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Background: On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally., Methods: MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant., Results: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively)., Discussion: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420., Competing Interests: Potential conflicts of interest. S. A. R. received research grants from Gilead Sciences and Merck. P. L. A. received research contracts from Gilead Sciences paid to his institution. S. L. H. received research grants and consulting fees from Merck. G. F. D. received research grants from Gilead Sciences. C. W. H. has received clinical research funding from Gilead Sciences and Merck; he is a coinventor of 2 issued US patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Inflammatory bowel disease [IBD] patients have a relapsing-remitting disease course, and amongst environmental factors that aggravate the disease course, common drugs aside from non-steroidal anti-inflammatory drugs have not been studied in detail. While the microbiome is considered to play a significant role on the disease course, the impact of antibiotics is poorly understood. This study investigated the potential impact of different classes of antibiotics on the course of disease in IBD using the Danish National Patient Registry., Methods: Danish IBD patients were studied using two nested case-control cohorts exploring associations between antibiotic types and IBD flare-ups, defined as IBD-related hospitalizations and/or high-dose systemic steroid exposure. Multivariate logistic regression and eXtreme Gradient Boosted decision tree [GBDT] machine learning methods evaluated antibiotic risks., Results: Two cohorts with 15 636 and 5178 patients were analysed for risk of hospitalization and course of steroids, respectively. The risk of a flare-up was significantly increased with antecedent exposure to quinolones (ATC:J01M; odds ratio [OR]: 3.04-3.82), antimycotics [ATC:J02A; OR: 1.50-2.30], agents against amoebiasis and protozoal infections [ATC:P01A; OR: 1.95-3.18], intestinal anti-infectives [ATC:A07A; OR: 2.09-2.32], and beta-lactam antibiotics [ATC:J01C; OR: 1.36]. The GBDT models achieved an area under the curve of 0.71-0.85 for predicting flare-ups, with the same above-mentioned antibiotics being in the ten most important variables., Conclusion: We found distinctive antibiotics to be significantly associated with an increased risk of IBD flare-ups. Our findings are corroborated by our GBDT machine learning models. Healthcare providers should be aware of the deleterious potential of specific antibiotic groups in patients with IBD only using these agents in a restrictive manner or preferentially consider alternative antibiotic groups., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Delayed eardrum healing has been observed in the ear opposite to the ear treated with otic quinolones (OQ) in rats. Case reports describe tendinopathies after OQ treatment, suggesting adverse systemic effects., Methods: We studied patients aged 19 to 64 years with diagnosis of otitis externa or media in private insurance between 2005 and 2015. We compared OQ treatment against otic neomycin, oral amoxicillin, or azithromycin. Outcomes included Achilles tendon rupture (ATR), Achilles tendinitis (AT), and all-type tendon rupture (ATTR). We applied an active comparator, new-user design with 1-year look-back and ceased follow-up at initiation of systemic steroids or oral quinolones, external injury, hospitalization, and after 35 days. We used trimmed stabilized inverse probability of treatment weights to balance comparison groups in a survival framework. Negative outcomes (clavicle fractures or sports injuries) were examined to rule out differences from varied physical activity (unmeasured confounding)., Results: We examined 1 501 009 treated otitis episodes. Hazard ratios (HR) for OQ exposure associated with ATR were 4.49 (95% confidence interval [CI], 1.83-11.02), AT 1.04 (95% CI, 0.73-1.50), and ATTR 1.71 (95% CI, 1.21-2.41). Weighted risk differences (RD) per 100 000 episodes for OQ exposure were ATR 7.80 (95% CI, 0.72-14.89), AT 1.01 (95% CI, -12.80 to 14.81), and ATTR 18.57 (95% CI, 3.60-33.53). Corresponding HRs for clavicle fractures and sports injuries were HR,1.71 (95% CI, 0.55-5.27) and HR,1.45 (95% CI, 0.64-3.30), suggesting limited residual confounding., Conclusions: OQ exposure may lead to systemic consequences. Clinicians should consider this potential risk and counsel patients accordingly. Risk factors and mechanisms for this rare, adverse effect deserve further evaluation. Mechanistic and other clinical studies are warranted to corroborate this finding., Competing Interests: Potential conflicts of interest. A. W. reports grants or contracts from Merch, Sharpe, Dohme; NIH; AHRQ; PCORI, FDA, Bill and Melinda Gates Foundation; state of Florida; none related to this work; consulting fees from Arbor Pharmaceuticals; Genentech. P. J. A. reports a research grant on ototoxicity of agents used to clear bacterial biofilms from NextScience; payment or honoraria from UpToDate for authoring a chapter on cochlear implant infections and from Stryker for teaching a temporal bone dissection course; payment for expert testimony on numerous cases, none pertaining to topic of this manuscript; US patents for otologic devices, none related to the topic of this manuscript; participation on otologic advisory board for Janssen Research & Development and Akouos; role as Past-President, executive council, unpaid, for American Otological Society; PA reports grants or contracts from Merch, Sharpe, Dohme; none related to this work., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822., (© Crown copyright 2021.)

Background: This study examined whether the use of quinolone ear drops increased the risk of perforation with intact tympanic membranes and acute otitis externa (AOE)., Methods: This was a retrospective cohort study using Medicaid clinical encounter and pharmacy billing records from 1999 through 2010. Children and adults had to have 24 months continuous enrollment in Medicaid prior to the first antibiotic ear drop dispensing (index date), and they had to maintain their enrollment for at least 18 months thereafter. Included ear drops were ofloxacin, ciprofloxacin plus hydrocortisone, ciprofloxacin plus dexamethasone, and neomycin plus hydrocortisone. Tympanic membrane perforation (TMP) was identified as 2 inpatient or outpatient encounters associated with TMP diagnosis at least 30 days apart. A Cox regression model adjusting for patient demographics, calendar year, and the number of ear drop prescriptions was used to compare TMP risk between quinolone and neomycin-exposed patients., Results: A total of 94 333 patients entered the study cohort. Use of quinolone ear drops was associated with increased risk for TMP compared with neomycin plus hydrocortisone, with an adjusted hazard ratio of 2.26 (95% confidence interval [CI], 1.34-3.83). Adjusted hazard ratios were 2.53 (95% CI, 1.27-5.05) for ofloxacin, 2.24 (95% CI, 1.03-4.85) for ciprofloxacin plus hydrocortisone, and 2.30 (95% CI, 1.09-4.87) for ciprofloxacin plus dexamethasone. Sensitivity analyses were consistent with the primary analysis., Conclusions: Use of quinolone ear drops to treat AOE is associated with a previously unreported increased risk of developing TMPs. Selection of otic preparations to treat self-limited conditions with intact tympanic membranes should consider TMP risk., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Inflammatory bowel disease (IBD) causes serious morbidity and disability, and the incidence is increasing. The disease etiology is not well understood, though inflammatory reactions after antibiotic exposure may be associated with development of IBD. We investigated the association between IBD and prior antibiotic use., Methods: We conducted this case-control study among individuals in the United Kingdom Clinical Practice Research Datalink GOLD (CPRD GOLD). Each case of IBD was matched to 4 controls on age, sex, general practice, and registration year in the CPRD GOLD. Antibiotic exposure was classified by ever or never use, number of prescriptions, and class of antibiotic before the index date. Odds ratios were calculated using conditional logistic regression., Results: We identified 461 cases of ulcerative colitis (UC) and 683 cases of Crohn's disease (CD). There was no association between ever use of any antibiotic and UC (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.72-1.44) or CD (OR, 1.01; 95% CI, 0.73-1.39) compared with never use. A slightly increased CD risk was observed among ever users of quinolones (OR, 1.76; 95% CI, 1.00-3.11) and metronidazole (OR, 1.43; 95% CI, 0.87-2.34) compared with never users. CD was associated with antibiotic exposure before age 5 (OR, 2.20; 95% CI, 0.75-6.43) in an analysis restricted to individuals followed from birth., Conclusions: There was no association between UC or CD and overall prior use of antibiotics, though prior use of metronidazole and quinolones was associated with a slightly increased risk of CD. Antibiotic use in early childhood may increase the risk of CD., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed., Methods: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose)., Results: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50)., Conclusions: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Objectives: To evaluate the durability of three integrase strand transfer inhibitors (INSTIs) and two NRTIs in ART-naive individuals., Methods: The study design was observational. Patients were HIV-positive, ART-naive subjects starting raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs. The primary endpoint was time to treatment failure, i.e. occurrence of virological failure (first of two consecutive plasma HIV RNAs  ≥200 copies/mL after 24 weeks) or INSTI discontinuation for any reason apart from simplification. Secondary endpoints were INSTI discontinuation due to toxicity/intolerance and CD4 count response. Survival analysis was done using Kaplan-Meier and Cox regression., Results: Two thousand and sixteen patients were included: 310 (15.4%) started raltegravir-based regimens, 994 (49.3%) started dolutegravir-based regimens and 712 (35.3%) started elvitegravir/cobicistat-based regimens. Over a median of 11 months, 167 patients experienced treatment failure; the 1 year probability of treatment failure was 6.5% for raltegravir, 5.4% for dolutegravir and 6.7% for elvitegravir/cobicistat (P = 0.001). Sixty-eight patients (3.4%) discontinued INSTIs owing to toxicity/intolerance. By multivariable analysis, patients starting raltegravir had a 2.03-fold (95% CI = 1.2-3.2) higher risk and patients on elvitegravir/cobicistat a 1.88-fold (95% CI = 1.2-2.9) higher risk of treatment failure versus dolutegravir; there was no difference in risk of discontinuation due to toxicity/intolerance when comparing dolutegravir and raltegravir and marginal evidence for a difference when comparing elvitegravir/cobicistat and dolutegravir (adjusted relative hazard = 1.94 for elvitegravir/cobicistat versus dolutegravir, 95% CI = 1.00-3.76, P = 0.05)., Conclusions: In our real-life setting, INSTI-based regimens showed high potency and durability. Among regimens currently recommended in Europe, those including dolutegravir are associated with a lower risk of treatment failure., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To analyse the frequency and causes of treatment discontinuation in patients who were treated with an integrase strand transfer inhibitor (INSTI), with a focus on neuropsychiatric adverse events (NPAEs)., Methods: Patients in 18 HIV reference centres in France were prospectively included in the Dat'AIDS cohort. Data were collected from all patients starting an INSTI-containing regimen between 1 January 2006 and 31 December 2016. All causes of INSTI-containing regimen discontinuations were analysed, and patients' characteristics related to discontinuation due to NPAEs were sought., Results: INSTIs were prescribed to 21315 patients: 6274 received dolutegravir, 3421 received elvitegravir boosted by cobicistat, and 11620 received raltegravir. Discontinuation was observed in 12.5%, 20.2% and 50.9% of the dolutegravir-, elvitegravir- and raltegravir-treated patients, respectively (P < 0.001). Discontinuation for NPAEs occurred in 2.7%, 1.3% and 1.7% of the dolutegravir-, elvitegravir-, and raltegravir-treated patients, respectively (P < 0.001). In the multivariate analysis, discontinuation for NPAEs was related to dolutegravir versus elvitegravir (HR = 2.27; 95% CI 1.63-3.17; P < 0.0001) and versus raltegravir (HR = 2.46; 95% CI 2.00-3.40; P < 0.0001), but neither gender (HR for women = 1.19; 95% CI 0.97-1.46; P = 0.09) nor age (P = 0.12) was related. The association with abacavir was not retained in the final model., Conclusions: Although discontinuation for side effects was less frequent with dolutegravir than with boosted elvitegravir, discontinuation for NPAEs, although rare (2.7%), was more frequent with dolutegravir. No patient characteristic was found to be associated with these side effects in this very large population., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Brexpiprazole is a serotonin-dopamine activity modulator with efficacy in acute schizophrenia and relapse prevention. The aim of this Phase 3, multicenter study was to assess the long-term safety, tolerability, and efficacy of treatment with brexpiprazole flexible-dose 1-4 mg/d., Methods: Patients rolled over into this 52-week open-label study (amended to 26 weeks towards the end) from 3 randomized, double-blind, placebo-controlled Phase 3 studies. De novo patients, not part of the previous studies, were also enrolled. The primary outcome variable was the frequency and severity of treatment-emergent adverse events. Efficacy was assessed as a secondary objective using the Positive and Negative Syndrome Scale and the Personal and Social Performance scale., Results: A total of 1072 patients was enrolled (952 for 52 weeks and 120 for 26 weeks), 47.4% of whom completed the study. Among patients who took at least one dose of brexpiprazole, 14.6% discontinued due to treatment-emergent adverse events, most commonly schizophrenia (8.8%) and psychotic disorder (1.5%). Treatment-emergent adverse events with an incidence of ≥5% were schizophrenia (11.6%), insomnia (8.6%), weight increased (7.8%), headache (6.4%), and agitation (5.4%). Most treatment-emergent adverse events were mild or moderate in severity. The mean increase in body weight from baseline to week 26 was 1.3 kg and to week 52 was 2.1 kg. There were no clinically relevant findings related to prolactin, lipids, and glucose, or QT prolongation. On average, patients' symptoms and functioning showed continual improvement., Conclusions: Treatment with brexpiprazole 1-4 mg/d was generally well tolerated for up to 52 weeks in patients with schizophrenia., Clinicaltrials.gov Identifier: NCT01397786 (https://clinicaltrials.gov/show/NCT01397786).

Background: Evidence on the effectiveness of first-line treatment for chronic Q fever, tetracyclines (TET) plus hydroxychloroquine (HCQ), and potential alternatives is scarce., Methods: We performed a retrospective, observational cohort study to assess efficacy of treatment with TET plus quinolones (QNL), TET plus QNL plus HCQ, QNL monotherapy, or TET monotherapy compared to TET plus HCQ in chronic Q fever patients. We used a time-dependent Cox proportional hazards model to assess our primary (all-cause mortality) and secondary outcomes (first disease-related event and therapy failure)., Results: We assessed 322 chronic Q fever patients; 276 (86%) received antibiotics. Compared to TET plus HCQ (n = 254; 92%), treatment with TET plus QNL (n = 49; 17%), TET plus QNL plus HCQ (n = 29, 10%), QNL monotherapy (n = 93; 34%), or TET monotherapy (n = 54; 20%) were not associated with primary or secondary outcomes. QNL and TET monotherapies were frequently discontinued due to insufficient clinical response (n = 27, 29% and n = 32, 59%). TET plus HCQ, TET plus QNL, and TET plus QNL plus HCQ were most frequently discontinued due to side effects (n = 110, 43%; n = 13, 27%; and n = 12, 41%)., Conclusions: Treatment of chronic Q fever with TET plus QNL appears to be a safe alternative for TET plus HCQ, for example, if TET plus HCQ cannot be tolerated due to side effects. Treatment with TET plus QNL plus HCQ was not superior to treatment with TET plus HCQ, although this may be caused by confounding by indication. Treatment with TET or QNL monotherapy should be avoided; switches due to subjective, insufficient clinical response were frequently observed., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Mycoplasma pneumoniae strains with resistance to macrolides have been spreading worldwide. Here, we aimed to clarify which antimicrobial agent is a better treatment for patients with M. pneumoniae pneumonia in a setting with large epidemics of macrolide resistance., Methods: Adult patients hospitalized with laboratory-confirmed M. pneumoniae pneumonia from 2010 to 2013 were identified from the Japanese Diagnosis Procedure Combination national database. Drug switching, length of stay (LOS), 30-day mortality, and total costs for patients who underwent macrolide, quinolone, and tetracycline therapy were compared using propensity score analyses., Results: Eligible patients (N = 1650) from 602 hospitals were divided into the macrolide group (n = 508), quinolone group (n = 569), or tetracycline group (n = 573). We found that 52.8%, 21.8%, and 38.6% of patients in the macrolide, quinolone, and tetracycline groups, respectively, had to switch drugs (P < .0001). There was no significant difference in the LOS and the 30-day mortality rates among these 3 groups. Cost was highest in the quinolone group (P = .0062). The propensity score-matched pairs (n = 487×2) generated from the quinolone and tetracycline groups also showed a lower proportion of patients who require switches in the quinolone group than in the tetracycline group (21.2% vs 39.6%, P < .0001) but not in the LOS, mortality, and cost., Conclusions: There were no significant differences in the LOS and mortality among any antimycoplasmal drugs as initial treatment for hospitalized M. pneumoniae pneumonia patients despite the lower switching rate in the quinolone group., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them., Aims: We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients., Methods: Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models., Results: Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P  =   0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P  =   0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P  =   0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P  =   0.0007) was the only independent risk factor for early discontinuation due to toxicity., Conclusions: Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: This study investigated whether quinolone ear drops, with or without corticosteroids, increase the risk of perforation requiring tympanoplasty following tympanostomy tube (TT) placement in children., Methods: This was a retrospective cohort study using Medicaid encounter and pharmacy billing data from 29 US states between 1999 and 2006. Children <18 years old without predisposing factors for perforation during a 6-month look-back period entered the cohort after TT placement and first dispensing of antibiotic ear drops. Included ear drops were quinolones (ofloxacin, ciprofloxacin plus hydrocortisone, or ciprofloxacin plus dexamethasone) or neomycin plus hydrocortisone. Children were followed until end of 2006, end of Medicaid enrollment, or occurrence of study outcome. A Cox regression model, adjusted for age, sex, race/ethnicity, initial TT indication, reinsertion of TT, adenoidectomy, and number of ear drop prescriptions was used to compare the rate of perforation between quinolone and neomycin plus hydrocortisone ear drop-exposed children. Perforation was defined by its diagnosis code followed by a tympanoplasty code., Results: A total of 96595 children entered the study cohort. Patients exposed to quinolone ear drops had a higher risk of perforation, with an adjusted hazard ratio of 1.61 (95% confidence interval [CI], 1.15-2.26). The adjusted hazard ratios were 1.49 (95% CI, 1.05-2.09) for ofloxacin, 1.94 (95% CI, 1.32-2.85) for ciprofloxacin plus hydrocortisone, and 2.00 (95% CI, 1.18-3.41) for ciprofloxacin plus dexamethasone., Conclusions: Exposure of children with TT to quinolone ear drops is associated with increased risk of perforations requiring tympanoplasty, which appears to be further exaggerated by corticosteroids. Clinicians should consider the risk of perforation and counsel patients/families accordingly when prescribing quinolone ear drops., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Chronic kidney disease (CKD) is a critical comorbidity for patients living with HIV, with an estimated prevalence between 2.4 and 17%. Such patients are increasingly affected by diseases associated with ageing, including cardiovascular disease and CKD, and the prevalence of risk factors such as smoking and dyslipidaemia is increased in this population. Proteinuria is also now recognized as a common finding in individuals living with HIV. While combination antiretroviral (ARV) treatments reduce CKD in the HIV-infected population overall, some ARV drugs have been shown to be nephrotoxic and associated with worsening renal function. Over the last few years, several highly efficacious new ARV agents have been introduced. This brief review will look at the novel agents dolutegravir, raltegravir, elvitegravir, cobicistat, tenofovir alafenamide fumarate and atazanavir, all of which have been licensed relatively recently, and describe issues relevant to renal function, creatinine handling and potential nephrotoxicity. Given the prevalence of CKD, the wide range of possible interactions between HIV, ARV therapy, CKD and its treatments, nephrologists need to be aware of these newer agents and their possible effect on kidneys., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs)., Objectives: We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen., Methods: Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample. Sanger sequencing and UDS were performed on the integrase gene using Roche 454 GS-Junior. A bioinformatic workflow was developed to identify the major DRMs, accessory mutations and the linkage between mutations., Results: In Sanger sequencing and UDS, no MRV in the integrase gene was detected at baseline in either the mother or the child. The major DRM N155H conferring resistance to raltegravir and elvitegravir was detected in 4% of the sequences by week 4 using UDS, whereas it was not detected by Sanger sequencing. The double mutant E92Q + N155H, conferring resistance to the entire integrase inhibitor class, including dolutegravir, emerged at week 8 (16%) and became rapidly dominant (57% by week 13). At the last timepoint under raltegravir (week 17), Y143R emerged, leading to different resistance mutation patterns: single mutants N155H (47%) and Y143R (24%) and double mutants E92Q + N155H (13%), Y143R + N155H (2%) and E92Q + Y143R (2%). The polymorphic substitution M50I was preferentially selected on resistant variants, especially on E92Q + N155H variants., Conclusions: This case study illustrates the usefulness of UDS in detecting early MRVs and determining the dynamics of selected HIV-1 variants in longitudinal analysis., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Approximately 50% of patients with major depressive disorder do not respond adequately to their antidepressant treatment, underscoring the need for more effective treatment options. The objective of this study was to investigate the effect of adjunctive brexpiprazole on depressive symptoms in patients with major depressive disorder who were not responding to adjunctive or combination therapy of their current antidepressant treatments with several different classes of agents (NCT02012218)., Methods: In this 6-week, open-label, phase 3b study, patients with major depressive disorder who had an inadequate response to ≥1 adjunctive or combination therapy, in addition to history of ≥1 failure to monotherapy antidepressant treatment, were switched to adjunctive brexpiprazole. Efficacy was assessed by change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score. Patient functioning was assessed using the Sheehan Disability Scale and the Cognitive and Physical Functioning Questionnaire. Safety and tolerability were also assessed., Results: A total of 51/61 (83.6%) patients completed 6 weeks of treatment with adjunctive brexpiprazole. Improvements in depressive symptoms were observed (least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale total score, -17.3 [P < .0001]) as well as improvements in general and cognitive functioning (mean changes from baseline to week 6: Sheehan Disability Scale, -3.1 [P < .0001]; Massachusetts General Hospital-Cognitive and Physical Functioning Questionnaire, -9.2 [P < .0001]). The most common adverse event was fatigue (14.8%); akathisia was reported by 8.2% of patients., Conclusions: In patients with major depressive disorder who had switched to open-label adjunctive brexpiprazole following inadequate response to previous adjunctive or combination therapy, improvements were observed in depressive symptoms, general functioning, cognitive function, and energy/alertness., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Background: Brexpiprazole has previously demonstrated efficacy in acute schizophrenia trials. The objective of this trial was to assess the efficacy, safety, and tolerability of maintenance treatment with brexpiprazole in adults with schizophrenia., Methods: Patients with an acute exacerbation of psychotic symptoms were converted to brexpiprazole (1-4mg/d) over 1 to 4 weeks and entered a single-blind stabilization phase. Those patients who met stability criteria for 12 weeks were randomized 1:1 to double-blind maintenance treatment with either brexpiprazole (at their stabilization dose) or placebo for up to 52 weeks. The primary efficacy endpoint was the time from randomization to impending relapse. Safety and tolerability were also assessed., Results: A total of 524 patients were enrolled, 202 of whom were stabilized on brexpiprazole and randomized to brexpiprazole (n=97) or placebo (n=105). Efficacy was demonstrated at a prespecified interim analysis (conducted after 45 events), and so the trial was terminated early. The final analysis showed that time to impending relapse was statistically significantly delayed with brexpiprazole treatment compared with placebo (P<.0001, log-rank test). The hazard ratio for the final analysis was 0.292 (95% confidence interval: 0.156, 0.548); mean dose at last visit, 3.6mg. The proportion of patients meeting the criteria for impending relapse was 13.5% with brexpiprazole and 38.5% with placebo (P<.0001). During the maintenance phase, the incidence of adverse events was comparable to placebo., Conclusions: or patients with schizophrenia already stabilized on brexpiprazole, maintenance treatment with brexpiprazole was efficacious, with a favorable safety profile., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Objective: Gut microbiota influence metabolic pathways related to the pathogenesis of obesity, insulin-resistance and diabetes. Antibiotic therapy can alter the microbiota, and is commonly used in western countries. We sought to evaluate whether past antibiotic exposure increases diabetes risk., Research Design and Methods: We conducted a nested case-control study using a large population-based database from the UK. The cases were defined as those with incident diagnosis of diabetes. For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1 year before index-date. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression. The risk was adjusted for BMI, smoking, last glucose level, and number of infections before index-date, as well as past medical history of coronary artery disease and hyperlipidaemia., Results: The study included 208 002 diabetic cases and 815 576 matched controls. Exposure to a single antibiotic prescription was not associated with higher adjusted diabetes risk. Treatment with two to five antibiotic courses was associated with increase in diabetic risk for penicillin, cephalosporins, macrolides and quinolones with adjusted OR ranging from 1.08 (95% CI 1.05-1.11) for penicillin to 1.15 (95% CI 1.08-1.23) for quinolones. The risk increased with the number of antibiotic courses and reached 1.37 (95% CI 1.19-1.58) for more than 5 courses of quinolones. There was no association between exposure to anti-virals and anti-fungals and diabetes risk., Conclusions: Exposure to certain antibiotic groups increases diabetes risk., (© 2015 European Society of Endocrinology.)

Large health care databases are used extensively for pharmacoepidemiologic studies. Unique methodological issues arise when applying self-controlled designs (i.e., using within-person comparisons) for active surveillance of newly marketed drugs. We use 3 examples to illustrate bias related to population-level exposure time trends when using outcome-indexed self-controlled (i.e., case-crossover) designs for active surveillance and evaluate the ability of the case-time-control design to adjust for bias from population-level exposure time trends. We mimicked active surveillance by conducting sequential analyses after market entry for 3 medications and outcomes (valdecoxib for myocardial infarction (MI), aripiprazole for MI, and telithromycin for acute liver failure) using Medicaid Analytic eXtracts (from all 50 US states, 2000-2006). The case-crossover exposure odds ratio (EOR) in the months immediately following valdecoxib market entry implausibly suggested a 12-fold higher risk of MI during exposed time relative to unexposed time; among age-, sex-, and time-matched controls, the corresponding EOR of 4.5 indicated strong population-level exposure time trends. Over subsequent monitoring periods, case-crossover EORs rapidly dropped to 1.4. Adjustment for bias from population-level exposure time trends with the case-time-control analysis resulted in more consistent associations between valdecoxib and MI across sequential monitoring periods. Similar results were observed in each example. Strong population-level exposure time trends can bias case-crossover studies conducted among "first-wave" users of newly marketed medications. Suggested strategies can help assess and adjust for population-level exposure time trends., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens.

Background: Systemic antibiotics are a major cause of severe cutaneous adverse reactions (SCARs). The selection of alternative antibiotics and management for SCARs patients with underlying infections can be challenging., Methods: We retrospectively analyzed 74 cases of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), related to use of systemic antibiotics in Taiwan from January 2006 to January 2012. We analyzed the causative antibiotics, clinical features, organ involvements, and mortality. We also assessed patient tolerability to alternative antibiotics after the development of antibiotic-related SCARs., Results: The most common causes of SCARs were penicillins and cephalosporins for SJS/TEN and AGEP; glycopeptides for DRESS. Fatality was more frequent in the SJS/TEN group. In patients with SJS/TEN, higher mortality was associated with old age and underlying sepsis before the development of SCARs. The majority of patients with penicillin- or cephalosporin-related SCARs were able to tolerate quinolones, glycopeptides, and carbapenems., Conclusions: Complicated underlying conditions and infections may increase mortality in patients with antibiotic-related SCARs. The selection of structurally different alternative drugs is important to avoid recurrence.

Purpose: A probable case of aripiprazole-induced syndrome of inappropriate antidiuretic hormone (SIADH) is reported., Summary: A 65-year-old Caucasian man arrived in the emergency department (ED) with dizziness, headache, abdominal pain, nausea, and vomiting. There had been no recent additions or changes to the patient's medication regimen except for an increase in the daily dose of aripiprazole (from 10 to 20 mg) about two months prior. On admission, the patient's serum sodium concentration was 108 meq/L, prompting discontinuation of aripiprazole use and fluid restrictions. Over the next 72 hours, the serum sodium level increased to a near-normal concentration (127 meq/L), and the man was discharged back to a nursing facility. Three days later, the patient was readmitted to the ED with recurrent symptoms and a serum sodium concentration of 118 meq/L, a serum osmolality of 254 mOsm/kg, a urine osmolality of 575 mOsm/kg, and a urine sodium concentration of 101 meq/L. It was learned that aripiprazole use had been inappropriately resumed at the nursing facility. Aripiprazole was again discontinued, and fluid restrictions were imposed, with subsequent abatement of hyponatremia over four days. Application of the adverse drug reaction probability scale of Naranjo et al. in this case yielded a score of 7, indicating probable aripiprazole-associated SIADH., Conclusion: A 65-year-old man developed severe hyponatremia after an aripiprazole dosage increase. Hyponatremia resolved promptly with the discontinuation of aripiprazole. After discharge from the hospital, the patient inadvertently received aripiprazole again and was subsequently readmitted with another episode of severe hyponatremia.

Objective: We aimed to confirm the effect of combined treatment with celecoxib and rebamipide would be more effective than celecoxib alone for prevention of upper gastrointestinal (GI) events., Methods: Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on 100 mg of rebamipide three times a day). The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group., Results: Seventy-five patients were enrolled. Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 ± 13 years). The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were 6/34 (17.6%) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252., Conclusions: The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events.

Background: Typhoid is a leading cause of fever in returning travelers. The prevalence is highest in migrants visiting friends and relatives (VFR travelers) in the Indian subcontinent, where reports of resistance have been of concern. This study is a retrospective analysis of patients with typhoid, seen over a 5-year period, in a tertiary center that serves a large immigrant population., Methods: Patients with blood cultures positive for Salmonella Typhi were identified between 2006 and 2010. Charts were reviewed for demographic data, travel history, symptoms and signs, basic laboratory results, susceptibility profiles, treatment, and clinical course. Resistance to nalidixic acid was used as a marker of decreased susceptibility to quinolones., Results: Seventeen patients were identified with S Typhi. The median age was 12 years (range: 2-47 y) and 94% (16 of 17) were hospitalized with a median stay of 7 days; two were admitted to the intensive care unit. Fourteen patients (82%) had a history of recent travel. Twelve were VFR travelers in Bangladesh and Pakistan and two had recently immigrated. In our study, typhoid patients had low eosinophil counts and elevated transaminases. Seventy-six percent (12 of 17) of all isolates were resistant to nalidixic acid, 23.5% (4 of 17) were resistant to ampicillin and co-trimoxazole, and one was resistant to ciprofloxacin. All isolates were susceptible to third-generation cephalosporins., Conclusions: Younger VFR travelers appear to be at greater risk of acquiring infection and developing complications. Absolute eosinopenia and increased liver function test values could be useful early diagnostic clues in a returning traveler with fever, once malaria has been excluded. There was a high rate of decreased susceptibility to fluoroquinolones, confirming that the use of third-generation cephalosporins or macrolides in patients from the Indian subcontinent is most appropriate. Prevention in VFR travelers to South Asia is critical and efforts should be targeted at better education and pre-travel immunization., (© 2012 International Society of Travel Medicine.)

While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success.

Purpose: Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins., Patients and Methods: We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle., Results: We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue., Conclusions: Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.

Objectives: Ciprofloxacin is the most frequently used member of the fluoroquinolones during initial eradication therapy of Pseudomonas aeruginosa, as well as during acute pulmonary exacerbations. However, its long-term effect on the susceptibility of the commensal flora within the cystic fibrosis (CF) airways has not yet been examined. The aim of this study was therefore to examine the consequence of oral ciprofloxacin usage on the resistance of the commensal viridans group streptococci (VGS), in terms of MICs and mutational analysis of the quinolone resistance-determining regions (QRDRs)., Methods: The MICs of ciprofloxacin, efflux activities and amino acid substitutions in the QRDRs for 190 isolates of VGS, originating from the sputa of adult CF patients who had been exposed constantly to ciprofloxacin, were examined. VGS organisms included Streptococcus salivarius, Streptococcus mitis, Streptococcus sanguinis, Streptococcus oralis, Streptococcus parasanguinis, Streptococcus infantis, Streptococcus gordonii, Streptococcus anginosus, Streptococcus cristatus, Streptococcus australis and Streptococcus mutans. Ciprofloxacin susceptibility was determined by broth microdilution and QRDRs within the gyrA, gyrB, parC and parE gene loci were explored using sequence analysis., Results: Twenty-seven (14.2%) streptococcal isolates were resistant to ciprofloxacin (MICs ≥8 mg/L) and 21 (11.1%) had reduced susceptibility (MICs 4 mg/L). As a comparator, clinically non-significant and non-invasive VGS organisms were examined in 12 consecutive non-CF patients in the community, where no resistance to ciprofloxacin was observed. Five novel QRDR PCR assays were developed to elucidate mutations within the CF VGS population, where there were six positions, which corresponded to previously reported quinolone resistance responsible mutations, and eight novel potential QRDR resistance mutations. Double mutations in gyrA and parC/parE led to MICs of 16 to >64 mg/L, while single mutations in parC or parE resulted in MICs of 8-32 mg/L and 8 mg/L, respectively. The mean homologies of each species to Streptococcus pneumoniae R6 were: gyrA, 70.3%-95%; gyrB, 69.6%-96.2%; parC, 76.1%-94.8%; and parE, 70.7%-94.7%. The close relatives of S. pneumoniae, S. mitis and S. oralis, showed high similarity for all four genes (more than 86%)., Conclusions: Treatment of P. aeruginosa with oral ciprofloxacin in patients with CF may concurrently reduce antibiotic susceptibility in the commensal VGS flora, where these organisms may potentially act as a reservoir of fluoroquinolone resistance gene determinants for newly acquired and antibiotic-susceptible pathogens, particularly the Streptococcus milleri group.

Purpose: A case of neuroleptic malignant syndrome (NMS) secondary to aripiprazole in a schizophrenic patient previously managed with clozapine is reported., Summary: A 42-year-old Caucasian woman with a history of schizophrenia (chronic paranoid type) arrived at the emergency department (ED) with a chief complaint of altered mental status and oliguria. The patient was previously managed with clozapine for 14 years, which was well tolerated until the patient developed urinary retention. As a result, clozapine was gradually discontinued over several weeks. Aripiprazole 30 mg orally once daily was initiated four days before her arrival at the ED. Approximately four days after starting aripiprazole therapy, the patient began experiencing tremors, confusion, and rigidity. Physical examination revealed poor inspiratory effort, diffuse abdominal tenderness, and decreased muscle strength. Initial blood work confirmed acute renal failure and leukocytosis. The patient developed both hypokalemia and hypomagnesemia; her urine myoglobin level was suggestive of rhabdomyolysis. In light of her fever, encephalopathy, autonomic instability, elevated creatine kinase levels, and muscle rigidity, a diagnosis of NMS was made. Supportive care in the form of cooling blankets, electrolyte management, and blood pressure control was provided to the patient. Bromocriptine was also initiated to restore her dopamine balance. Twenty days after the initial presentation, the patient was initiated on paliperidone 3 mg orally at bedtime, which was slowly increased to 9 mg over several weeks. Follow-up evaluation demonstrated no signs or symptoms of NMS. Laboratory test values were also within normal limits., Conclusion: A 42-year-old Caucasian woman with schizophrenia who could no longer tolerate therapy with clozapine developed NMS secondary to the initiation of aripiprazole.

Aripiprazole has been used effectively to treat schizophrenia in the clinic; however, its mechanisms of action are not clear. This study examined how short- and long-term aripiprazole treatment affects dopaminergic transmission in mesolimbic and nigrostriatal pathways. For comparison, the effects of haloperidol and olanzapine treatment were also examined. Aripiprazole significantly increased D2 receptor mRNA expression and decreased tyrosine hydroxylase (TH) mRNA expression in the ventral tegmental area (VTA) after 1- and 12-wk treatment, but had no effect in substantia nigra (SN) and nucleus accumbens (NAc). Aripiprazole also decreased dopamine transporter (DAT) binding density in NAc (for 1- and 12-wk treatment) and VTA (1-wk treatment). In contrast, haloperidol significantly increased D2 receptor binding density and decreased DAT binding density in NAc and caudate putamen (CPu) after 1- and 12-wk treatment, and it also decreases DAT binding in VTA after 12-wk treatment. Olanzapine had less widespread effects, namely an increase in D2 receptor mRNA in VTA after 12-wk treatment and decreased DAT binding in NAc after 1-wk treatment. These results suggest that aripiprazole has selective effects on the mesolimbic dopaminergic pathway. Selectively reducing dopamine synthesis in VTA is a possible therapeutic mechanism for the long-term efficacy of aripiprazole in controlling schizophrenia symptoms with reduced extrapyramidal side-effects.

The effects of rebamipide on dry mouth and salivary secretion in Sjögren's syndrome patients were investigated in a double-blind placebo-controlled study. Rebamipide (100 mg TID) or placebo was administered for eight weeks and patient-assessed improvement of dry mouth and increase in salivary secretion measured by the Saxon test were evaluated. At two, four, and eight weeks, dry mouth improvement rates were, respectively, 26.0, 44.0, and 46.9% for rebamipide and 20.0, 27.1, and 39.1% for placebo, and mean increases in salivary secretion were, respectively, 0.14, 0.24, and 0.35 g for rebamipide and 0.03, 0.09, and 0.17 g for placebo, indicating higher values in the rebamipide group for both parameters at all timepoints but no significant differences between the two groups. Analysis by baseline characteristics suggested a statistically significant salivary secretion increasing effect of rebamipide in cases of primary Sjögren's syndrome. No difference in the incidence of adverse events was seen between the two groups, confirming the safety of rebamipide. As a salivary secretion increasing effect was strongly suggested in cases of primary Sjögren's syndrome, further study on the administration of rebamipide for the treatment of dry mouth in patients with Sjögren's syndrome is required.

Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM.

A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine (Meth) addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind in-patient clinical pharmacology study to assess potential interactions between intravenous (i.v.) Meth (15 mg and 30 mg) and oral aripiprazole (15 mg). In addition, the effects of aripiprazole treatment on abstinence-related craving and cue-induced craving were evaluated. Participants included non-treatment-seeking, Meth-dependent patients (n=16), aged 18-45 yr, currently using Meth. Following baseline Meth dosing (15 mg and 30 mg), participants received 2 wk treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and Meth-related cues. Meth dosing (15 mg and 30 mg) was then repeated. Aripiprazole treatment had no effect on cue-induced Meth craving, or on daily baseline craving assessed over the course of medication treatment, although aripiprazole treatment was associated with increased craving independent of Meth dosing. Aripiprazole treatment was associated with significantly higher ratings on Addiction Research Center Inventory (ARCI) subscales reflecting euphoria and amphetamine-like effects following Meth dosing. Aripiprazole treatment was also associated with significant reductions in ratings of 'bad effects' and reductions on the ARCI subscale for sedation effects following Meth dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following Meth dosing, but had no other effects on cardiovascular responses to Meth. Aripiprazole treatment did not alter the pharmacokinetics of Meth. These findings indicate that aripiprazole treatment appears to be safe in volunteers with Meth dependence, although the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute Meth suggests that 15 mg aripiprazole is unlikely to be efficacious for the treatment of Meth dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for Meth dependence.

Objectives: The aim of this study was to evaluate the comparative effectiveness and safety of short (5 days) and long (7 or 10 days) duration antimicrobial treatment of patients with acute exacerbations of chronic bronchitis (AECB)., Methods: We performed a meta-analysis of randomized controlled trials (RCTs) comparing regimens of the same antibiotic (same dosage and same route of administration) administered for a different time period. We searched PubMed, the Cochrane Central Register of Controlled Trials and reference lists from publications, with no language restrictions., Results: Of the 1031 reports retrieved initially, seven RCTs, enrolling 3083 patients with AECB, met our inclusion criteria. The antimicrobials studied in these seven RCTs were quinolones, cefixime and clarithromycin. There was no difference between the short- and long-duration therapies with regard to treatment success in intention-to-treat [relative risk (RR) = 0.99, 95% confidence interval (CI) 0.95-1.03], clinically evaluable (RR = 0.99, 95% CI 0.96-1.02) or microbiologically evaluable (RR = 0.98, 95% CI 0.93-1.02) patients. Short-duration treatment, when compared with long, was associated with fewer adverse events (RR = 0.84, 95% CI 0.72-0.97)., Conclusions: Short-duration treatment seems to be as effective as and safer than long-duration antimicrobial treatment of patients with AECB. Additional research is required to clarify the long-term outcomes (namely the exacerbation-free interval after the resolution of an initial episode) of the compared regimens.

The purpose of this study is to estimate the maximum-tolerated dose (MTD) and describe toxicities and preliminary clinical effects of tipifarnib, a farnesyltransferase (FTase) inhibitor, administered concurrently with radiation therapy in children with newly diagnosed intrinsic diffuse brainstem glioma (BSG). Children >or=3 and

Background: Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs., Objectives: To evaluate the risk for different drugs of causing AGEP., Patients and Methods: A multinational case-control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls. Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26-infinity), ampicillin/amoxicillin (CI 10-infinity), quinolones (CI 8.5-infinity), (hydroxy)chloroquine (CI 8-infinity), anti-infective sulphonamides (CI 7.1-infinity), terbinafine (CI 7.1-infinity) and diltiazem (CI 5.0-infinity). No significant risk was found for infections and a personal or family history of psoriasis (CI 0.7-2.2)., Conclusions: Medications associated with AGEP differ from those associated with Stevens-Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.

Metabolic abnormalities occur frequently in patients treated with antipsychotics and are of growing concern to clinicians. This study sought to determine whether antipsychotic-associated metabolic abnormalities identified through intensive monitoring can be reversed by switching to aripiprazole. Recent evidence suggests that aripiprazole may exhibit a favorable metabolic safety profile. The study population is a subset of a large (n > 500) ongoing prospective cohort. Thirty-one consecutive patients with schizophrenia who were started on aripiprazole were included in the study. All patients underwent an extensive metabolic evaluation, including an oral glucose tolerance test, at baseline, at 6 weeks, and at 3 months post switch. Metabolic abnormalities were defined as any of the following: new onset diabetes, impaired fasting glucose, impaired glucose tolerance, metabolic syndrome (MetS) according to various definitions, and dyslipidemia. After 3 months of treatment with aripiprazole (mean daily dose 16.3 mg), there was a significant decrease in body weight, body mass index, and waist circumference. There was a significant reduction in fasting glucose, fasting insulin, insulin resistance index, and serum lipids levels (cholesterol, triglycerides, low-density lipoprotein (LDL), LDL/HDL, Chol/HDL, and non-HDL cholesterol). There was also a significant reduction in prolactin levels. All 7 cases of recent onset diabetes were reversed at 3 months follow-up. The MetS was reversed in 50% of patients at 3 months follow-up. Our results support the reversibility of recent onset diabetes on antipsychotic medication when detected early and followed by a switch to aripiprazole.

Purpose: A case of extrapyramidal symptoms (EPS) following administration of aripiprazole to a man with developmental disabilities who had never received antipsychotic medications and had no history of movement disorders is presented., Summary: The patient was a 40-year-old male with developmental disabilities. He was nonverbal, profoundly mentally retarded, and diagnosed with obsessive compulsive disorder (OCD) and orthopedic problems. He developed episodic movements possibly consistent with EPS secondary to aripiprazole usage. The patient was antipsychotic naive before initiation of aripiprazole 5 mg daily. Concurrent medications at the time of EPS onset included oxazepam, baclofen, and citalopram. Baclofen and oxazepam were prescribed secondary to right-sided hemiparesis contractures. Aripiprazole, 5 mg daily, was initiated in November 2004 as an augmentation strategy for the diagnosis of OCD. Facial, tongue, and arm movements were first reported approximately five weeks after the initiation of aripiprazole. Initial symptoms resolved after approximately 24 hours. The dosage was increased to 10 mg daily two weeks later. Dystonic episodes continued on an intermittent basis, and the patient presented with lower-lip thrusting and upper-limb athetosis. These movements interfered with the patient's eating, chewing, and holding of utensils. Several of the standard treatment strategies for EPS were used. Initially, diphenhydramine hydrochloride 25 mg was administered orally every six hours. The patient's movements resolved following diphenhydramine administration. Aripiprazole was subsequently discontinued secondary to its lack of efficacy for OCD and the development of a movement disorder., Conclusion: A patient with developmental disabilities who had no history of movement disorders developed EPS following initiation of aripiprazole.

As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.

Aripiprazole, an antipsychotic recently introduced for clinical use, may worsen psychotic symptoms, even at low dose. In other cases, aripiprazole may exercise an antipsychotic action and induce extrapyramidal side-effects, even at low dose. There are no clear-cut criteria to differentiate the patients whose psychotic symptoms will or will not respond to aripiprazole favourably. Conversely, the effectiveness on negative symptoms seem consistent both in patients with or without antipsychotic response. A low dose may be indicated at the beginning of treatment to assess the kind of response.

"Collateral damage" is a term used to refer to ecological adverse effects of antibiotic therapy; namely, the selection of drug-resistant organisms and the unwanted development of colonization or infection with multidrug-resistant organisms. The risk of such damage can be assessed for different antibiotic classes by a variety of epidemiologic studies. Cephalosporin use has been linked to subsequent infection with vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, beta-lactam-resistant Acinetobacter species, and Clostridium difficile. Quinolone use has been linked to infection with methicillin-resistant Staphylococcus aureus and with increasing quinolone resistance in gram-negative bacilli, such as Pseudomonas aeruginosa. Neither third-generation cephalosporins nor quinolones appear suitable for sustained use in hospitals as "workhorse" antibiotic therapy.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of aripiprazole are discussed. Aripiprazole is a third-generation antipsychotic agent indicated for use in the treatment of schizophrenia. Unlike other antipsychotics, aripiprazole demonstrates mixed D2 and serotonin (5-HT1A) receptor agonist-antagonist activity that is hypothesized to improve schlzophrenia's positive and negative symptoms; the drug has been referred to as a dopamine-serotonin stabilizer. Aripiprazole is well absorbed, with peak plasma concentrations occurring within three to five hours after administration. The oral availability is 87%. The mean elimination half-life is about 75 hours for aripiprazole and 94 hours for its active metabolite. In controlled, randomized, multicenter trials, aripiprazole has demonstrated efficacy in the treatment of schizophrenia comparable to that of haloperidol and superior to placebo. In a single clinical trial, aripiprazole was superior to placebo in the treatment of acute mania. The most frequent adverse effects are headache, anxiety, insomnia, nausea, vomiting, and lightheadedness. Because aripiprazole is a substrate of both cytochrome P-450 isoenzymes 3A4 and 2D6, there is a potential for other drugs to affect its metabolism. The recommended starting dosage is 10 or 15 mg daily, preferably administered with meals. Aripiprazole offers an alternative to second-generation antipsychotic agents in the treatment of schizophrenia.

Aripiprazole is a novel atypical antipsychotic for the treatment of schizophrenia. It is a D2 receptor partial agonist with partial agonist activity at 5-HT1A receptors and antagonist activity at 5-HT2A receptors. The long-term efficacy and safety of aripiprazole (30 mg/d) relative to haloperidol (10 mg/d) were investigated in two 52-wk, randomized, double-blind, multicentre studies (using similar protocols which were prospectively identified to be pooled for analysis) in 1294 patients in acute relapse with a diagnosis of chronic schizophrenia and who had previously responded to antipsychotic medications. Aripiprazole demonstrated long-term efficacy that was comparable or superior to haloperidol across all symptoms measures, including significantly greater improvements for PANSS negative subscale scores and MADRS total score (p<0.05). The time to discontinuation for any reason was significantly greater with aripiprazole than with haloperidol (p=0.0001). Time to discontinuation due to adverse events or lack of efficacy was significantly greater with aripiprazole than with haloperidol (p=0.0001). Aripiprazole was associated with significantly lower scores on all extrapyramidal symptoms assessments than haloperidol (p<0.001). In summary, aripiprazole demonstrated efficacy equivalent or superior to haloperidol with associated benefits for safety and tolerability. Aripiprazole represents a promising new option for the long-term treatment of schizophrenia.

Treatment with some quinolones is associated with an abnormal skin reaction following exposure to sunlight (photosensitivity). The objective of the current study was to compare the photosensitizing potential of a new quinolone, trovafloxacin, with that of ciprofloxacin, lomefloxacin and placebo. Forty-eight healthy males (age range 19-45 years) were randomized to receive a 7 day course of treatment with: (i) trovafloxacin 200 mg od; (ii) ciprofloxacin 500 mg bd; (iii) lomefloxacin 400 mg od; or (iv) placebo bd. Minimal erythema doses (MEDs) were assessed using a monochromator at baseline and on day 5 of treatment, for wavelengths of 305 +/- 5, 335 +/- 30, 365 +/- 30, 400 +/- 30 and 430 +/- 30 nm; 335 +/- 30 and 365 +/- 30 nm are within the UVA range. Immediate reaction MEDs were similar in all treatment groups. However, between baseline and day 5, the mean decreases in delayed-reaction MED (24 h) at 335 +/- 30 nm were only 18.99% for trovafloxacin versus placebo (P = 0.1267), compared with 53.77% (P 0.0001) and 64.13% (P 0.0001) for ciprofloxacin and lomefloxacin, respectively. Similarly, at 365 +/- 30 nm, trovafloxacin produced the smallest reduction in delayed MED versus placebo (43.66%), compared with ciprofloxacin (61.53%) and lomefloxacin (75.81%). These differences between trovafloxacin and ciprofloxacin and lomefloxacin were significant at both 335 +/- 30 and 365 +/- 30 nm (P 0.029). All MED values returned to baseline levels within 2 days of drug cessation. These results show that trovafloxacin has significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin. This photosensitivity appears to be induced only by wavelengths in the UVA region, is maximal at 24 h and is a short-term effect.

Moxifloxacin, a broad-spectrum fluoroquinolone with the methoxy group at position 8 of the quinolone structure that is believed to confer reduced phototoxicity, was investigated in 32 healthy human male volunteers by a randomized double-blind placebo and positive control (lomefloxacin) phototest technique. A comparison of pre- and on-drug photosensitivity levels tested with an irradiation monochromator using relevant sunlight wavelengths, failed to demonstrate phototoxicity after administration of either placebo or moxifloxacin (200 mg or 400 mg/day) for 7 days. As expected, lomefloxacin (400 mg/day) phototoxicity was revealed at the UVA wavebands 335 +/- 30 nm and 365 +/- 30 nm (maximal at 24 h), with a phototoxic index of 3-4. The susceptibility to this effect rapidly normalized within 48 h of stopping the drug. No special protection from UVA wavelengths is necessary for those taking moxifloxacin.