Exposure to Zinc Oxide Nanoparticles Disrupts Endothelial Tight and Adherens Junctions and Induces Pulmonary Inflammatory Cell Infiltration.

Zinc oxide nanoparticles (ZnONPs) are frequently encountered nanomaterials in our daily lives. Despite the benefits of ZnONPs in a variety of applications, many studies have shown potential health hazards of exposure to ZnONPs. We have shown that oropharyngeal aspiration of ZnONPs in mice increases lung inflammation. However, the detailed mechanisms underlying pulmonary inflammatory cell infiltration remain to be elucidated. Endothelium functions as a barrier between the blood stream and the blood vessel wall. Endothelial barrier dysfunction may increase infiltration of immune cells into the vessel wall and underlying tissues. This current study examined the effects of ZnONPs exposure on endothelial barriers. ZnONPs exposure increased leukocyte infiltration in the mouse lungs. In endothelial cells, ZnONPs reduced the continuity of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1) at the cell junctions. ZnONPs induced adherens junction protein VE-cadherin internalization from membrane to cytosol and dissociation with ß-catenin, leading to reduced and diffused staining of VE-cadherin and ß-catenin at cell junctions. Our results demonstrated that ZnONPs disrupted both tight and adherens junctions, compromising the integrity and stability of the junction network, leading to inflammatory cell infiltration. Thus, ZnONPs exposure in many different settings should be carefully evaluated for vascular effects and subsequent health impacts.

Bactericidal activity of hexylresorcinol lozenges against oropharyngeal organisms associated with acute sore throat.

OBJECTIVE: For the majority of people with acute sore throat, over-the-counter treatments represent the primary option for symptomatic relief. This study evaluated the in vitro bactericidal activity of lozenges containing the antiseptic hexylresorcinol against five bacteria associated with acute sore throat: Staphylococcus aureus, Streptococcus pyogenes, Moraxella catarrhalis, Haemophilus influenzae and Fusobacterium necrophorum. RESULTS: Hexylresorcinol 2.4 mg lozenges were dissolved into 5 mL of artificial saliva medium. Inoculum cultures were prepared in triplicate for each test organism to give an approximate population of 108 colony-forming units (cfu)/mL. Bactericidal activity was measured by log reduction in cfu. Greater than 3log10 reductions in cfu were observed at 1 min after dissolved hexylresorcinol lozenges were added to S. aureus (log10 reduction cfu/mL ± standard deviation, 3.3 ± 0.2), M. catarrhalis (4.7 ± 0.4), H. influenzae (5.8 ± 0.4) and F. necrophorum (4.5 ± 0.2) and by 5 min for S. pyogenes (4.3 ± 0.4). Hexylresorcinol lozenges achieved a > 99.9% reduction in cfu against all tested organisms within 5 min, which is consistent with the duration for a lozenge to dissolve in the mouth. In conclusion, in vitro data indicate that hexylresorcinol lozenges offer rapid bactericidal activity against organisms implicated in acute sore throat.

Priorities of human papillomavirus-associated oropharyngeal cancer patients at diagnosis and after treatment.

INTRODUCTION: Little is known regarding how human papillomavirus-positive oropharyngeal cancer (HPV-OPC) patient goals change with treatment. This study evaluates whether patient ranking of non-oncologic priorities relative to cure and survival shift after treatment as compared to priorities at diagnosis. MATERIALS AND METHODS: This is a prospective study of HPV-OPC patient survey responses at diagnosis and after treatment. The relative importance of 12 treatment-related priorities was ranked on an ordinal scale (1 as highest). Median rank (MR) was compared using Wilcoxon matched-pairs signed-rank tests. Prevalence of high concern for 11 treatment-related issues was compared using paired t-test. The effect of patient characteristics on change in priority rank and concern was evaluated using linear regression. RESULTS: Among 37 patients, patient priorities were generally unchanged after treatment compared with at diagnosis, with cure and survival persistently ranked top priority. Having a moist mouth uniquely rose in importance after treatment. Patient characteristics largely did not affect change in priority rank. Concerns decreased after treatment, except concern regarding recurrence. DISCUSSION: Treatment-related priorities are largely similar at diagnosis and after treatment regardless of patient characteristics. The treatment experience does not result in a shift of priorities from cure and survival to non-oncologic domains over cure and survival. The rise in importance of moist mouth implies that xerostomia may have been underappreciated as a sequelae of treatment. A decrease in most treatment-related concerns is encouraging, whereas the persistence of specific areas of concern may inform patient counseling.

Growth Media for Mixed Multispecies Oropharyngeal Biofilm Compositions on Silicone.

AIMS: Microbial colonization of silicone voice prostheses by bacteria and Candida species limits the device lifetime of modern voice prostheses in laryngectomized patients. Thus, research focuses on biofilm inhibitive properties of novel materials, coatings, and surface enhancements. Goal of this in vitro study was the evaluation of seven commonly used growth media to simulate growth of mixed oropharyngeal species as mesoscale biofilms on prosthetic silicone for future research purposes. METHODS AND RESULTS: Yeast Peptone Dextrose medium (YPD), Yeast Nitrogen Base medium (YNB), M199 medium, Spider medium, RPMI 1640 medium, Tryptic Soy Broth (TSB), and Fetal Bovine Serum (FBS) were used to culture combined mixed Candida strains and mixed bacterial-fungal compositions on silicone over the period of 22 days. The biofilm surface spread and the microscopic growth showed variations from in vivo biofilms depending on the microbial composition and growth medium. CONCLUSION: YPD and FBS prove to support continuous in vitro growth of mixed bacterial-fungal oropharyngeal biofilms deposits over weeks as needed for longterm in vitro testing with oropharyngeal biofilm compositions. SIGNIFICANCE AND IMPACT OF STUDY: The study provides data on culture conditions for mixed multispecies biofilm compositions that can be used for future prosthesis designs.

Studies of selective digestive decontamination as a natural experiment to evaluate topical antibiotic prophylaxis and cephalosporin use as population-level risk factors for enterococcal bacteraemia among ICU patients.

BACKGROUND: Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) regimens appear protective against ICU-acquired overall bacteraemia. These regimens can be factorized as topical antibiotic prophylaxis (TAP) with (SDD) or without (SOD) protocolized parenteral antibiotic prophylaxis (PPAP) using cephalosporins. Both TAP and cephalosporins are risk factors for enterococcal colonization although their impact on enterococcal bacteraemia within studies of SDD/SOD remains unclear. OBJECTIVES: To benchmark the enterococcal bacteraemia incidence within component (control and intervention) groups of SDD/SOD studies among ICU patients versus studies without intervention (observational groups). METHODS: The literature was searched for SDD/SOD studies reporting enterococcal bacteraemia incidence data. In addition, component groups of studies of various non-antibiotic interventions served to provide additional points of reference. RESULTS: The mean incidence per 100 patients (and 95% CI) for enterococcal bacteraemia among 19 SDD/SOD studies was equally increased among concurrent control (2.1; 1.0%-4.7%) and intervention (2.3; 2.0%-2.7%) groups versus the benchmark incidence (0.8; 0.6%-1.2%) derived from 16 observational study groups and also versus 9 component groups from non-antibiotic studies. These higher incidences remained apparent (P < 0.02) in a meta-regression model adjusting for groupwide factors such as PPAP use, mechanical ventilation proportion, group mean length of stay >7 days and publication year. CONCLUSIONS: The incidences of enterococcal bacteraemia within both concurrent control and intervention groups of SDD/SOD studies are unusually high compared with the literature-derived benchmark. The impact of parenteral cephalosporin used as PPAP additional to TAP on enterococcal bacteraemia incidence was indeterminate in this analysis.

Systematic review of case reports of oropharyngeal dysphagia following the use of antipsychotics / Revisión sistemática de los casos clínicos que relacionan la disfagia orofaríngea con el uso de antipsicóticos

Objective: The purpose of this systematic review was to examine the effect of antipsychotic medication on dysphagia based on clinical case reports. Patients and methods: Literature searches were performed using the electronic databases PubMed and Embase. In PubMed, we used the MeSH terms "antipsychotic agents" OR "tranquilizing agents" combined with "deglutition disorders" OR "deglutition". In Embase, we used the Emtree terms "neuroleptic agents" combined with "swallowing" OR "dysphagia". Two reviewers assessed the eligibility of each case independently. Results: A total of 1043 abstracts were retrieved, of which 36 cases met the inclusion criteria; 14 cases were related to typical antipsychotics and 22 to atypical antipsychotics. Dysphagia occurred together with extrapyramidal symptoms in half of the cases and was the only prominent symptom in the other half. The most common strategy against dysphagia was changing to another antipsychotic (n=13, 36.1%). Conclusions: The data from this review indicate that antipsychotics can increase the prevalence of dysphagia

Objetivo: El propósito de esta revisión sistemática fue examinar el efecto de los fármacos antipsicóticos en la disfagia según los casos clínicos reportados. Pacientes y métodos: La búsqueda bibliográfica se realizó utilizando las bases de datos electrónicas PubMed y Embase. En PubMed, utilizamos los términos MeSH «agentes antipsicóticos» o «agentes tranquilizantes» combinados con «trastornos de deglución» o «deglución». En Embase, utilizamos los términos de Emtree «agentes neurolépticos» combinados con «deglutir» o «disfagia». Dos revisores evaluaron la elegibilidad de cada caso de forma independiente. Resultados: Se obtuvieron un total de 1.043 resúmenes, de los cuales 36 casos cumplieron los criterios de inclusión; 14 casos estuvieron relacionados con antipsicóticos típicos y 22 con antipsicóticos atípicos. La disfagia se produjo junto con síntomas extrapiramidales en la mitad de los casos, y fue el único síntoma prominente en la otra mitad. La estrategia más común contra la disfagia fue cambiar a otro antipsicótico (n=13; 36,1%). Conclusiones: Los datos de esta revisión sistemática indican que los antipsicóticos pueden aumentar la prevalencia de la disfagia

The Effect of Sedating Agents on Drug-Induced Sleep Endoscopy Findings.

OBJECTIVE: Drug-induced sleep endoscopy (DISE) has gained interest for upper airway evaluation in patients with snoring and obstructive sleep apnea (OSA), and different drugs have been used to induce sedation. Nevertheless, all drugs have presented specific advantages and disadvantages with differential effects on respiratory physiology. This study evaluated and compared the effects of midazolam, propofol and dexmedetomidine on DISE findings, O2 nadir, and bispectral index (BIS) in the same sample of patients. STUDY DESIGN: Case series prospective study. METHODS: Consecutive patients who elected to undergo surgery for OSA treatment and were intolerant to conservative therapies underwent DISE with propofol, dexmedetomidine, and midazolam between July 2015 and July 2016. RESULTS: Fifty-two patients were analyzed, and 43 (82.7%) were men. Agreement among drugs for both degree and patterns of obstruction was excellent at all sites (velum, oropharynx, and epiglottis) except for the tongue base. Dexmedetomidine had the least complete collapse sites and highest O2 nadir and was the only drug for which apnea severity and obstruction levels (upper, lower, or combined) were correlated. The variability among drug treatments for the BIS index was considerable, and propofol had the lowest variability and average value. CONCLUSION: Drug selection had a relevant influence in DISE findings. Compared with dexmedetomidine, midazolam and propofol presented higher incidence of tongue base collapse, lower O2 levels, and lower BIS index values. Propofol resulted in an O2 nadir that most resembled that observed during polysomnography. The BIS index variability differed among drugs, and its use was considered relevant for sedation orientation. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:506-513, 2019.

Carriage of antibiotic-resistant Gram-negative bacteria after discontinuation of selective decontamination of the digestive tract (SDD) or selective oropharyngeal decontamination (SOD).

BACKGROUND: Selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) reduce colonization with antibiotic-resistant Gram-negative bacteria (ARGNB), incidence of nosocomial infections and improve survival in ICU patients. The effect on bacterial gut colonization might be caused by growth suppression by antibiotics during SDD/SOD. We investigated intestinal colonization with ARGNB after discharge from ICU and discontinuation of SDD or SOD. METHODS: We performed a prospective, observational follow-up study in regular hospital wards of three teaching hospitals in the Netherlands in patients discharged from the ICU, who were participating in a cluster randomized trial comparing SDD with SOD. We determined rectal carriage with ARGNB at ICU discharge (time (T) = 0) and 3, 6 and 10 days after discharge. The primary endpoint was time to first colonization with ARGNB that was not present at T = 0. Bacteria that are intrinsically resistant to antibiotics were not included in the primary analysis, but were included in post-hoc analysis. RESULTS: Of 1370 patients screened for inclusion, 996 patients had samples at T = 0 (507 after SDD and 489 after SOD). At ICU discharge, the prevalence of intestinal carriage with any ARGNB was 22/507 (4.3%) after SDD and 87/489 (17.8%) after SOD (p < 0.0001): 426 (SDD) and 409 (SOD) patients had at least one follow-up sample for analysis. The hazard rate for acquiring carriage of ARGNB after discontinuation of SDD, compared to SOD, in the ICU was 0.61 (95% CI 0.40-0.91, p = 0.02), and cumulative risks of acquisition of at least one ARGNB until day 10 were 13% (SDD) and 18% (SOD). At day 10 after ICU discharge, the prevalence of intestinal carriage with ARGNB was 11.3% (26/230 patients) after SDD and 12.5% (28/224 patients) after SOD (p = 0.7). In post-hoc analysis of all ARGNB, including intrinsically resistant bacteria, colonization at ICU discharge was lower after SDD (4.9 vs. 22.3%, p < 0.0001), but acquisition rates after ICU discharge were similar in both groups. CONCLUSIONS: Intestinal carriage at ICU discharge and the acquisition rate of ARGNB after ICU discharge are lower after SDD than after SOD. The prevalence of intestinal carriage with ARGNB at 10 days after ICU discharge was comparable in both groups, suggesting rapid clearance of ARGNB from the gut after ICU discharge. TRIAL REGISTRATION: Netherlands Trial Registry, NTR3311 . Registered on 28 february 2012.

Assessment of indomethacin oral spray for the treatment of oropharyngeal mucositis-induced pain during anticancer therapy.

PURPOSE: The efficacy and safety of indomethacin (IM) oral spray (OS) as a pain control therapy for oropharyngeal mucositis due to anticancer chemo- and radiotherapy were assessed in patients with head and neck carcinomas and haematological tumours. METHOD: We observed 35 patients (male/female, 20/15; 53 ± 17 years) with oropharyngeal mucositis who were treated with IM-OS preparation for pain relief at University of Tsukuba Hospital, Japan. Analgesic effects were assessed using the six-grade face scale for pain in 28 patients at the start of IM oral spray treatment. Systemic exposure was assessed by determining urinary excretions of IM in seven patients. RESULTS: Pain relief was achieved in 26 (93%) patients at 25 (5-60) min after applying the IM-OS preparation (15.6 ± 3.4 µg/kg) and analgesic effects were maintained for 120 (10-360) min. The pain was significantly decreased after using the spray (3.6 ± 0.7 vs. 2.4 ± 0.9, p < 0.01). Moreover, urinary IM excretion rates after applying the IM spray preparation were 1.8 ± 0.8% of the IM oral spray dose (130.5 ± 77.7 µg/kg/day), which was markedly lower than that following oral administration of IM (60%). No adverse events were observed following application of the spray. CONCLUSIONS: The present IM spray is an effective and safe preparation for pain relief and can be used as an alternative therapeutic option for oropharyngeal mucositis in cancer patients.

PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.

BACKGROUND: The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC. METHODS: Confocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC. RESULTS: We show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-ß, resulted in near arrest of MSC chemotaxis (p < 0.0001). CONCLUSIONS: Tumor microenvironment expression of PDGFR-α has been shown to correlate with a worse prognosis in patients with prostate, breast, ovarian, non-small cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the malignant phenotype in this setting.

Cytotoxic and Genotoxic Effects of Electronic Cigarette Liquids on Human Mucosal Tissue Cultures of the Oropharynx.

The popularity of electronic cigarettes (ECs) is rapidly growing and ECs are claimed to be an uncritically regarded alternative to conventional cigarettes. The mucosal tissue of the upper aerodigestive tract (UADT) is the first contact organ for xenobiotics such as liquids of ECs. The aim of this study is to investigate the bimolecular effects of e-liquids on human pharyngeal tissue cultures to evaluate whether e-liquids and their components present a risk factor for head and neck squamous cell carcinoma. Fresh tissue samples of healthy oropharyngeal mucosa were assembled into mucosal tissue cultures. Two fruit-flavored liquids (FLs), one tobacco-flavored liquid (TL) (all containing nicotine), and the corresponding base mixtures (free of nicotine and flavor) were used in three different dilutions. Cytotoxicity was assessed using the water-soluble tetrazolium-8 assay. DNA fragmentation was quantified using alkaline microgel electrophoresis. All liquids caused a significant reduction in cell viability. FLs especially showed a higher toxicity than TL. DNA fragmentation significantly increased by incubation with FL, whereas treatment with TL did not show serious DNA damage. E-liquids are cytotoxic to oropharyngeal tissue, and some liquids can induce relevant DNA damage. Thus, mutagenicity for mucosa of the UADT and e-liquids as risk factors for head and neck cancer cannot entirely be ruled out. Only the implementation of standards and regulations for liquid production and distribution can ensure a valid scientific investigation and assessment of carcinogenic potential of long-term EC use.

The role of Fusobacterium necrophorum in pharyngotonsillitis - A review.

Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome. In addition, it is also associated with peritonsillar abscess formation and otitis media in small children. Recent research has shown that F. necrophorum may be involved in pharyngotonsillitis especially in adolescent and young adults and that it may be the second most common bacterial cause of pharyngotonsillitis after Streptococcus pyogenes (Group A streptococci). Peritonsillar abscesses and Lemierre's syndrome due to F. necrophorum are also found in this age group, suggesting that they may be complications of F. necrophorum pharyngotonsillitis. In this review we present the present knowledge about the role of F. necrophorum in pharyngotonsillitis with special emphasis on the age distribution. We argue that F. necrophorum is an important pathogen involved in pharyngotonsillitis in the age group of 13-40 years of age and we urge clinical microbiology labs to set up the appropriate techniques to be able to detect F. necrophorum from throat swabs.

A retrospective cephalometric study on pharyngeal airway space changes after rapid palatal expansion and Herbst appliance with or without skeletal anchorage.

BACKGROUND: The aim of this study is to investigate the pharyngeal airway space changes in patients treated with rapid palatal expansion (RPE) and Herbst appliance with or without skeletal anchorage. METHODS: A 40-patient study group treated with the Herbst RME combination was included; moreover, a comparison between two subgroups based on whether miniscrews were used was evaluated. A subgroup 1 included 20 patients who were treated with RPE and an acrylic splint Herbst with miniscrews, and subgroup 2 included 20 patients who were treated with RPE and an acrylic splint Herbst. A cephalometric analysis was performed before (T1) and after (T2) treatment. The skeletal parameters of the sagittal occlusion analysis of Pancherz were utilized together with some extra measurements to evaluate the airways. RESULTS: An increased nasopharyngeal airway space was observed in group 1 (p < 0.05) from T1 to T2. Furthermore, the increase in nasopharyngeal airway space was significantly higher in subgroup 1 (p < 0.05) in comparison to the subgroup 2. Oropharyngeal (OA) and laryngopharyngeal (LA) dimensions were significantly increased in the subgroup 1 at the end of the treatment. In the subgroup 1, a significant decrease in SNA, a significant increase in SNB, and a significant decrease in ANB were observed from T1 to T2. In the subgroup 2, the treatment resulted in a significant decrease in ANB. In both groups, Pogonion increased significantly from T1 to T2. CONCLUSIONS: The results suggest that the RPE and the Herbst appliance allow a slight improvement of the sagittal dimensions of the airways. The oropharyngeal dimension increased significantly more in the skeletal anchorage group.

Randomized clinical trial on 7-days-a-week post-operative radiotherapy vs concurrent post-operative radiochemotherapy in locally advanced cancer of the oral cavity/oropharynx: a report on acute normal tissue reactions.

OBJECTIVE: The purpose of the study was to evaluate acute normal tissue reactions and treatment compliance in a randomized clinical trial on 7-days-a-week post-operative radiotherapy (p-CAIR) vs post-operative concurrent radiochemotherapy (p-RTCT) in locally advanced cancer of the oral cavity/oropharynx. The sample analyzed at present represents approximately 30% of the intended future trial size. METHODS: The patients were randomly assigned to receive 63 Gy in 1.8-Gy fractions 7 days a week (n = 44) or 63 Gy in 1.8-Gy fractions 5 days a week with concurrent cisplatin 80-100 mg per square metre of body surface area on Days 1, 22 and 43 of the course of radiotherapy (n = 40). Acute mucosal reactions were scored using the modified Dische system. RESULTS: 15 (17.9%) patients, including 5 patients in p-CAIR and 10 patients in p-RTCT, did not comply with the assigned radiation treatment, mostly because of rapid tumour progression or deteriorating general performance. In p-RTCT, 22 (55%) patients received less than the intended three courses of chemotherapy mostly owing to haematological toxicity. The average maximum mucosal severity score was 14.2 in p-CAIR compared with 13.4 in p-RTCT; the difference was not statistically significant (p = 0.31). CONCLUSION: The schedules compared (p-CAIR and p-RTCT) did not differ considerably with respect to acute mucosal reactions. Haematological toxicity in p-RTCT was elevated compared with p-CAIR. Both schedules were considered tolerable with respect to acute toxicity, which justifies further recruitment to the trial. ADVANCES IN KNOWLEDGE: The results show that early mucosal reactions are comparable in both trial arms but haematological toxicity is more pronounced during radiochemotherapy.

Antibacterial resistance in Streptococcus pyogenes (GAS) from healthy carriers and tonsillitis patients and association with antibacterial sale in the Faroe Islands.

The aim of this study was to investigate the antibacterial resistance of Streptococcus pyogenes (GAS), and correlate the findings with the sales of erythromycin and tetracycline. General practitioners in the Faroe Islands were recruited to send oropharyngeal swabs. From an ongoing pneumococcal study, nasopharyngeal swabs were sampled from healthy children 0-7 years of age. Erythromycin susceptibility data from Iceland were obtained from the reference laboratory at the Landspitali University Hospital. Susceptibility testing in the Faroe Islands and Iceland was performed according to CLSI methods and criteria. The resistance rate to erythromycin and tetracycline found in patients in the Faroe Islands in 2009/2010 was 6% and 30% respectively. Tetracycline resistance in patients declined significantly from 2009 to 2010 (37-10%, p-value = 0.006 < 0.05) and differed significantly between age groups (p-value = 0.03 < 0.05). In Iceland, there was a peak in erythromycin resistance in 2008 (44%) and a substantial decrease in 2009 (5%). Although the prevalence of erythromycin and tetracycline resistance in the Faroe Islands and Iceland may be associated with antimicrobial use, sudden changes can occur with the introduction of new resistant clones.

Antibiotic-Induced Within-Host Resistance Development of Gram-Negative Bacteria in Patients Receiving Selective Decontamination or Standard Care.

OBJECTIVE: To quantify antibiotic-associated within-host antibiotic resistance acquisition rates in Pseudomonas aeruginosa, Klebsiella species, and Enterobacter species from lower respiratory tract samples of ICU patients receiving selective digestive decontamination, selective oropharyngeal decontamination, or standard care. DESIGN: Prospective cohort. SETTING: This study was nested within a cluster-randomized crossover study of selective digestive decontamination and selective oropharyngeal decontamination in 16 ICUs in The Netherlands. PATIENTS: Eligible patients were those colonized in the respiratory tract with P. aeruginosa, Klebsiella species, or Enterobacter species susceptible to one of the marker antibiotics and with at least two subsequent microbiological culture results from respiratory tract samples available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Antibiotic resistance acquisition rates were defined as the number of conversions from susceptible to resistant for a specific antibiotic per 100 patient-days or 100 days of antibiotic exposure within an individual patient. The hazard of antibiotic use for resistance development in P. aeruginosa was based on time-dependent Cox regression analysis. Findings of this study cohort were compared with those of a previous cohort of patients not receiving selective digestive decontamination/selective oropharyngeal decontamination. Numbers of eligible patients were 277 for P. aeruginosa, 174 for Klebsiella species, and 106 for Enterobacter species. Resistance acquisition rates per 100 patient-days ranged from 0.2 (for colistin and ceftazidime in P. aeruginosa and for carbapenems in Klebsiella species) to 3.0 (for piperacillin-tazobactam in P. aeruginosa and Enterobacter species). For P. aeruginosa, the acquisition rates per 100 days of antibiotic exposure ranged from 1.4 for colistin to 4.9 for piperacillin-tazobactam. Acquisition rates were comparable for patients receiving selective digestive decontamination/selective oropharyngeal decontamination and those receiving standard care. Carbapenem exposure had the strongest association with resistance development (adjusted hazard ratio, 4.2; 95% CI, 1.1-15.6). CONCLUSION: Within-host antibiotic resistance acquisition rates for systemically administered antibiotics were comparable between patients receiving selective decontamination and those receiving standard care and were highest during carbapenem use.

ICU-acquired candidemia within selective digestive decontamination studies: a meta-analysis.

PURPOSE: To estimate the direct and indirect (contextual) effects of the factorized constituents of selective digestive decontamination and selective oropharyngeal decontamination (SDD/SOD), being topical antibiotic (TA) and protocolized antifungal prophylaxis (PAFP), on ICU-acquired candidemia. METHODS: A broad range of ICU candidemia incidence studies were sourced to serve as points of reference. The candidemia incidence was extracted from component (control and intervention) groups decanted from studies of various designs (concurrent or non-concurrent) and whether investigating SDD/SOD versus non-TA methods of ICU infection prevention. The candidemia incidences were summarized in regression models using generalized estimating equation (GEE) methods. Groups derived from observational studies (no prevention method under study) provided an overarching external benchmark candidemia incidence for calibration. RESULTS: Within studies investigating SDD/SOD, the mean (and 95% confidence interval) candidemia incidence among concurrent component groups (40 control; 2.4%; 1.7-3.2% and 43 intervention groups; 2.4%; 1.6-3.1%), but not non-concurrent control groups (11 groups; 1.6%; 0.1-2.7%), is higher than that of the benchmark candidemia incidence derived from 54 observational groups (1.5%; 1.2-1.9%). The TA constituent within SDD/SOD has significant direct and indirect (contextual) effects in GEE models even after adjusting for the publication year and the group-wide presence of either candidemia risk factors or PAFP use. CONCLUSION: The TA constituent of SDD/SOD is associated with a contextual effect on candidemia incidence which is similar in magnitude to that of the conventional candidemia risk factors and against which PAFP partially attenuates. This increase is inapparent within individual SDD/SOD studies examined in isolation.

Drug release from an oromucosal paste for the selective decontamination of the oropharynx (in ICU patients and healthy volunteers).

Selective oropharyngeal decontamination (SOD) is used in many ICUs in the Netherlands and some other European countries. While its clinical effect has been studied intensively, no studies have been done to assess the biopharmaceutical aspects of the paste, i.e. it is not known which local concentrations exist. For this study, five healthy volunteers were subjected to 400mg of the generally used paste. Ten ICU patients were treated according to the normal standard in the ICU of the University Medical Center Utrecht. Salivary levels of the various substances were measured over time using two separate analytical methods. Also the microbial burden of the oropharynx was assessed. The results show significant variation in release, both ICU patients and healthy volunteers. The antimicrobials tobramycin and colistin showed a relatively fast release, while nystatin exhibited a controlled release-like pattern. Amphotericin B is hardly released from the formulation. The concentration of the antimicrobial agents drop to sub-MIC levels relatively fast. From a biopharmaceutical perspective, amphotericin B should be replaced by nystatin. The application of the mouth paste is subject to massive variation in daily practice; each nurse applies a different amount, in a different way. In addition, the formulation is hard to apply and unpleasant with regards to the taste and feel for the conscious patients. This is not a clinical study, but a study that aimed to give a biopharmaceutical justification for SOD Both the clinical practice and the clinically determined levels of drugs enable critical evaluation of the outcome of clinical studies performed until now.