A targeted infection prevention intervention in nursing home residents with indwelling devices: a randomized clinical trial.

IMPORTANCE: Indwelling devices (eg, urinary catheters and feeding tubes) are often used in nursing homes (NHs). Inadequate care of residents with these devices contributes to high rates of multidrug-resistant organisms (MDROs) and device-related infections in NHs. OBJECTIVE: To test whether a multimodal targeted infection program (TIP) reduces the prevalence of MDROs and incident device-related infections. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 12 community-based NHs from May 2010 to April 2013. Participants were high-risk NH residents with urinary catheters, feeding tubes, or both. INTERVENTIONS: Multimodal, including preemptive barrier precautions, active surveillance for MDROs and infections, and NH staff education. MAIN OUTCOMES AND MEASURES: The primary outcome was the prevalence density rate of MDROs, defined as the total number of MDROs isolated per visit averaged over the duration of a resident's participation. Secondary outcomes included new MDRO acquisitions and new clinically defined device-associated infections. Data were analyzed using a mixed-effects multilevel Poisson regression model (primary outcome) and a Cox proportional hazards model (secondary outcome), adjusting for facility-level clustering and resident-level variables. RESULTS: In total, 418 NH residents with indwelling devices were enrolled, with 34,174 device-days and 6557 anatomic sites sampled. Intervention NHs had a decrease in the overall MDRO prevalence density (rate ratio, 0.77; 95% CI, 0.62-0.94). The rate of new methicillin-resistant Staphylococcus aureus acquisitions was lower in the intervention group than in the control group (rate ratio, 0.78; 95% CI, 0.64-0.96). Hazard ratios for the first and all (including recurrent) clinically defined catheter-associated urinary tract infections were 0.54 (95% CI, 0.30-0.97) and 0.69 (95% CI, 0.49-0.99), respectively, in the intervention group and the control group. There were no reductions in new vancomycin-resistant enterococci or resistant gram-negative bacilli acquisitions or in new feeding tube-associated pneumonias or skin and soft-tissue infections. CONCLUSIONS AND RELEVANCE: Our multimodal TIP intervention reduced the overall MDRO prevalence density, new methicillin-resistant S aureus acquisitions, and clinically defined catheter-associated urinary tract infection rates in high-risk NH residents with indwelling devices. Further studies are needed to evaluate the cost-effectiveness of this approach as well as its effects on the reduction of MDRO transmission to other residents, on the environment, and on referring hospitals. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01062841.

New acquisition of antibiotic-resistant organisms in skilled nursing facilities.

The epidemiology of new acquisition of antibiotic-resistant organisms (AROs) in community-based skilled nursing facilities (SNFs) is not well studied. To define the incidence, persistence of, and time to new colonization with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and ceftazidime-resistant (CAZ(r)) and ciprofloxacin-resistant (CIP(r)) Gram-negative bacteria (GNB) in SNFs, SNF residents were enrolled and specimens from the nares, oropharynx, groin, perianal area, and wounds were prospectively cultured monthly. Standard microbiological tests were used to identify MRSA, VRE, and CAZ(r) and CIP(r) GNB. Residents with at least 3 months of follow-up were included in the analysis. Colonized residents were categorized as having either preexisting or new acquisition. The time to colonization for new acquisition of AROs was calculated. Eighty-two residents met the eligibility criteria. New acquisition of AROs was common. For example, of the 59 residents colonized with CIP(r) GNB, 28 (47%) were colonized with CIP(r) GNB at the start of the study (96% persistent and 4% intermittent), and 31 (53%) acquired CIP(r) GNB at the facility (61% persistent). The time to new acquisition was shortest for CIP(r) GNB, at a mean of 75.5 days; the time to new acquisition for MRSA was 126.6 days (P = 0.007 versus CIP(r) GNB), that for CAZ(r) was 176.0 days (P = 0.0001 versus CIP(r) GNB), and that for VRE was 186.0 days (P = 0.0004 versus CIP(r) GNB). Functional status was significantly associated with new acquisition of AROs (odds ratio [OR], 1.24; P = 0.01). New acquisition of AROs, in particular CIP(r) GNB and MRSA, is common in SNFs. CIP(r) GNB are acquired rapidly. Additional longitudinal studies to investigate risk factors for ARO acquisition are required.

Patterns of ciprofloxacin-resistant gram-negative bacteria colonization in nursing home residents.

We evaluated the prevalence of colonization with all gram-negative bacilli (GNB) and with ciprofloxacin-resistant GNB among nursing home residents with and without indwelling devices. We found that device presence increases the risk of colonization with all GNB and with ciprofloxacin-resistant GNB. Colonization with ciprofloxacin-resistant GNB increases with decreasing functional status.

Complex rhythmicity of growth hormone secretion in humans.

To better characterize the 24 hr GH secretion pattern in humans, we studied frequently sampled 24 hr GH profiles in 93 young (18-45 years of age) healthy, fed volunteers: men (n=67) and women (n=26) with BMI<26 kg/m(2). Analysis of the composite GH series in men revealed 3 significant GH "waves" with peaks occurring at midnight (p<0.0001), at noon (p<0.02) and at 1800 h (p<0.0001). In women, similar pattern was seen, with three GH "waves" peaking at midnight (p<0.0001), 1100 h (p<0.02) and at 1600 h (p<0.002). We conclude that the 24 hr rhythmicity of GH secretion is far more complex than currently appreciated. The attribution of the two daytime GH "waves" to food consumption is unlikely but cannot be excluded at the present time. The complex temporal pattern of pulsatile GH secretion may have important effects on regulation of target cell function.

Endogenous circulating ghrelin does not mediate growth hormone rhythmicity or response to fasting.

GH secretory profiles in humans are pulsatile and exhibit nocturnal elevation during the early hours of sleep. Fasting augments GH output and rhythmicity. Ghrelin was suggested to exhibit nocturnal increases and to rise in response to nutritional deprivation. We examined whether ghrelin may be an underlying mechanism of GH rhythmicity and response to fasting. We studied nine young healthy subjects during normal feeding and after 2 d of complete fasting. Plasma GH was measured every 10 min, and plasma total and active ghrelins were measured every 20 min. Fasting augmented mean daily plasma GH (1.47 +/- 0.25 vs. 3.30 +/- 0.6 microg/liter; P = 0.012). Neither mean daily total ghrelin (4.19 +/- 0.64 vs. 4.35 +/- 0.74 microg/liter; P = 0.75) nor mean daily active ghrelin (0.13 +/- 0.02 vs. 0.13 +/- 0.02 microg/liter; P = 0.34) changed as a result of fasting. All subjects exhibited nocturnal augmentation of GH secretion; there were no corresponding nocturnal increases in either total or active ghrelin concentrations. Similarly, cross-correlation analysis failed to find any relation between GH and ghrelin pulses. We conclude that ghrelin is unlikely to be of importance in the generation of rhythmic or nutritionally mediated GH secretion.

Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep.

OBJECTIVES: A temporal association between non-rapid eye movement (NREM) sleep stages 3 and 4 and nocturnal augmentation of GH release was found long ago, yet the precise mechanism for this association has not been identified. It has been shown, however that pulsatile GHRH administration increases both slow-wave sleep (SWS) and GH. Based on these data, a role for GHRH as an inducer of SWS was proposed. To test this hypothesis, we have performed the corollary experiment whereby the action of endogenous GHRH has been antagonized. DESIGN: Healthy men (20-33 years old) had an infusion of GHRH antagonist ((N-Ac-Tyr(1), D-Arg(2)) GHRH-29 (NH(2))) or saline for a 12-h period, between 2100 and 0900 h. An i.v. bolus of GHRH was given at 0700 h and GH samples were drawn from 0700 to 0900 h to document the efficacy of GH suppression by the GHRH antagonist. METHODS: A limited montage sleep study was recorded from 2300 to 0700 h during each admission. Plasma GH concentrations were analyzed by the use of a sensitive chemiluminometric assay. RESULTS: Effectiveness of the GHRH antagonist was validated in all subjects by demonstrating 93+/-1.8% (P=0.012) suppression of GH response to a GHRH bolus. Polysomnography demonstrated that the percentage of SWS was not different when saline and GHRH antagonist nights were compared (P=0.607); other quantifiable sleep parameters were also unchanged. CONCLUSIONS: We conclude that endogenous GHRH is indispensable for the nocturnal augmentation of GH secretion, but that it is unlikely to participate in the genesis of SWS.

Raloxifene decreases serum IGF-I in male patients with active acromegaly.

OBJECTIVE: Most patients with acromegaly require additional treatments after trans-sphenoidal surgery. Although traditional methods of treatment aim at suppressing GH hypersecretion from the pituitary tumor, recent studies on the use of the GH receptor antagonist have shown that targeting the action of GH on peripheral tissues may be more effective. Estrogens and the selective estrogen receptor modulator tamoxifen have been used previously to suppress circulating IGF-I levels in patients with acromegaly. Positive effects of raloxifene in women with active acromegaly have been reported recently. This study was designed to examine the potential role of raloxifene in the treatment of acromegaly in male patients. DESIGN: We studied eight men with active acromegaly despite the fact that they were receiving traditional treatments. All subjects were treated with raloxifene (60 mg twice a day) for a median of 5 weeks. METHODS: The effects of raloxifene on GH secretion were assessed by obtaining 24-h GH profiles and studying the response of GH to various stimuli before and after treatment with raloxifene. Serum IGF-I was measured before and after raloxifene treatment. RESULTS: Raloxifene did not affect basal GH secretion or response of GH to TRH, GHRH or glucose, but it decreased circulating IGF-I by 16+/-4% (P=0.001), and normalized plasma IGF-I in two patients. No changes in clinical parameters were observed. Prolactin levels, the prolactin response to TRH and free testosterone levels remained unchanged. Raloxifene was well tolerated. CONCLUSION: Raloxifene might be useful in the treatment of male patients with active acromegaly, but longer term studies are clearly needed.

Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men.

GH secretory patterns in humans are sexually dimorphic in terms of pulse regularity, amplitude of the diurnal rhythm, and magnitude of basal (trough) secretion. The neuroendocrine mechanisms of gender-specific GH regulation in humans are currently unknown, but the interpulse GH levels are generally assumed to be controlled by somatostatin. In rats, however, administration of antiserum to GHRH lowers GH interpulse levels in females but not males. In this study, using a competitive antagonist to GHRH in humans, we investigated whether endogenous GHRH has differential, gender-specific effects on the interpulse GH levels. Six healthy men and five healthy women (20-28 yr old) who were nonobese, did not smoke, and were on no medications known to influence GH secretion were studied. Each served as his or her own control during an infusion of GHRH antagonist or saline for a 27-h period. A control bolus of GHRH was given near the end of the infusion. In both sexes during GHRH antagonist infusion, mean GH, pulse amplitude, and GH response to GHRH decreased significantly, whereas pulse frequency remained unchanged. However, during the GHRH antagonist infusion, trough GH did not significantly change in men (P = 0.54) but significantly decreased in women (P = 0.008). Deconvolution analysis confirmed the lack of a significant change in basal secretion in men (P = 0.81) as opposed to women (P = 0.006). We conclude that sexual dimorphism in the neuroendocrine regulation of GH secretion in humans involves a differential role of endogenous GHRH in maintaining baseline GH.

Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.

We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.