before obtaining the specimen (erythromycin: odds ratio [OR]: 2.13, 95% confidence interval [CI]: 1.10 to 4.13; clindamycin: OR: 2.31, 95% CI: 1.21, 4.42). Premature rupture of membranes (PROM) had an association of borderline significance.
In the urgent treatment of GBS-colonized pregnant women, the subject's history of previous sore throat and PROM should be considered when choosing appropriate antibiotics.
PMCID: PMC3848523  PMID: 24396631
Antibiotic resistance; Clindamycin; Erythromycin; Risk factors; Streptococcus agalactiae

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