Trends in Australian dental prescribing of antibiotics: 2005-2016.

BACKGROUND: Prescribing of antibiotics by dentists for surgical prophylaxis or as an adjunct to managing dental infections is a substantial part of the overall landscape for prescribed antibiotics in health care settings. METHODS: We explored trends in the antibiotic prescribing patterns of Australian dentists over the 12-year period, 2005-2016. We obtained data on dispensed prescriptions of antibiotics from registered dentists subsidized on the Pharmaceutical Benefits Scheme. RESULTS: Australian dentists were responsible for almost 7 million dispensed prescriptions of antibiotics over 12 years; an average of 24 prescriptions per year per dentist. The most commonly prescribed antibiotic was amoxicillin, followed by amoxicillin + clavulanic acid and metronidazole. These top three antibiotics constituted more than 80% of all antibiotics prescribed and their use increased dramatically over time. There was a large increase in the prescribing of broad-spectrum antibiotics over time, most of which occurred from 2011 to 2016. CONCLUSIONS: Excessive prescribing of broad-spectrum antibiotics runs contrary to national antimicrobial stewardship (AMS) initiatives and guidelines. Multifaceted educational strategies are essential to align prescribing with current best practice. High-level evidence to inform clear guidelines on antibiotic prescribing in dental infections, with audit and feedback, should reduce the inappropriate use of antibiotics in dentistry.

Longitudinal impact of the Women's Health Initiative study on hormone therapy use in Australia.

Purpose: This study aimed to examine the longitudinal impact of evidence changes on menopausal hormone therapy (MHT) use in Australia. Methods: We analyzed two datasets of subsidized and total MHT use (2000-2016) using segmented regression analysis to explore the impact of the Women's Health Initiative (WHI) 2002 and 2007 studies. Analyses were stratified by class, route, and strength. Use was measured in defined daily dose/1000 women/day (DDD/1000/day) or packs/1000 women/month (packs/1000/month). Results: The drop in total MHT use after the WHI 2002 was substantial. The biggest decreases in class, route, and strength were estrogens (28.99 DDD/1000/day, 95% confidence interval [CI] 23.97, 34.01), oral (46.07 DDD/1000/day, 95% CI 41.13, 51.01), and medium strength (34.95 packs/1000/month, 95% CI 30.17, 39.73), respectively. However, vaginal use remained stable (-1.83 DDD/1000/day, 95% CI -3.83, 0.17). Profiles of total and subsidized use were similar over time. Utilization levels were relatively unchanged after 2007. Decreased utilization contributed to product discontinuation, with a lag of up to 4 years. Product discontinuation in 2009 further decreased utilization. Discussion and conclusions: MHT use remained low after 2002 despite evidence favoring its use in women younger than 60 years or within 10 years postmenopause. Continued low use could relate to the WHI 2002 media coverage, therapy objectives, key stakeholder uncertainty, health policies, and medicine availability.

The impact of clozapine on hospital use: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis of studies reporting the impact of clozapine on hospital use in people with a psychotic illness. METHOD: PubMed, EMBASE, PsycINFO and the Cochrane Schizophrenia Group Trials Register were systematically searched from inception to 12 October 2016. We included all trials and observational studies, except case reports. RESULTS: Thirty-seven studies were included. Clozapine significantly reduced the proportion of people hospitalised compared to control medicines (RR = 0.74; 95% CI: 0.69-0.80, P < 0.001, 22 studies, n = 44 718). There were significantly fewer bed days after clozapine treatment compared to before clozapine treatment in both controlled (MD = -34.41 days; 95% CI: -68.22 to -0.60 days, P = 0.046, n = 162) and uncontrolled studies (MD = -52.86 days; 95% CI: -79.86 days to -25.86 days, P < 0.001, n = 2917). Clozapine and control medicines had a similar time to rehospitalisation (-19.90 days; 95% CI: -62.42 to 22.63 days, P = 0.36). CONCLUSION: Clozapine treatment reduced the number of people hospitalised and the number of bed days after treatment compared with before treatment. Clozapine has the potential to reduce acute hospital use among people with treatment refractory schizophrenia.

Triptan use in Australia 1997-2015: A pharmacoepidemiological study.

OBJECTIVE: This study examined the use of triptan derivatives in Australia between 1997 and 2015, based on a national drug reimbursement database, and compared patterns of use with available international data. METHODS: We obtained publically available data on the number of prescriptions for triptans marketed in Australia (sumatriptan, eletriptan, rizatriptan, zolmitriptan, naratriptan). Dispensed use was measured as defined daily dose (DDD per 1000 population per day) for Australia's concessional beneficiaries (low-income earners, people with disabilities, and seniors). RESULTS: Total triptan use increased at an average annual rate of 112% over the 18-year period. Sumatriptan was the preferred triptan throughout (average annual increase 45%). Zolmitriptan and naratriptan use peaked in 2004, then decreased. Rizatriptan and eletriptan became available in 2010. There were 3.2-fold and 5.9-fold annual increases in their use from 2011 to 2105. There was some evidence suggesting that pattern of triptan use in concessional beneficiaries probably reflected pattern of overall triptan use in Australia. CONCLUSIONS: The use of triptan derivatives in Australia per head of population for treating migraine attacks continued to increase over the 18-year period studied, with use of recently introduced derivatives more than substituting for decreased use of older triptans. This suggests that the available treatments of migraine attacks had achieved what were considered less than adequate therapeutic outcomes.

Prescribing patterns of dental practitioners in Australia from 2001 to 2012. Antimicrobials.

BACKGROUND: The development of antibiotic resistance by bacteria is of global concern. Inappropriate prescribing has the potential to exacerbate this issue. We aimed to examine the patterns of prescribing of antimicrobial medicines by dental practitioners in Australia from 2001 to 2012. METHODS: Data were collected from Medicare Australia on prescriptions from dental practitioners dispensed to concessional beneficiaries between 2001 and 2012. We examined patterns of use over time. RESULTS: There was an overall increase in number of prescriptions and in dispensed use (standardized by dose and population) of antibiotics and antifungals for the concessional population over the 12-year period. The use of dentally prescribed antibiotics increased 50%. Amoxicillin was the most commonly prescribed antibiotic accounting for 66% of all prescriptions in 2012. Generally, there was preferential prescribing of the highest dose formulations. The use of the two antifungals increased 30% over the study period with a preference for amphotericin B (74%) rather than nystatin. CONCLUSIONS: These data show a concerning increase in prescribing of antibiotics and antifungals by dentists in Australia. It would appear that Australian dentists may not be prescribing these medicines appropriately; however, further research is needed to understand prescribing behaviours and decision-making by dentists.

Off-label use of tumour necrosis factor-alpha inhibitors and anakinra at an Australian tertiary hospital.

BACKGROUND: Tumour necrosis factor-alpha inhibitors (anti-TNFα) and anakinra are monoclonal antibodies against pro-inflammatory cytokines overexpressed in many systemic inflammatory diseases. In Australia, they are registered for the treatment of several rheumatological, gastroenterological and dermatological indications. Despite increasing observational evidence for their use in off-label indications, there is a paucity of outcome research from the Australian hospital sector. AIMS: To describe the off-label use of anti-TNFα and anakinra at a tertiary referral hospital in Queensland, Australia and consideration of a drug register to inform future clinical decision-making. METHODS: We performed an in-depth retrospective chart audit of off-label treatment with anti-TNFα or anakinra at the Royal Brisbane and Women's Hospital from mid-2010 to mid-2014, linking demographic, phenotypic, pathology and outcome data with these drugs. RESULTS: Off-label use was identified in 10 patients. The most frequent indications were sarcoidosis and dermatological conditions. Three patients required sequential therapy with a second anti-TNFα (total responses = 13). Complete response occurred in 46%, partial response in 38% and primary non-response in 8%. Response was unable to be determined in 8%. We recorded 14 adverse events (infections most common). CONCLUSION: This study suggests that anti-TNFα may be beneficial for some off-label indications (e.g. sarcoidosis). However, the observational design of this study (and pre-existing research) limits the ability to infer causality and generalise results. We propose the creation of a mandatory drug register to monitor off-label use. Whilst comparative efficacy cannot be established without a matched placebo arm, a register would enable some reporting on effectiveness in rare diseases and identify infrequent but serious adverse events.

Continuous intrafetal infusion of prostaglandin E2 prematurely activates the hypothalamo-pituitary-adrenal axis and induces parturition in sheep.

This study has investigated the effect of continuous intrafetal infusion of PGE2 or saline on hormone concentrations and the length of gestation in sheep. Fetal and maternal vascular catheters were surgically implanted at 112.3 +/- 1.3 days (n = 10), and the infusions were started at 121 +/- 1.2 days of gestation (term = 147). Fetuses were infused with either PGE2 (n = 5; 2 micrograms/min for 48 h and then increased to 4 micrograms/min for the remainder of the experiment) or the vehicle solution (n = 5; sterile isotonic saline) via the fetal carotid artery. In the PGE2-infused group, fetal and maternal plasma PGE2 concentrations increased (P < 0.001) after the change to the higher dose rate (4 micrograms/min) and remained elevated, fetal plasma immunoreactive ACTH (ir-ACTH) concentrations dramatically increased after the start of the infusion being maximal at 11 h before decreasing to match concentrations exhibited by the saline-infused group. Fetal plasma cortisol concentrations increased after the start of the PGE2 infusion (P = 0.05) and increased further after the change to the higher dose rate of 4 micrograms/min (P < 0.001). Concentrations of PGE2, ir-ACTH, and cortisol in the saline-infused group did not change until labor. Plasma concentrations of PGE2 (P < 0.001) and ir-ACTH (P < 0.005) increased on the day of labor in both treatment groups, and fetal cortisol concentrations increased (P < 0.001) in both groups in the last few days before labor. The proportion of low molecular weight ir-ACTH in the plasma of PGE2-infused fetuses was significantly higher than that of saline-infused fetuses (P < 0.001) during the first 15 days of infusion. In the saline-infused group, the proportion of low molecular weight ir-ACTH increased in the last few days before labour (P = 0.001), whereas no change was seen in PGE2-infused fetuses at this time. Maternal plasma progesterone concentrations decreased in both groups in the last few days before labor (P < 0.001). Fetuses infused with PGE2 delivered at 138.4 +/- 2.1 days, whereas control fetuses infused with saline delivered at 148.2 +/- 0.5 days (P < 0.001). The spontaneous increase in PGE2 preceding normal labor may thus play an important role in activation and maturation of the hypothalamic-pituitary-adrenal axis in fetal sheep.

Rebound increase in fetal breathing movements after 24-h prostaglandin E2 infusion in fetal sheep.

We investigated the hypothesis that the precipitous decrease in prostaglandin E2 (PGE2), a potent inhibitor of fetal breathing, from high plasma concentrations during labor causes a rebound stimulation of breathing without newborn concentrations falling below prelabor fetal values. Fetal plasma PGE2 concentration was gradually increased from 384 +/- 82 (SE) pg/ml in 2-h steps [0 (baseline), 1.5, 3, and 6 micrograms/min] to labor levels (1,230 +/- 381 pg/ml at 6 micrograms/min) and then was maintained for 24 h (n = 9). PGE2 at 1.5 micrograms/min significantly decreased breathing incidence [from 42 +/- 4 (baseline) to 14 +/- 4%] and breath amplitude (from 2.1 +/- 0.5 to 1.5 +/- 0.2 arbitrary units) and increased breath-to-breath interval (from 1.16 +/- 0.07 to 1.56 +/- 0.06 s). No further dose-related changes were observed. During the first 2 h after PGE2 infusion was stopped, PGE2 concentration returned to basal (352 +/- 64 pg/ml) but breathing incidence and amplitude were significantly higher (74 +/- 8% and 2.4 +/- 0.3 arbitrary units, respectively) and breath-to-breath interval was significantly lower (0.95 +/- 0.10 s) than were basal levels. Changes arose within approximately 15 min and were maintained for at least 4 h. Breathing did not change significantly in the saline-treated group (n = 7). Results suggest that the rapid decrease in plasma PGE2 concentration at birth promotes the onset of breathing.

Prostaglandin E2 administered to fetal sheep increases the plasma concentration of adrenocorticotropin (ACTH) and the proportion of ACTH in low molecular weight forms.

This study investigated the effects of repeated short term (2-h) intrafetal infusions of prostaglandin E2 (PGE2) on ACTH and cortisol release in fetal sheep during late gestation (119-144 days). We compared the effects of administration of PGE2 (2 micrograms/min) into the fetal carotid artery or jugular vein. PGE2 infusion significantly (P < 0.001) increased fetal plasma immunoreactive (ir-) ACTH and cortisol concentrations regardless of the vessel used for administration. Saline infusion did not alter the concentrations of ir-ACTH or cortisol for the duration of the experiment. To compare the responses of fetal ir-ACTH and cortisol to repeated intracarotid infusions of PGE2, the hormone data were grouped into five gestational age ranges (119-125, 126-130, 131-135, 136-140, and 141-145 days). Fetal ir-ACTH was stimulated by PGE2 infusion at all gestational ages studied; the greatest response was achieved at the earliest gestational age range, 119-125 days. PGE2 infusion preferentially stimulated the release of low mol wt ACTH [ACTH-(1-39); 60 min from the start of infusion] at all gestational ages (P < 0.01), but basal low mol wt ACTH did not increase with gestational age until after 140 days. Cortisol concentrations were increased within 30 min of infusion at all gestational ages studied. These results suggest that PGE2 may play a role in maintaining elevated ir-ACTH concentrations in the face of high levels of cortisol in fetal sheep before parturition.

Chronic administration of low doses of adrenocorticotropin to hypophysectomized fetal sheep leads to normal term labor.

Parturition in the sheep is preceded by an increase in the plasma concentration of fetal ACTH and an increase in the plasma cortisol concentration. The role and importance of the increase in fetal ACTH in stimulating fetal glucocorticoid synthesis and the subsequent onset of labor require closer examination, as it has been demonstrated that the fetal adrenal becomes more responsive to ACTH in late gestation. This study sets out to determine whether the increase in plasma ACTH in the late gestation fetal sheep is essential for maturation of the fetal adrenal gland and normal delivery. Fetal sheep were either hypophysectomized (HX) and cannulated or cannulated only (intact) at 125 days gestation. Immediately after surgery, HX fetuses were infused with a constant dose of ACTH-(1-24) (ACTH/HX; 100 ng/h.kg, i.v.) or saline (SAL/HX) until uterine electromyography indicated the onset of labor or 161 days gestation was reached (term = 147 +/- 2.6 days). The mean gestational age at labor of the ACTH/HX group was 147 +/- 2.9 days, whereas none of the animals in the SAL/HX entered labor, and they were killed at 161 days gestation. The concentration of ACTH in both ACTH/HX and SAL/HX fetal plasma was less than 2.2 pg/ml throughout the study. The concentration of cortisol in ACTH/HX fetuses mimicked that in intact fetuses in late gestation, reaching 80 ng/ml at term. The concentration of cortisol in SAL/HX fetuses remained less than 5 ng/ml. This study supports the hypothesis that the ovine fetal adrenal becomes increasingly responsive to ACTH in late gestation and indicates that ACTH may only be permissive in the activation of adrenal function. In intact fetal sheep there may be endogenous inhibition of the fetal adrenal, requiring relatively high plasma concentrations of ACTH [100-250 pg/ml ACTH-(1-39)] in late gestation.

Effect of late hypothalamo-pituitary disconnection on the development of the HPA axis in the ovine fetus and the initiation of parturition.

The studies of Liggins et al. (1) in which fetuses stalk-sectioned from day 116 onwards delivered at or near term, suggested that a connection between the fetal hypothalamus and pituitary is not essential for parturition to occur. The objective of this study was to repeat these experiments on the effects of pituitary stalk sections at different gestational ages and include information on the plasma concentrations of key fetal hormones. We have used the more sophisticated technique of hypothalamo-pituitary disconnection (HPD) at either of two gestational age ranges (123-127 days or 133-135 days). Completeness of the procedure was assessed by demonstrating an attenuated prolactin response to chlorpromazine challenge. Following HPD, gestation was prolonged for at least eight days beyond term (146.2 +/- 1.5 days) in 9 of the 10 fetuses operated. Fetal plasma ACTH1-39 concentrations were not different between the HPD and control fetuses, increasing in all groups with increasing gestation. Fetal plasma cortisol concentrations increased (P < 0.01) in control fetuses over gestation. Cortisol concentrations did not change significantly in the day 125 HPD group following HPD but increased in the day 135 HPD group (P < 0.05) with advancing gestation. These latter concentrations, however were markedly less (P < 0.001) than those for control fetuses prior to parturition. Fetal and maternal plasma PGE2 concentrations increased (P < 0.01) in the control group over gestation but did not change following HPD. Maternal plasma progesterone concentrations decreased (P < 0.05) after day 143 in the control group but did not change in the HPD group.(ABSTRACT TRUNCATED AT 250 WORDS)

The trigger for parturition in sheep: fetal hypothalamus or placenta?

The fetal pituitary-adrenal axis plays a pivotal role in the mechanisms leading to parturition in sheep. Fetal cortisol concentrations gradually increase in the last 15 days before term, with a marked increase occurring in the last 3-4 days. Some mechanism causes a marked increase in the stimulatory drive to the fetal pituitary resulting in increased secretion of ACTH from the pituitary, and subsequent cortisol secretion from the adrenal gland. In this paper we discuss the roles of the hypothalamus and placenta in triggering the onset of labour in sheep. We have shown that prostaglandin E2 can stimulate the release of ACTH and cortisol in the intact fetus and we believe that this could be mediated by the release of CRH and AVP. Although CRH and AVP are present in the fetal hypothalamus and are capable of being released, these factors may not be released until approximately 135 days of gestation. One fundamental question in relation to parturition remains unanswered: how are the high concentrations of cortisol in fetal plasma sustained given that cortisol has an inhibitory feedback effect on the release of CRH and ACTH secretion? We discuss the possibility that the placenta provides an additional trophic drive to both the pituitary and adrenal glands which contributes towards the sustained elevated cortisol concentrations needed to initiate parturition. The placenta may initiate the hypothalamus and PGE2 and/or CRH, secreted by the placenta, may stimulate pituitary ACTH release.

Prostaglandin G/H synthase activity in ovine cotyledons: a gestational profile.

A polarographic oxygen electrode technique was used to quantify the activity of prostaglandin G/H synthase present in microsomes prepared from cotyledons of ewes at 74 to 147 days of gestation (n = 25). Microsomal oxygen consumption was stimulated by arachidonic acid and suppressed significantly (p less than 0.0001) by indomethacin, a specific inhibitor of prostaglandin G/H synthase. A residual indomethacin-incentive oxygen consumption was identified but the magnitude of this component did not change during gestation. During gestation prostaglandin G/H synthase (PGHS) activity, present in ovine cotyledons, increased 22-fold, from 0.6 +/- 0.19 at 70-80 days (n = 3) to 13.22 +/- 2.08 nmol O2/min/mg protein at greater than 145 days of gestation (n = 8; p less than 0.001). This gestational increase in the PGHS activity present in ovine cotyledons was not observed when fetal hypophysectomy was performed at 70-80 days of gestation. The data obtained in this study are consistent with the hypothesis that cotyledonary PGHS activity is increased during the second half of gestation and that this increase may be dependent upon fetal pituitary factors.