Direct Detection of Carbapenem-Resistant Organisms from Environmental Samples Using the GeneXpert Molecular Diagnostic System.

In this pilot study, traditional culture and PCR methods were compared to the Cepheid GeneXpert IV molecular diagnostic system with the Xpert Carba-R assay (Carba-R assay) for detection of carbapenem resistance genes in primary environmental samples collected during a health care-related outbreak. Overall, traditional culture-dependent PCR and the Carba-R assay demonstrated 75% agreement. The Carba-R assay detected carbapenemase genes in five additional samples and in two samples that had additional genes when compared to culture-dependent PCR. The Carba-R assay could be useful for prioritizing further testing of environmental samples during health care-related outbreaks.IMPORTANCE Use of the Carba-R assay for detection of carbapenem-resistant Gram-negative organisms (CROs) can provide data for implementation of a rapid infection control response to minimize the spread of CROs in the health care setting.

Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

On the history and definition of Preiser's disease.

In 1910, Georg Preiser (1876-1913) described five cases of rarifying osteitis. Based on his imaging studies, he diagnosed post-traumatic avascular necrosis (AVN) of the scaphoid without any sign of primary fracture. This was followed by an article in 1911 in which Preiser related his findings to Kienböck's disease and Köhler's disease of the tarsal navicular. Upon searching the literature, we found descriptions and discussions of Preiser's imaging; however, the original images have never been published. We reproduce Preiser's original imaging in this current review. All of these appear to show a fracture and no signs of AVN, suggesting that Georg Preiser misinterpreted his findings. There is no apparent uniformity in the literature regarding the definition, description, or aetiology of Preiser's disease, and it is for this reason that we find the use of eponyms to be confusing.

An in vitro evaluation of disinfection protocols used for needleless connectors of central venous catheters.

UNLABELLED: A repeatable and sensitive method to evaluate the effect of three antiseptics and two disinfection techniques on viable micro-organisms on luer-activated catheter needleless connectors (NCs) was developed. NCs were inoculated with Staphylococcus epidermidis or Klebsiella pneumoniae and disinfected with 3·15% chlorhexidine gluconate + 70% isopropanol (CGI), 70% isopropanol (IPA) or 10% PVP povidone-iodine (PI) antiseptic pads using: (i) scrubbing the NC septum and threaded external surfaces or (ii) wiping only the surface of the septum. Treatments were also evaluated against NCs pretreated with human serum and exposed for 18 h to Staph. epidermidis prior to testing. Viable cells were quantified by plate count. The method for inoculation and recovery of luminal micro-organisms was repeatable (SD, 0·31; n = 28). IPA disinfection provided an approximate 3 log10  CFU reduction; CGI and PI provided 3-4 log10 reductions. PI and CGI were more effective than IPA (P < 0·05), but differences between CGI and PI were not significant for either disinfection method. IPA, but not CGI and PI was also less effective (P < 0·05) against NCs inoculated with Kl. pneumoniae than Staph. epidermidis. Pretreatment with serum and prolonged Staph. epidermidis inoculation removed the advantage seen with CGI and PI; log10 reductions were 1·80, 1·73 and 2·50 for CGI, PI and IPA, respectively. PI or CGI may be more effective than IPA for NC disinfection but effectiveness may be reduced on NCs contaminated with blood or serum. SIGNIFICANCE AND IMPACT OF THE STUDY: sensitive and repeatable protocol was developed to evaluate antiseptics for disinfecting catheter needleless connectors (NCs). Povidone-iodine (PI) and chlorhexidine gluconate plus isopropanol (CGI) were more effective than isopropanol (IPA) for reducing Staphylococcus epidermidis contamination of NCs. The effectiveness of PI and CGI was reduced on NCs pre-exposed to human serum and prolonged bacterial inoculation. IPA was also less effective against NCs contaminated with Klebsiella pneumoniae.

Is there an increased risk for drug treated attention deficit/hyperactivity disorder in children born after in vitro fertilization?

BACKGROUND: There is mounting evidence that children born after in vitro fertilization (IVF) run an increased risk of neurological complications and notably cerebral palsy. Whether developmental disturbances occur more often than expected is debated. AIM: To investigate the risk for ADHD in children conceived after IVF. METHODS: Children conceived after IVF and born between 1982 and 2005 were identified from all IVF clinics in Sweden. Children who developed attention deficit/hyperactivity disorder (ADHD) were identified with the use of a register over all prescribed drugs in Sweden, using prescriptions for methylphenidate or atomixetine as indicators of ADHD. Maternal and neonatal characteristics were obtained by linkage with the Medical Birth Register and relevant confounders were adjusted for using Mantel-Haenszel procedures. We studied 28 158 children born after IVF and compared them with 2 417 886 children in the population. RESULTS: After adjustment for year of birth, maternal age, parity, smoking, BMI, and maternal education and after exclusion of women who did not cohabit, a weak but statistically significant association was found with an odds ratio=1.18, 95% confidence interval 1.03-1.36. The effect was stronger in girls (OR=1.40) than boys (OR=1.11) but this difference could be random. After adjustment for length of involuntary childlessness, the OR decreased slightly and lost statistical significance. CONCLUSIONS: The study suggests a weak association between IVF and drug treated ADHD.

Cerebral palsy in children born after in vitro fertilization. Is the risk decreasing?

BACKGROUND: Infants born after in vitro fertilization (IVF) differ from spontaneously conceived infants in a number of aspects which could increase the risk for future cerebral palsy (CP), e.g., multiple births, preterm births, neonatal complications. AIMS: To follow up children conceived by IVF with respect to risk for CP. METHODS: Infants born after IVF were identified from all IVF clinics in Sweden 1982-2007. Perinatal characteristics were obtained by linkage with the Medical Birth Register. The presence of CP in children born after IVF and in other children was identified from the Patient Register which contains diagnoses given at hospitalizations or specialist outpatient clinics. The risk for CP after IVF was studied after adjustment for year of birth, maternal age, parity, and smoking, all factors which co-vary both with IVF and with CP. Stratification was made for singletons and multiple births and for various neonatal outcomes. RESULTS: The adjusted odds ratio for CP after IVF was 1.81 (95% confidence interval, 95% CI 1.52-2.13), lower and not statistically significant when singletons or when unlike-sexed twins were analyzed. Stratification for various neonatal characteristics also reduced odds ratios to non-significant levels. For the last few years of the study (2004-2007) when the twinning rate after IVF was <10%, the odds ratio for CP was 0.97 (95% CI 0.57-1.66). CONCLUSIONS: The moderately increased risk for CP was most likely a consequence of an increased risk of neonatal morbidity, notably associated with multiple births.

Staphylococcus aureus community-onset pneumonia in patients admitted to children's hospitals during autumn and winter of 2006-2007.

Staphylococcus aureus is a relatively uncommon cause of community-onset pneumonia (COP) that may complicate influenza infection. We reviewed admissions to children's hospitals to describe more systematically this entity. Records of patients hospitalized at three children's hospitals between 1 October 2006 and 30 April 2007 who had a positive S. aureus culture from a sterile site or respiratory specimen were reviewed and data were abstracted for episodes of primary S. aureus COP. Overall, 30 episodes met criteria for primary S. aureus COP; 12 (41%) involved methicillin-resistant S. aureus. Patients in 11 (37%) episodes were seen by a healthcare provider for their symptoms prior to hospital admission; three received an antimicrobial, none of which had activity against the S. aureus isolated. Mechanical ventilation was required in 21 (70%) episodes; five (17%) patients died. When evaluating patients with severe COP, providers should be aware of the potential for S. aureus, including methicillin-resistant strains.

In search of a rational approach to chronic kidney disease detection and management.

Rates of incident end-stage renal disease persist above established goals, driving efforts for early identification of chronic kidney disease (CKD) to reduce progression. The detection of CKD using existing electronic data sources has been proposed as an efficient identification method; however, this method is not without potential challenges and limitations.

Pharmacokinetics and systemic activity of fluticasone via Diskus and pMDI, and of budesonide via Turbuhaler.

AIMS: To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids. METHODS: Twenty-one subjects (13 healthy and 8 mild asthmatic patients) received fluticasone propionate via a chlorofluorocarbon-propelled pressurized metered-dose inhaler (pMDI) (healthy subjects only) and Diskus and budesonide via Turbuhaler, 1000 microg twice daily for 7 days. Intravenous doses (200 microg) of both compounds were used as references. Plasma concentrations of fluticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC-MS-MS). Plasma concentrations of cortisol were determined by LC-MS every second hour for 24 h at baseline, and following each treatment. RESULTS: The volume of distribution was found to be larger and the elimination half-life and mean absorption time longer for fluticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% confidence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of fluticasone via pMDI was significantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2-fold [1.7, 2.9] higher than that of fluticasone pMDI and 3.4-fold [2.8, 4.0] higher than that of fluticasone Diskus. In addition, the lung deposition of fluticasone via pMDI was 1.5-fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was significantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for fluticasone pMDI, which was significantly lower (ratio 0.32 [0.24, 0.42]) than that for fluticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ significantly between treatments with fluticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]). CONCLUSIONS: Budesonide and fluticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for fluticasone. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of fluticasone via pMDI and similar to that of fluticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of fluticasone and budesonide.

A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA-axis in healthy subjects.

AIMS: To investigate the effect on the hypothalamo-pituitary-adrenal (HPA) axis of treatment with budesonide, 400 microg once daily, morning or evening, or 200 microg twice daily, and 800 microg twice daily via Turbuhaler in a randomized, placebo-controlled, double-blind, double-dummy crossover study. METHODS: Healthy men received budesonide, 400 microg in the morning (08.00-09.00 h) or evening (20.00-21.00 h), budesonide, 200 microg twice daily, 800 microg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty-five subjects completed all treatments, and 27 were included in the analysis. RESULTS: The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 microg in the morning, 92% (83, 100) for 400 microg in the evening, 95% (86, 104) for 200 microg twice daily, and 76% (70, 84) for 800 microg twice daily. CONCLUSIONS: Budesonide at a dose of 400 microg day-1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 microg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.

A randomized controlled assessment of the systemic activity of budesonide when given once or twice daily via Turbuhaler.

OBJECTIVE: To compare the effects on the hypothalamo-pituitary-adrenal (HPA) axis of budesonide, delivered via Turbuhaler at doses of 800 microg once daily in the morning or evening or 400 microg twice daily. METHODS: Healthy men (n = 24) received four treatments in random order: budesonide, 800 Fg in the morning and placebo in the evening; budesonide, 800 microg in the evening and placebo in the morning; budesonide, 400 microg in the morning and evening; placebo in the morning and evening. Each treatment was given for 1 week, with a 2-week washout period between treatments. Blood samples for measurement of plasma cortisol were obtained before the evening dose on day 6 of each treatment period and over the following 22 h. RESULTS: All three budesonide regimens produced a statistically significant reduction (mean 16-19%) in the area under the curve of plasma cortisol concentration versus time over 22 h (AUC0-22h) compared with placebo. There were no statistically significant differences among the three regimens. These reductions in plasma cortisol concentrations were not considered to be clinically significant. Analysis of the fractional AUCs measured 0-10 h and 10-22 h after dosing showed that evening dosing had a greater effect on nocturnal cortisol than morning dosing; daytime cortisol was reduced by all treatments. CONCLUSION: There was no significant difference between the effects on plasma cortisol of budesonide 400 microg twice daily and 800 microg once daily in the morning or evening.

Canines as sentinels for Lyme disease in San Diego County, California.

Prevalence of Lyme borreliosis in canine sentinels has been shown to correlate with infection in humans. One thousand canine sera (917 dogs, 83 coyotes) obtained from animal control authorities and area veterinarians were screened by ELISA for antibodies to Borrelia burgdorferi. Results were validated by Western blot and indirect fluorescent antibody (IFA) tests at referee laboratories. Criterion for a positive Western blot was presence of 5 of 10 of the most common antigen IgG bands; for IFA, >1:128 or the equivalent when correcting for interlaboratory variability. Twenty-two of 1,000 canines were confirmed serologically positive (21 dogs and 1 coyote; seroprevalence 2.3% and 1.2%, respectively). Lifestyle, breed size, gender, and age were not statistically predictive of seropositive status. No regional clustering of seropositive animals was detected. The low prevalence of seropositivity in sentinel canines suggests the Lyme borreliosis hazard in San Diego County is minimal.

Increase in community-acquired methicillin-resistant Staphylococcus aureus at a Naval Medical Center.

A retrospective review of methicillin-resistant Staphylococcus aureus isolates from the Naval Medical Center, San Diego, for the years 1994 through 1997, found that the annual number of community-acquired MRSA isolates increased during the period. These outpatient isolates were more likely than inpatient isolates to be sensitive to a greater number of antibiotics.

16alpha-bromoepiandrosterone, a dehydroepiandrosterone (DHEA) analogue, inhibits Plasmodium falciparum and Plasmodium berghei growth.

Dehydroepiandrosterone (DHEA) and its analogue, 16alpha-bromoepiandrosterone (alpha-epi-Br), may have activity against viral and parasitic infections, including human immunodeficiency virus (HIV) and Cryptosporidium parvum. Therefore, we evaluated its antimalarial effects on Plasmodium falciparum and Plasmodium berghei. In vitro, chloroquine (CQ)-sensitive and resistant strains of P. falciparum parasitized red blood cells were incubated with escalating doses of alpha-epi-Br or CQ. In vivo, 62 rats were infected with P. berghei and treated with CQ or alpha-epi-Br. At the highest doses tested against a CQ-sensitive strain, parasitemias decreased from 25.4% in the saline control group to 4.3% and 4.8% in the alpha-epi-Br and CQ groups, respectively (P < 0.05). Against two CQ-resistant strains, parasitemias decreased from 22.3-28.8% and 24.8-30% in the CQ and saline groups, respectively, to 2.5-2.7% in the alpha-epi-Br groups (P = 0.003). In vivo, on Day 4, parasitemias decreased from 23% in the saline group to 9-12% and 12% in the in alpha-epi-Br and CQ groups, respectively (P < 0.05). These data demonstrate that alpha-epi-Br shows activity against CQ-sensitive and resistant strains of P. falciparum in vitro. At the doses tested against P. berghei in vivo in rats, alpha-epi-Br is comparable to CQ.

Dose-proportional pharmacokinetics of budesonide inhaled via Turbuhaler.

AIMS: The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg, 800 microg or 1600 microg administered twice daily by a dry-powder inhaler (Turbuhaler ) in adult patients with mild asthma. METHODS: A total of 38 patients received budesonide by inhalation, 13 received 400 microg twice daily, 12 received 800 microg twice daily and 13 received 1600 microg twice daily. Mean FEV1 at inclusion was 3.4, 4.0 and 3.9 l min-1 in the three groups, respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry. RESULTS: Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (tmax ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1. 4(2.0) nmol l-1 (single (repeated) doses), 2.6(3.6) nmol l-1 and 5. 4(6.4) nmol l-1 after 400, 800 and 1600 microg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l-1 min. Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0, infinity,SD)(P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. CONCLUSIONS: In this relatively small study, budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.

Dose response studies: how do we make them conclusive?

In this paper we discuss how to make meaningful use of a dose response study. It is argued that concepts like the minimal effective dose are not clinically meaningful and that the purpose of a dose response study should be to identify the drug potency in relation to a known active control. We also discuss various ways of carrying out the analysis.

Efficacy of cumulative doses of salbutamol administered via Turbuhaler or Diskhaler in patients with reversible airway obstruction.

The study aimed to estimate the relative dose potency of salbutamol inhaled via Turbuhaler and Diskhaler. The 24 adult patients participating had chronic reversible airway obstruction. The study was of a double-blind, double-dummy, crossover, randomized design. Five doses of salbutamol Turbuhaler, 50, 50, 100, 200, and 400 microg, were given on one study day at intervals of 30 min. On another study day, five doses of salbutamol Diskhaler, 200, 200, 400, 800, and 1600 microg, were given with the same interval. The treatment days were separated by a washout period of at least 24 h. The inhalation technique was standardized and supervised. Efficacy variables were recorded before and after each study dose. The primary efficacy variable was forced expiratory volume in 1 s (FEV1). When parallel and linear cumulative dose-response curves were statistically compared on a logarithmic scale, the dose potency of salbutamol Turbuhaler vs salbutamol Diskhaler was 1.99 (95% confidence interval 1.52-2.54). This study indicates that only half the dose of salbutamol is required via Turbuhaler as via Diskhaler for the same bronchodilating effect.

Atypical Pneumocystis carinii infection in AIDS: massive cervical lymphadenitis and fever of unknown origin.

Pulmonary Pneumocystis carinii infections are relatively common in patients with the acquired immunodeficiency syndrome (AIDS). Extrapulmonary pneumocystis is a less common manifestation, particularly when it occurs without concurrent Pneumocystis carinii pneumonia. Disseminated pneumocystis is most commonly found in lymph nodes, the liver, and the spleen and may result in nonspecific debilitating illness, which is often overlooked in the absence of pulmonary symptoms. We present the case of an AIDS patient who had massive cervical pneumocystis lymphadenitis and minimal pulmonary infiltrates of undetermined etiology and a clinical picture of severe wasting and fever of unknown origin.