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The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) surveillance study evaluates in vitro antibiotic resistance among Staphylococcus aureus, coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae isolates from ocular infections. Here we report resistance rates and trends among conjunctival-sourced ocular isolates collected across the US from 2009 through 2016. A total of 1198 conjunctival isolates (483 S. aureus, 305 CoNS, 208 H. influenzae, 118 S. pneumoniae, and 84 P. aeruginosa) were collected from patients with presumed bacterial conjunctivitis from 57 sites across 40 states. A large proportion of staphylococci demonstrated resistance to oxacillin and azithromycin, while resistance was low against the majority of antibiotics tested for S. pneumoniae, P. aeruginosa, and H. influenzae. Multidrug resistance (≥3 antibiotic classes) was found in 30.2% of S. aureus and 39.0% of CoNS isolates, and methicillin resistance more than doubled the rate of multi-drug resistance (methicillin-resistant S. aureus [MRSA], 76.5%; methicillin-resistant CoNS isolates, 72.8%). There was a pattern of increasing mean percent resistance with increasing age by decade of life among S. aureus, MRSA, and CoNS (P≤0.038). Over the eight-year study period, there were small yet significant decreases in resistance rates among S. aureus to azithromycin, ciprofloxacin, tobramycin, trimethoprim, and oxacillin (P≤0.003), and among CoNS and P. aeruginosa (both P<0.05) to ciprofloxacin. These data indicate that antibiotic resistance is high, but did not increase, among conjunctival-sourced isolates collected in the US from 2009 through 2016. For certain antibiotic/pathogen combinations, there was a trend of decreased resistance, including a decrease in oxacillin resistance among S. aureus., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: PA Asbell has received: grants from Bausch + Lomb, the National Eye Institute, the Office of Dietary Supplements (NIH), Novartis, MC2 Therapeutics, Rtech, and Miotech; speaker fees from Santen, Medscape, ScientiaCME, Oculus, and Vindico; advisory board/consultancy fees from Bausch + Lomb, Shire, Novartis, MC2 Therapeutics, Allergan, Rtech, Miotech; non-financial support from Bausch + Lomb, CLAO, Santen, and Shire. HH DeCory is an employee of Bausch + Lomb. This does not alter our adherence to PLOS ONE policies on sharing data and materials related to this analysis.

Background: Low socioeconomic status is correlated with worse outcomes in patients with cystic fibrosis (CF). Whether insurance status impacts adherence to care in this population is unknown., Methods: Patients ≥18 years old in the CF Foundation Patient Registry (2005-2013) were grouped based on reported annual insurance as private, public (Medicaid, Medicare or state medical assistance program), others or no insurance. Random effects logistic regression evaluated association between change in insurance status and annual use of recommended routine care., Results: A total of 18 358 patients contributed 94 690 years of data to the analysis. In descriptive analysis, adherence to recommended routine care (≥4 clinic visits, ≥4 respiratory cultures and ≥2 pulmonary function tests per year) and recommended chronic medications for those with moderate to severe lung disease (dornase alfa and inhaled tobramycin or aztreonam if Pseudomoas aeruginosa in respiratory cultures) was most common in public insurance compared to other insurance types. In multivariable logistic regression, public insurance was associated with greater use of recommended care relative to private insurance (OR = 1.16; 95% confidence interval: 1.10-1.22; P < .001), while being uninsured was associated with lower odds of using recommended care (OR = 0.37; 95% confidence interval: 0.31-0.46; P < .001)., Conclusions: For adults with CF in the United States, public insurance was associated with greater use of routine care than private coverage. Being uninsured was strongly associated with not using routine care. Further efforts to improve access to CF care should address the feasibility of universal and continuous insurance coverage in the CF population., (© 2018 John Wiley & Sons Ltd.)

Background: Emerging evidence suggests that the prevalence of pathogens common in cystic fibrosis (CF) may be unevenly distributed across the United States (U.S.). However, very little is known regarding the U.S. distribution of other CF modifiers such as medication usage and patient demographics. Therefore, we sought to determine if regional differences exist in the distribution of demographic variables and patient disease characteristics in the U.S. that may play a role in differential CF outcomes., Methods: Data were analyzed from the 30,896 subjects in the U.S. CF Foundation Patient Registry during the years 2007-2012, via geographical grouping of states based upon the Nationwide Inpatient Sample classification., Results: Significant differences in racial distribution were seen, including half of the total U.S. African-American CF population residing in the South. Both African-Americans and Hispanics had increased Medicaid usage (52.2%, 41.8%, respectively). Culture-reported pathogens were markedly different across the U.S., with the highest percentage of patients with Methicillin-resistant Staphylococcus aureus (41.9%), Pseudomonas aeruginosa (71.2%), and non-tuberculous mycobacterium (10.0%) in the South. The South region also had the lowest mean body mass index and forced expiratory volume in one second. Chronic medication usage such as inhaled tobramycin or macrolides followed P. aeruginosa distribution, while inhaled dornase alfa was most used in the West (84.7%). Co-morbid conditions varied, with the highest percentage of depressed subjects in the Midwest (18.3%). Mean regional mortality rates were not statistically different among regions, although highest in each age grouping of the South., Conclusions: The U.S. has significant regional variations in CF demographics, insurance, pathogens, medication usage, and co-morbidities, without an overall impact on regional mortality. Regional variations in care practices should be studied further based on the findings., (© 2015 Wiley Periodicals, Inc.)

Objective: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis with recently acquired Pseudomonas aeruginosa infection., Design: Randomized controlled trial., Setting: Multicenter trial in the United States., Participants: Three hundred four children with cystic fibrosis aged 1 to 12 years within 6 months of P aeruginosa detection., Interventions: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures., Main Outcome Measures: The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of P aeruginosa -positive cultures., Results: The intention-to-treat analysis included 304 participants. There was no interaction between treatments. There were no statistically significant differences in exacerbation rates between cycled and culture-based groups (hazard ratio, 0.95; 95% confidence interval [CI], 0.54-1.66) or ciprofloxacin and placebo (hazard ratio, 1.45; 95% CI, 0.82-2.54). The odds ratios of P aeruginosa- positive culture comparing the cycled vs culture-based group were 0.78 (95% CI, 0.49-1.23) and 1.10 (95% CI, 0.71-1.71) comparing ciprofloxacin vs placebo. Adverse events were similar across groups., Conclusions: No difference in the rate of exacerbation or prevalence of P aeruginosa positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits., Trial Registration: ClinicalTrials.gov Identifier: NCT00097773.

Tobramycin Inhalation Solution USP (TOBI), a therapy developed to treat lung infections associated with cystic fibrosis (CF), was presented as a demonstration case for collaborative pharmaceutical development at a Clinical and Translational Science Awards Industry Forum on "Promoting Efficient and Effective Collaborations Among Academia, Government, and Industry" held in February 2010. TOBI was developed by PathoGenesis Corporation (Seattle, WA) in collaboration with the academic inventors, the National Institutes of Health, the U.S. Food and Drug Administration, and the CF Foundation. The presenters, representing the academic, industry, and foundation partners, each reviewed the program from their perspectives and identified challenges that existed during the discovery, development, and commercialization of TOBI. The attendees were asked to consider other collaborative opportunities that might have further improved TOBI development, including the optimal roles of the academic researchers, foundations, and other agencies when industry drives development and commercialization decisions.

Background: Pseudomonas aeruginosa (PA) is the most common airway pathogen in cystic fibrosis (CF) patients. The objective of this analysis was to determine the costs of managing PA infection in CF patients with a chronic regimen of tobramycin inhalation solution (TIS)., Methods: A budget impact model of CF patients was developed to evaluate the costs of TIS from a US managed-care organization (MCO) perspective. The Microsoft Excel model compared TIS treatment plus standard care with standard care alone over a 4-year time horizon and included the cost of drugs, medical care, and annual probabilities of hospitalization and IV anti-pseudomonal (anti-PA) antibiotics administration., Results: For an MCO with 5,000,000 members, 389 members 6 years of age or older were estimated to have CF, and 218 (56%) had PA infection. Assuming that use of TIS increased from 20% to 25%, the 1-year budget increased $231,251 or from $0.049 to $0.053 per member per month (PMPM). The net drug budget increase was $243,919, while medical costs associated with exacerbation management decreased $12,669 over the first year. Increasing utilization of TIS, from 20% to 40% over 4 years resulted in an incremental overall budget increase of $925,002, a 3% decrease in hospitalizations, and a 4% decrease in administrations of IV anti-PA antibiotics. These reductions translated to a medical care cost saving of $50,676 over 4 years. Limitations of this study include that the clinical data for the model are from clinical trials conducted in 1996 and the estimation of TIS use for CF patients with chronic PA infections can be impacted by TIS adherence., Conclusion: Model results suggest that increasing the use of TIS decreases medical care costs due to decreased hospital admissions and the use of IV anti-PA antibiotics at the expense of higher drug costs.

Rationale: Pseudomonas aeruginosa lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis., Objectives: This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection., Methods: A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis., Measurements: Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively., Main Results: An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%)., Conclusions: The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.

Rationale: We recently reported a randomized, placebo-controlled trial of azithromycin in patients with cystic fibrosis (CF) that demonstrated a 6.2% improvement in the 168-d relative change in FEV1 among azithromycin participants compared with placebo participants., Objectives: In the current analyses, heterogeneity of treatment response and the association between FEV1 and the risk of pulmonary exacerbations were investigated., Methods: The time to first pulmonary exacerbation, hospitalization rates, and antibiotic use were compared between participants categorized by their relative change in FEV1 % predicted (>or= 5 vs. < 5% improvement) at Day 168. Pulmonary function and exacerbation responses were compared in subgroups of participants characterized by long-term concomitant medications and baseline lung function., Measurements: All available data from the 185 randomized participants in the azithromycin trial were included in these analyses., Main Results: Compared with placebo participants, a reduced risk of pulmonary exacerbations was observed both among azithromycin participants with >or= 5% and those with < 5% relative improvement in FEV1. Similarly, decreased hospitalization rates and decreased use of oral quinolone and nonquinolone antibiotics were observed in azithromycin participants regardless of improvement in FEV1. Subgroup analyses demonstrated that overall, participants on long-term aerosolized tobramycin and/or rhDNase had worse baseline lung function, but still benefited from azithromycin, as evidenced by a lower risk of exacerbations., Conclusions: Azithromycin participants experienced benefits in exacerbation parameters regardless of FEV1 response or subgroup. These data have implications for clinical practice and the design of clinical trials.

Study Objectives: To describe the pharmacokinetics and bioavailability of inhaled tobramycin (TOBI; Chiron Corporation; Seattle, WA), 300-mg dose, delivered by a nebulizer (PARI LC Plus; Pari Respiratory; Richmond, VA) and a compressor (Pulmo-Aide, model 5650D; DeVilbiss Health Care; Somerset, PA) in cystic fibrosis (CF) patients during the pivotal phase III trials., Design: Data from two identical, 24-week, randomized, double-blind, placebo-controlled, parallel-group studies., Setting: US sites randomized 258 patients with CF to receive tobramycin, 300 mg twice daily, in three 28-day on/28-day off treatment cycles., Measurement: Tobramycin sputum concentrations were assessed 10 min after the first and last doses were administered in the 20-week study. Serum tobramycin concentrations were assessed before and 1 h after the first and last doses had been administered. The population estimate of the apparent clearance was used to estimate the bioavailability fraction., Results: The mean peak sputum concentration was 1,237 microg/g. About 95% of patients achieved sputum concentrations > 25 times the minimum inhibitory concentration of the Pseudomonas aeruginosa isolates. One hour after the dose, the mean serum concentration was 0.95 microg/mL. Tobramycin did not accumulate in the sputum or serum over the course of the study. Pharmacokinetic data were best represented by a two-compartment model with biexponential decay and slope estimates comparable to those following parenteral administration. The estimated systemic bioavailability after aerosol administration was 11.7% of the nominal dose., Conclusions: The administration of tobramycin, 300 mg bid, in a 28-day off/28-day on regimen produced low serum tobramycin concentrations, reducing the potential for systemic toxicity. High sputum concentrations ensure efficacious antibiotic levels at the site of the infection. Inhaled tobramycin significantly improved the therapeutic ratio over that of parenteral aminoglycosides.

During a phase III national collaborative study of aerosolized tobramycin (1 July 1995 through 30 September 1996), the microbiology of specimens from 595 patients at 69 cystic fibrosis (CF) centers was examined. Samples from three screening visits were processed in a single laboratory by means of standardized techniques for identification and susceptibility testing. From 1,753 pretreatment specimens, 5,128 pathogens were isolated (average, 2.9/specimen). Of the 3,936 Pseudomonas aeruginosa isolates, 56.7% were mucoid. The specimens of 125 patients (21.0%) yielded tobramycin-resistant P. aeruginosa (213 isolates); 61 (10.3%), Stenotrophomonas maltophilia; and 52 (8.7%), Alcaligenes xylosoxidans. Isolation of Burkholderia cepacia was an exclusion criterion. Only visit 3 sputum samples were cultured for gram-positive organisms and fungi (n = 465 patients); samples from 201 patients (43.2%) yielded Staphylococcus aureus (18.8% of isolates were oxacillin-resistant), and those from 114 (24.5%) yielded an Aspergillus species. Compared with the Cystic Fibrosis Foundation Patient Registry, the current study identified many more patients colonized with S. maltophilia, A. xylosoxidans, Aspergillus species, and oxacillin-resistant S. aureus, suggesting the utility of standardized processing of CF specimens.

Admission of a patient with group A streptococcal cellulitis and bacteremia to the intensive care unit of a tertiary care teaching hospital was followed by two subsequent cases of group A streptococcal bacteremia with pneumonia in the unit. All streptococcal isolates were the same M- and T-type. Endotracheal intubation with respiratory ventilation was a risk factor for disease acquisition. The characteristics of onset of the two nosocomially acquired cases suggested that a staff member may have been, at least transiently, a streptococcal carrier, but no such carrier was identified. No further cases occurred subsequent to a period when all patients in the unit received antibiotics effective for group A streptococcal therapy.

A retrospective review of 114 patient charts was conducted at three geographically different hospitals to compare the costs of ceftazidime (CTZ) with the combination of tobramycin and ticarcillin (T/T) in the treatment of hospital-acquired pneumonias and/or septicemias. Variables analyzed to determine the cost of the therapy included duration of treatment, dosage and number of doses administered, side effects, and laboratory tests. Time and motion studies were also performed and the results included in the algorithm. In two of the three hospitals, the computer-calculated cost of CTZ therapy was significantly less than for T/T therapy ($1194 vs. $1668 and $93 vs $629). In the third hospital there was no significant difference in the costs of the two treatments ($1079 for CTZ vs. $1066 for T/T). The cost of each regimen per patient day followed a similar pattern, with CTZ therapy being significantly less expensive in the same two hospitals. Patients receiving CTZ therapy realized an average cost savings of $29.70 per day at the three institutions. These savings appeared to be due to a reduction in laboratory and administration costs resulting from the decreased frequency of CTZ administration. We conclude that CTZ therapy was less costly than T/T therapy at three geographically different institutions when the cost of supplies, laboratory tests, and personnel time were taken into account.