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1.  Niche Partitioning of Feather Mites within a Seabird Host, Calonectris borealis 
PLoS ONE  2015;10(12):e0144728.
According to classic niche theory, species can coexist in heterogeneous environments by reducing interspecific competition via niche partitioning, e.g. trophic or spatial partitioning. However, support for the role of competition on niche partitioning remains controversial. Here, we tested for spatial and trophic partitioning in feather mites, a diverse and abundant group of arthropods. We focused on the two dominant mite species, Microspalax brevipes and Zachvatkinia ovata, inhabiting flight feathers of the Cory’s shearwater, Calonectris borealis. We performed mite counts across and within primary and tail feathers on free-living shearwaters breeding on an oceanic island (Gran Canaria, Canary Islands). We then investigated trophic relationships between the two mite species and the host using stable isotope analyses of carbon and nitrogen on mite tissues and potential host food sources. The distribution of the two mite species showed clear spatial segregation among feathers; M. brevipes showed high preference for the central wing primary feathers, whereas Z. ovata was restricted to the two outermost primaries. Morphological differences between M. brevipes and Z. ovata support an adaptive basis for the spatial segregation of the two mite species. However, the two mites overlap in some central primaries and statistical modeling showed that Z. ovata tends to outcompete M. brevipes. Isotopic analyses indicated similar isotopic values for the two mite species and a strong correlation in carbon signatures between mites inhabiting the same individual host suggesting that diet is mainly based on shared host-associated resources. Among the four candidate tissues examined (blood, feather remains, skin remains and preen gland oil), we conclude that the diet is most likely dominated by preen gland oil, while the contribution of exogenous material to mite diets is less marked. Our results indicate that ongoing competition for space and resources plays a central role in structuring feather mite communities. They also illustrate that symbiotic infracommunities are excellent model systems to study trophic ecology, and can improve our understanding of mechanisms of niche differentiation and species coexistence.
PMCID: PMC4682861  PMID: 26650672
2.  Reliability of molecular host-identification methods for ticks: an experimental in vitro study with Ixodes ricinus 
Parasites & Vectors  2015;8:433.
Reliable information on host use by arthropod vectors is required to study pathogen transmission ecology and to predict disease risk. Direct observation of host use is often difficult or impossible and indirect methods are therefore necessary. However, the reliability of currently available methods to identify the last host of blood-feeding arthropods has not been evaluated, and may be particularly problematic for ticks because host blood has been digested at capture. Biases in host detection may lead to erroneous conclusions on both vector ecology and pathogen circulation.
Here, we experimentally tested for biases in host detection using the generalist three-host tick Ixodes ricinus as a model system. We fed ticks using an artificial feeding system and amplified blood meal traces post-moult (i.e., in the succeeding unfed life stage) via both a quantitative real-time polymerase chain reaction assay and a reverse line blotting method. We then experimentally tested for three types of biases in host detection: 1) time post-moult, 2) tick life stage and 3) host type (non-nucleated mammal blood versus nucleated avian blood), and compared these biases between the two molecular methods.
Our results show that all three factors can influence host detection in ticks but not necessarily in the expected way. Although host detection rates decreased with time post-moult, mammal blood tended to be more readily detected than bird blood. Tick life stage was also an important factor; detection was higher in nymphs than in adults and, in some cases, remnants from both larval and nymphal blood meals could be detected in the adult stage. These biases were similar for the two detection techniques.
We show that different factors associated with questing ticks may influence our ability to correctly infer previous host use and that these factors may bias inferences from field-based studies. As these biases may be common to other vector-borne disease systems, their implications for our understanding of vector ecology and disease transmission require more explicit consideration.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-015-1043-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4546307  PMID: 26296344
Host identification; Hematophagous arthropods; Ixodidae; Molecular methods; Detection biases; Vector-borne diseases
3.  The Recent Evolution of a Maternally-Inherited Endosymbiont of Ticks Led to the Emergence of the Q Fever Pathogen, Coxiella burnetii 
PLoS Pathogens  2015;11(5):e1004892.
Q fever is a highly infectious disease with a worldwide distribution. Its causative agent, the intracellular bacterium Coxiella burnetii, infects a variety of vertebrate species, including humans. Its evolutionary origin remains almost entirely unknown and uncertainty persists regarding the identity and lifestyle of its ancestors. A few tick species were recently found to harbor maternally-inherited Coxiella-like organisms engaged in symbiotic interactions, but their relationships to the Q fever pathogen remain unclear. Here, we extensively sampled ticks, identifying new and atypical Coxiella strains from 40 of 58 examined species, and used this data to infer the evolutionary processes leading to the emergence of C. burnetii. Phylogenetic analyses of multi-locus typing and whole-genome sequencing data revealed that Coxiella-like organisms represent an ancient and monophyletic group allied to ticks. Remarkably, all known C. burnetii strains originate within this group and are the descendants of a Coxiella-like progenitor hosted by ticks. Using both colony-reared and field-collected gravid females, we further establish the presence of highly efficient maternal transmission of these Coxiella-like organisms in four examined tick species, a pattern coherent with an endosymbiotic lifestyle. Our laboratory culture assays also showed that these Coxiella-like organisms were not amenable to culture in the vertebrate cell environment, suggesting different metabolic requirements compared to C. burnetii. Altogether, this corpus of data demonstrates that C. burnetii recently evolved from an inherited symbiont of ticks which succeeded in infecting vertebrate cells, likely by the acquisition of novel virulence factors.
Author Summary
How virulent infectious diseases emerge from non-pathogenic organisms is a challenging question. Here, we address this evolutionary issue in the case of Q fever. Its causative agent, the intracellular bacterium Coxiella burnetii, is extremely infectious to humans and a variety of animals. However, uncertainty persists regarding its evolutionary origin, including the identity and lifestyle of its ancestors. In this article, we show that C. burnetii arose from a rare evolutionary transformation of a maternally-inherited endosymbiont of ticks into a specialized and virulent pathogen of vertebrates. While arthropod symbionts are typically transmitted maternally and thought not to be infectious to vertebrates, we establish here that one Coxiella symbiont has evolved the necessary adaptations to exploit the vertebrate cell, leading to the emergence of Q fever.
PMCID: PMC4433120  PMID: 25978383
4.  Lobectomy in patients with cystic fibrosis 
Progressive lung disease is the primary contributor to morbidity and mortality in patients with cystic fibrosis. However, severe, localized refractory lung disease can develop in a subset of patients for whom surgical resection is the only treatment option. This study retrospectively reviewed and assessed the outcomes of lobectomy, particularly lung function and disease activity, in selected cystic fibrosis patients who failed standard therapies over a 15-year period.
Some patients with cystic fibrosis (CF) develop severe but localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional medical therapies.
The outcomes of lung resection in patients with CF and worsening localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional therapy (n=15) were evaluated by reviewing the medical records of all patients with CF followed at the CF Center at Nationwide Children’s Hospital (Columbus, Ohio, USA), who underwent lobectomy over a 15-year period (1998 to 2012).
The median age of the 15 patients (93% Caucasian) was 20 years (range two to 41 years) and their mean forced expiratory volume in 1 s (FEV1) was 59.5% of predicted one year before surgery. Three patients died within two years after lobectomy; all three deaths occurred in patients with an FEV1 ≤40% of predicted before surgery. There were no significant changes in mean height, weight, body mass index, hospital admissions or antibiotic use over time. The mean FEV1 decreased over time. Compared with at surgery, decline in FEV1 in the year before surgery was −5.4% (P=0.024) and decline in the year after surgery was −1.3% (P=0.513); however, the difference in the rate of decline was not statistically significant.
In patients with CF and localized worsening bronchiectasis and/or recurrent hemoptysis/pneumothorax, lobectomy carried a significant risk of mortality, especially in patients with FEV1 ≤40% of predicted, and should only be considered when all other measures fail.
PMCID: PMC4173894  PMID: 24524113
Cystic fibrosis; Lobectomy; Pulmonary function tests
5.  Massive Infection of Seabird Ticks with Bacterial Species Related to Coxiella burnetii 
Applied and Environmental Microbiology  2014;80(11):3327-3333.
Seabird ticks are known reservoirs of bacterial pathogens of medical importance; however, ticks parasitizing tropical seabirds have received less attention than their counterparts from temperate and subpolar regions. Recently, Rickettsia africae was described to infect seabird ticks of the western Indian Ocean and New Caledonia, constituting the only available data on bacterial pathogens associated with tropical seabird tick species. Here, we combined a pyrosequencing-based approach with a classical molecular analysis targeting bacteria of potential medical importance in order to describe the bacterial community in two tropical seabird ticks, Amblyomma loculosum and Carios (Ornithodoros) capensis. We also investigated the patterns of prevalence and host specificity within the biogeographical context of the western Indian Ocean islands. The bacterial community of the two tick species was characterized by a strong dominance of Coxiella and Rickettsia. Our data support a strict Coxiella-host tick specificity, a pattern resembling the one found for Rickettsia spp. in the same two seabird tick species. Both the high prevalence and stringent host tick specificity suggest that these bacteria may be tick symbionts with probable vertical transmission. Detailed studies of the pathogenicity of these bacteria will now be required to determine whether horizontal transmission can occur and to clarify their status as potential human pathogens. More generally, our results show that the combination of next generation sequencing with targeted detection/genotyping approaches proves to be efficient in poorly investigated fields where research can be considered to be starting from scratch.
PMCID: PMC4018846  PMID: 24657860
Identify whether the bacterial protein, Integration Host Factor (IHF), is present within sputum solids collected from Cystic Fibrosis (CF) patients and thus might contribute to the structural stability of biofilms within the lungs.
The presence of IHF in sputum was determined by immunohistochemistry. The role of IHF in stabilizing biofilms within sputum was tested in vitro wherein anti-IHF was used to attempt to dissolve sputum solids.
Thirty-seven of 44 sputum samples (84%) were positive for anti-IHF staining. Treatment with anti-IHF or DNase of 6 representative samples, dissolved sputum solids significantly better than treatment with normal saline in vitro, and strong synergism was observed when these agents were used in combination.
IHF was detected in the majority of sputum samples from patients with CF and in vitro treatment with anti-IHF induced dissolution of sputum solids. These data support further investigation of IHF as a potential therapeutic target for patients with CF.
PMCID: PMC3582735  PMID: 23168017
Cystic Fibrosis; biofilms; Integration Host Factor; airway clearance; Pseudomonas aeruginosa
7.  Rickettsia spp. in Seabird Ticks from Western Indian Ocean Islands, 2011–2012 
Emerging Infectious Diseases  2014;20(5):838-842.
We found a diversity of Rickettsia spp. in seabird ticks from 6 tropical islands. The bacteria showed strong host specificity and sequence similarity with strains in other regions. Seabird ticks may be key reservoirs for pathogenic Rickettsia spp., and bird hosts may have a role in dispersing ticks and tick-associated infectious agents over large distances.
PMCID: PMC4012800  PMID: 24751287
host specificity; Rickettsia spp.; seabird ticks; western Indian Ocean; Rickettsia africae; Amblyomma loculosum ticks; Carios capensis ticks; Rickettsia hoogstraalii; Rickettsia bellii; genetic diversity; geographic range; host; parasites; terrestrial hosts; bacteria
8.  An 18-Month Study of the Safety and Efficacy of Repeated Courses of Inhaled Aztreonam Lysine in Cystic Fibrosis 
Pediatric pulmonology  2010;45(11):10.1002/ppul.21301.
Chronic airway infection with Pseudomonas aeruginosa (PA) causes morbidity and mortality in patients with cystic fibrosis (CF). Additional anti-PA therapies are needed to improve health status and health-related quality of life. AIR-CF3 was an international 18-month, open-label study to evaluate the safety and efficacy of repeated courses of aztreonam for inhalation solution (AZLI, now marketed as Cayston®) in patients aged ≥6 years with CF and PA infection who previously participated in one of two Phase 3 studies: AIR-CF1 or AIR-CF2. Patients received up to nine courses (28 days on/28 days off) of 75 mg AZLI two (BID) or three times daily (TID) based on randomization in the previous trials. 274 patients, mean age 28.5 years (range: 8–74 years), participated. Mean treatment adherence was high (92.0% BID group, 88.0% TID group). Hospitalization rates were low and adverse events were consistent with CF With each course of AZLI, FEV1 and scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Symptomscale improved and bacterial density in sputum was reduced. Benefits waned in the 28 days off therapy, but weight gain was sustained over the 18months. There were no sustained decreases in PA susceptibility. A dose response was observed; AZLI TID-treated patients demonstrated greater improvements in lung function and respiratory symptoms over 18 months. Repeated intermittent 28-day courses of AZLI treatment were well tolerated. Clinical benefits in pulmonary function, health-related quality of life, and weight were observed with each course of therapy. AZLI is a safe and effective new therapy in patients with CF and PA airway infection.
PMCID: PMC3867945  PMID: 20672296
antibiotic; Pseudomonas aeruginosa; pulmonary function; quality of life
9.  Inpatient Healthcare Trends Among Adult Cystic Fibrosis Patients in the U.S 
Pediatric pulmonology  2011;47(3):245-251.
Adult cystic fibrosis (CF) patients are an expanding cohort that is taken care of in a variety of hospital settings including adult centers located within pediatric institutions. This study compared costs and discharge rates among adult CF patient hospitalizations in terms of location of hospitalization.
The 2007 Nationwide Inpatient Sample was utilized to identify adult CF patient admission data on patients aged 18–44. Data were separated into pediatric and adult facilities based on percentage discharge rate for patients >18. Primary outcomes measures were length of stay (LOS) and total hospital charges. Secondary predictors were geographic, primary payer, and co-morbidity effects on LOS and total hospital charges.
LOS was higher for adult CF patient admissions in pediatric facilities compared to adult facilities by a mean of 2.5 days. Mean total hospital charges were not significantly different. Adult hospitals in the Western U.S. had a mean total charge more than $50,000 greater than any region in the U.S. Self-pay patients had significantly fewer hospital days and charges across all hospital types. Adult facilities had 7% more CF patients discharged home with home healthcare use. Depressed CF patients had longer LOS by 1.5 days regardless of facility type.
LOS for adult CF inpatient admissions was significantly lower in adult facilities compared to pediatric facilities without a significant difference in hospital charges and is influenced by geographic hospital location. Depressed patients had longer lengths of stay regardless of facility type. Self-insured adult CF patients have a significant reduction in LOS and hospital charges when compared to all other payers regardless of hospital type.
PMCID: PMC3805019  PMID: 21901854
healthcare utilization; socioeconomic factors; geographic factors
10.  Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation 
Thorax  2011;67(1):12-18.
VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.
A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.
The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.
In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904
PMCID: PMC3746507  PMID: 21825083
Cystic Fibrosis (CF) is accompanied with heightened inflammation worsened by drug resistant Burkholderia cenocepacia. Human CF macrophage responses to B. cenocepacia are poorly characterized and variable in the literature. Therefore, we examined human macrophage responses to the epidemic B. cenocepacia J2315 strain in order to identify novel anti-inflammatory targets. Peripheral blood monocyte derived macrophages were obtained from 23 CF and 27 non-CF donors. Macrophages were infected with B. cenocepacia J2315 and analyzed for cytokines, cytotoxicity, and microscopy. CF macrophages demonstrated significant increases in IL-1β, IL-10, MCP-1, and IFN-γ production in comparison to non-CF controls. CF patients on prednisone exhibited globally diminished cytokines compared to controls and other CF patients. CF macrophages also displayed increased bacterial burden and cell death. In conclusion, CF macrophages demonstrate exaggerated IL-1β, IL-10, MCP-1, and IFN-γ production and cell death during B. cenocepacia infection. Treatment with corticosteroids acutely suppressed cytokine responses.
PMCID: PMC3408781  PMID: 22728038
cystic fibrosis; burkholderia; macrophage; IL-1β; corticosteroids
12.  Host specialization in ticks and transmission of tick-borne diseases: a review 
Determining patterns of host use, and the frequency at which these patterns change, are of key importance if we are to understand tick population dynamics, the evolution of tick biodiversity, and the circulation and evolution of associated pathogens. The question of whether ticks are typically host specialists or host generalists has been subject to much debate over the last half-century. Indeed, early research proposed that morphological diversity in ticks was linked to host specific adaptations and that most ticks were specialists. Later work disputed this idea and suggested that ticks are largely limited by biogeographic conditions and tend to use all locally available host species. The work presented in this review suggests that the actual answer likely lies somewhere between these two extremes. Although recent observational studies support the view that phylogenetically diverse host species share ticks when found on similar ecological ranges, theory on host range evolution predicts that host specialization should evolve in ticks given their life history characteristics. Contemporary work employing population genetic tools to examine host-associated population structure in several tick systems support this prediction and show that simple species records are not enough to determine whether a parasite is a true host generalist; host specialization does evolve in ticks at local scales, but may not always lead to speciation. Ticks therefore seem to follow a pattern of being global generalists, local specialists. Given this, the notion of host range needs to be modified from an evolutionary perspective, where one simply counts the number of hosts used across the geographic distribution, to a more ecological view, where one considers host use at a local scale, if we are to better understand the circulation of tick-borne pathogens and exposure risks for humans and livestock.
PMCID: PMC3790072  PMID: 24109592
adaptation; Argasidae; Borrelia burgdorferi sensu lato; community diversity; epidemiology; Ixodidae; population genetic structure; transmission
13.  Health Literacy and Willingness to Use Online Health Information by Teens with Asthma and Diabetes 
Telemedicine Journal and e-Health  2011;17(9):676-682.
Objective: This study measured health literacy in a population of teens in treatment for asthma or diabetes and tested the association between health literacy and willingness to use online health resources. Materials and Methods: About 180 patients aged 13–18 years treated for asthma or diabetes in specialty care clinics completed assessments of demographic characteristics, health literacy, and Internet access and use. Teens were provided a resource page listing selected publically available health-related Web sites and asked about perceived ease of use, perceived usefulness, and intent to use the listed Web sites. The relationship between demographic characteristics, health literacy, and online health information use was tested using chi-squared or Fisher's exact test. Predictors of intent to use resource page Web sites were assessed using bivariate and multivariate ordinal logistic regression. Results: About 92% of participants had adequate health literacy. Over 50% of participants had previously searched online for health information. Older age was the only significant predictor of health information search. Most teens (79%) reported intent to use at least one Web site from the resource page at least occasionally within the next 3 months. Higher health literacy (odds ratio [OR]=6.24, p<0.01) and stronger perceived usefulness (OR=1.74, p=0.01) were associated with greater intent for regular use, after controlling for demographic and Internet access variables. Conclusions: Teens with lower health literacy searched online for health information as often as peers with higher literacy, but were less likely to express the intent to use recommended sites. Belief in the usefulness of a Web site is the strongest attitudinal predictor of intended future use.
PMCID: PMC3241926  PMID: 21943161
adolescents; asthma; diabetes; health literacy; Internet
14.  Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis 
Autophagy  2011;7(11):1359-1370.
Cystic fibrosis (CF) is the most common inherited lethal disease in Caucasians which results in multiorgan dysfunction. However, 85% of the deaths are due to pulmonary infections. Infection by Burkholderia cenocepacia (B. cepacia) is a particularly lethal threat to CF patients because it causes severe and persistent lung inflammation and is resistant to nearly all available antibiotics. In CFTR ΔF508 (ΔF508) mouse macrophages, B. cepacia persists in vacuoles that do not fuse with the lysosomes and mediates increased production of IL-1β. It is believed that intracellular bacterial survival contributes to the persistence of the bacterium. Here we show for the first time that in wild-type but not in ΔF508 macrophages, many B. cepacia reside in autophagosomes that fuse with lysosomes at later stages of infection. Accordingly, association and intracellular survival of B. cepacia are higher in CFTR-ΔF508 macrophages than in WT macrophages. An autophagosome is a compartment that engulfs nonfunctional organelles and parts of the cytoplasm then delivers them to the lysosome for degradation to produce nutrients during periods of starvation or stress. Furthermore, we show that B. cepacia downregulates autophagy genes in WT and ΔF508 macrophages. However, autophagy dysfunction is more pronounced in ΔF508 macrophages since they already have compromised autophagy activity. We demonstrate that the autophagystimulating agent, rapamycin markedly decreases B. cepacia infection in vitro by enhancing the clearance of B. cepacia via induced autophagy. In vivo, rapamycin decreases bacterial burden in the lungs of CF mice and drastically reduces signs of lung inflammation. Together, our studies reveal that if efficiently activated, autophagy can control B. cepacia infection and ameliorate the associated inflammation. Therefore, autophagy is a novel target for new drug development for CF patients to control B. cepacia infection and accompanying inflammation.
PMCID: PMC3359483  PMID: 21997369
autophagy; rapamycin; cystic fibrosis; host-pathogen interaction; Burkholderia cenocepacia; inflammation; macrophages
15.  Evidence That Head and Body Lice on Homeless Persons Have the Same Genotype 
PLoS ONE  2012;7(9):e45903.
Human head lice and body lice are morphologically and biologically similar but have distinct ecologies. They were shown to have almost the same basic genetic content (one gene is absent in head lice), but differentially express certain genes, presumably responsible for the vector competence. They are now believed to be ecotypes of the same species (Pediculus humanus) and based on mitochondrial studies, body lice have been included with head lice in one of three clades of human head lice (Clade A). Here, we tested whether head and body lice collected from the same host belong to the same population by examining highly polymorphic intergenic spacers. This study was performed on lice collected from five homeless persons living in the same shelter in which Clade A lice are prevalent. Lice were individually genotyped at four spacer loci. The genetic identity and diversity of lice from head and body populations were compared for each homeless person. Population genetic structure was tested between lice from the two body regions and between the lice from different host individuals.
We found two pairs of head and body lice on the same homeless person with identical multi locus genotypes. No difference in genetic diversity was found between head and body louse populations and no evidence of significant structure between the louse populations was found, even after controlling for a possible effect of the host individual. More surprisingly, no structure was obvious between lice of different homeless persons.
We believe that the head and body lice collected from our five subjects belong to the same population and are shared between people living in the same shelter. These findings confirm that head and body lice are two ecotypes of the same species and show the importance of implementing measures to prevent lice transmission between homeless people in shelters.
PMCID: PMC3458819  PMID: 23049889
16.  Aztreonam (for inhalation solution) for the treatment of chronic lung infections in patients with cystic fibrosis: an evidence-based review 
Core Evidence  2011;6:59-66.
Cystic fibrosis (CF) is a genetic disease caused by abnormal chloride transport across cellular membranes. In the respiratory tract, this molecular defect causes obstruction of the airways by mucus and chronic endobronchial infection. The majority of patients suffer early death from chronic respiratory disease. Pseudomonas aeruginosa is the predominant chronic airway pathogen in older children and adults with CF and is associated with worse outcomes. However, overall survival in CF has been greatly improved in recent decades due in large part to the aggressive treatment of chronic infections such as P. aeruginosa. While intravenous and oral antibiotics are commonly used in the management of CF respiratory infections, inhaled anti-infective therapies offer the benefit of delivering the drug directly to the site of infection and avoiding potential toxicities associated with systemic absorption. Aztreonam lysine (AZLI) has recently been developed as an inhaled antibiotic for chronic use in CF patients with endobronchial P. aeruginosa infection. This paper reviews background data and the clinical studies which contributed to AZLI’s formal FDA approval and growing role in the management of CF pulmonary disease.
PMCID: PMC3195667  PMID: 22022288
cystic fibrosis; aztreonam lysine; Pseudomonas aeruginosa; inhaled antibiotics
17.  Cryptic vector divergence masks vector-specific patterns of infection: an example from the marine cycle of Lyme borreliosis 
Evolutionary Applications  2010;3(4):391-401.
Vector organisms are implicated in the transmission of close to a third of all infectious diseases. In many cases, multiple vectors (species or populations) can participate in transmission but may contribute differently to disease ecology and evolution. The presence of cryptic vector populations can be particularly problematic as differences in infection can be difficult to evaluate and may lead to erroneous evolutionary and epidemiological inferences. Here, we combine site-occupancy modeling and molecular assays to evaluate patterns of infection in the marine cycle of Lyme borreliosis, involving colonial seabirds, the tick Ixodes uriae, and bacteria of the Borrelia burgdorferi s.l. complex. In this cycle, the tick vector consists of multiple, cryptic (phenotypically undistinguishable but genetically distinct) host races that are frequently found in sympatry. Our results show that bacterial detection varies strongly among tick races leading to vector-specific biases if raw counts are used to calculate Borrelia prevalence. These differences are largely explained by differences in infection intensity among tick races. After accounting for detection probabilities, we found that overall prevalence in this system is higher than previously suspected and that certain vector–host combinations likely contribute more than others to the local dynamics and large-scale dispersal of Borrelia spirochetes. These results highlight the importance of evaluating vector population structure and accounting for detection probability when trying to understand the evolutionary ecology of vector-borne diseases.
PMCID: PMC3352467  PMID: 25567933
Lyme disease bacteria; pathogen detection; seabirds; site-occupancy models; transmission ecology
18.  Inhaled Aztreonam Lysine for Chronic Airway Pseudomonas aeruginosa in Cystic Fibrosis 
Rationale: The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study.
Objectives: To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF.
Methods: After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; ⩾6 yr; ⩾3 TIS courses within previous year; FEV1 ⩾ 25% and ⩽75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV1), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored.
Measurements and Main Results: AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV1 (6.3%, P = 0.001), and sputum PA density (−0.66 log10 cfu/g, P = 0.006) compared with placebo; no AZLI dose–response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar.
Conclusions: AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated.
Clinical trial registered with (NCT 00104520).
PMCID: PMC2577727  PMID: 18658109
cystic fibrosis; Pseudomonas; aztreonam; inhaled antibiotics; patient-reported outcomes; respiratory symptoms
19.  Public information affects breeding dispersal in a colonial bird: kittiwakes cue on neighbours 
Biology Letters  2008;4(5):538-540.
Habitat selection and dispersal behaviour are key processes in evolutionary ecology. Recent studies have suggested that individuals may use the reproductive performance of conspecifics as a source of public information on breeding patch quality for dispersal decisions, but experimental evidence is still limited for species breeding in aggregates, i.e. colonial species. We addressed this issue by manipulating the local breeding success of marked individuals and that of their neighbours on a series of breeding patches of a colonial seabird, the black-legged kittiwake (Rissa tridactyla). Based on previous observations in this species, we predicted that individuals that lost their eggs on successful patches would attend their nest and come back to it the year after at a higher rate than individuals that lost their eggs on patches where their neighbours were also in failure. As predicted, the attendance of breeders and prospectors was strongly affected by the local level of breeding success, resulting in differential site fidelity and recruitment. This suggests that individuals used information conveyed by conspecific breeding performance to make decisions relative to breeding site selection. This process can amplify the response of these populations to environmental change and may have contributed to the evolution of colonial breeding.
PMCID: PMC2610090  PMID: 18647711
breeding habitat selection; coloniality; prospecting; conspecific performance
20.  Recurrent evolution of host-specialized races in a globally distributed parasite 
The outcome of coevolutionary interactions is predicted to vary across landscapes depending on local conditions and levels of gene flow, with some populations evolving more extreme specializations than others. Using a globally distributed parasite of colonial seabirds, the tick Ixodes uriae, we examined how host availability and geographic isolation influences this process. In particular, we sampled ticks from 30 populations of six different seabird host species, three in the Southern Hemisphere and three in the Northern Hemisphere. We show that parasite races have evolved independently on hosts of both hemispheres. Moreover, the degree of differentiation between tick races varied spatially within each region and suggests that the divergence of tick races is an ongoing process that has occurred multiple times across isolated areas. As I. uriae is vector to the bacterium responsible for Lyme disease Borrelia burgdorferi sensu lato, these results may have important consequence for the epidemiology of this disease. With the increased occurrence of novel interspecific interactions due to global change, these results also stress the importance of the combined effects of gene flow and selection for parasite diversification.
PMCID: PMC1559958  PMID: 16243689
colonial seabirds; ectoparasite; host-dependent dispersal; Ixodes uriae; population genetic structure; vector-borne disease

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