Association between Antibiotic Prescribing in Pregnancy and Cerebral Palsy or Epilepsy in Children Born at Term: A Cohort Study Using The Health Improvement Network

Background

Between 19%-44% pregnant women are prescribed antibiotics during pregnancy. A single, large randomised-controlled-trial (ORACLE Childhood Study II) found an increased risk of childhood cerebral palsy and possibly epilepsy following prophylactic antibiotic use in pregnant women with spontaneous preterm labour. We ascertained whether this outcome could be reproduced across the population of babies delivered at term and prospectively followed in primary-care using data from The Health Improvement Network.

Methods

We determined the risk of cerebral palsy or epilepsy in children whose mothers were prescribed antibiotics during pregnancy using a cohort of 195,909 women linked to their live, term-born, singleton children. We compared the effect of antibiotic class, number of courses and timing of prescribing in pregnancy. Analyses were adjusted for maternal risk factors (e.g. recorded infection, age, chronic conditions, social deprivation, smoking status). Children were followed until age seven years or cessation of registration with the primary-care practitioner.

Results

In total, 64,623 (33.0%) women were prescribed antibiotics in pregnancy and 1,170 (0.60%) children had records indicating cerebral palsy or epilepsy. Adjusted analyses showed no association between prescribing of any antibiotic and cerebral palsy or epilepsy (adj.HR 1.04, 95%CI 0.91–1.19). However, compared with penicillins, macrolides were associated with an increased risk of cerebral palsy or epilepsy (adj.HR 1.78, 95%CI 1.18–2.69; number needed to harm 153, 95%CI 71–671).

Conclusions

We found no overall association between antibiotic prescribing in pregnancy and cerebral palsy and/or epilepsy in childhood. However, our finding of an increased risk of cerebral palsy or epilepsy associated with macrolide prescribing in pregnancy adds to evidence that macrolide use is associated with serious harm.     

Spectrophotometric study of ketoconazole binding with citrate capped silver nanoparticles and its monitoring in human plasma samples

Ketoconazole or Nizoral is an antifungal medication used to treat various type of fungal infections. It has been reported that this antifungal agent is able to induce a variety of heart function side effects, such as long‐QT syndrome, and ventricular arrhythmias. Hence, prescribing, identifying and controlling the side effects of medications such as ketoconazole is essential for human safety. In this study, a distinct and fast colorimetric probe based on citrate capped silver nanoparticles (Cit‐AgNPs) was introduced for determination of trace amounts of ketoconazole. Cit‐AgNPs were synthesized trough a novel method and applied for the quantification of ketoconazole in human plasma samples. Ultraviolet‐visible spectroscopy, transmission electron microcopy, dynamic light scattering, and energy dispersive X‐ray spectroscopy analysis, have been utilized for characterization of Cit‐AgNPs. It was revealed that in the presence of ketoconazole, the absorption intensity of Cit‐AgNPs was decreased by increasing the ketoconazole concentration. Moreover, this reaction is accompanied by a color change from shiny yellow to brown/red in acidic pH. Under acidic pH and optimum condition, the calibration graph of the assay was linear in the range of 0.1 to 0.8 μM. According to the obtained results Cit‐AgNPs can be used as a novel probe for the sensitive and specific detection and determination of similar drugs in clinical samples. Also, this method open a new way to biomedical analyses of pharmaceutical samples which is necessary in TDM.     

In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines

Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100 micromolar range). Cetirizine demonstrated no effect on the investigated activities. A comparison of the inhibitory potencies of cetirizine, terfenadine, loratidine, astemizole and mizolastine with their corresponding plasma concentrations in humans suggests that these antihistamines are not likely to interfere with the metabolic clearance of coadministered drugs, with the exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency to warrant additional investigation.     

Inappropriate use of antibiotics in croup at three types of hospital.

Despite recent suggestions that bacterial infection is an increasingly important cause of serious croup, most authorities still consider croup a viral disease in which antibiotic therapy is unnecessary. To assess the frequency of antibiotic use in croup among children in hospital, we reviewed the records at three types of hospital in Ontario. Children with evidence of a concurrent infection that might be bacterial were considered to have received antibiotics appropriately. Whereas only 6% of cases at a university-affiliated children''s hospital were inappropriately treated with antibiotics, the proportions at a small rural community hospital staffed by general practitioners and a general hospital staffed by both pediatricians and general practitioners in a medium-sized city were 63% and 38%. Possible reasons for these differences are discussed.     

Structural determinants for histamine H1 affinity,hERG affinity and QTc prolongation in a series of terfenadine analogs

In the late 1980’s reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H₁ binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H₁ assays.     

Susceptibility to selected chemotherapeutics of Staphylococcus aureus strains resistant to methycyline isolated from clinical materials in the years 1991-1992 and 1997

The susceptibility to selected chemotherapeutic agents was determined in 100 strains of Staphylococcus aureus methicillin-resistant (MRSA) isolated from clinical materials in 1991-1992 (50 strains) and in 1997 (50 strains). Two methods were used for the determination: disc method and antibiotic dilution in agar. The minimal inhibitory concentration (MIC) was determined for vancomycin, teicoplanin, furazolidone, nitrofurantoin, ofloxacin, gentamicin, netilmicin and trimethoprim. The concentrations of the chemotherapeutics in the substrate ranged from 0.125 to 512 mg/l. The obtained results served for drawing of the following conclusions: all studied MRSA strains isolated in 1991-1992 and in 1997 were sensitive to glycopeptide antibiotics: vancomycin and teicoplanin, to nitrofurans: nitrofurantoin and furazolidone, and to fusidic acid. MRSA strains isolated in 1991-1992 were sensitive to ofloxacin, but in 1997 about 80% of the strains were resistant to that antibiotic, and this resistance was noted in S. aureus strains with homogeneous resistance to methicillin. Increasing frequency of resistance to mupirocin was found, in 1991-1992 4% of the strains were resistant, and in 1997 the resistance of MRSA to that antibiotic was found in 12%. No changes occurred in the sensitivity of staphylococci to trimethoprim/sulfamethoxazole (cotrimoxazole). About 94% of strains in 1991-1992 and 1997 were sensitive to that drug. The sensitivity to cotrimoxazole is connected with one of its components (trimethoprim), with 94% of MRSA strains sensitive to it.     

Hormone replacement therapy: a survey of Ontario physicians' prescribing practices

BACKGROUND: Although much has been written about hormone replacement therapy (HRT), there are few clearcut recommendations on its use. The purpose of this study was to determine Ontario physicians'' patterns of and reasons for prescribing HRT, their use of pretreatment investigations and their surveillance of HRT users, and to determine whether physicians'' reported practice is consistent with existing recommendations. METHODS: A self-administered questionnaire was mailed to a nonproportional stratified sample of 327 Ontario physicians (23.9% gynecologists, 76.1% general practitioners/family physicians [GP/FPs]). Outcome measures were ranking of reasons for prescribing HRT, nature of preliminary testing, regimens prescribed, duration of HRT and frequency of follow-up. RESULTS: The response rate was 60.9% overall (70.9% of the gynecologists, 58.3% of the GP/FPs). Prevention of osteoporosis was reported by 97.4% as an important or very important reason for prescribing HRT; prevention of coronary artery disease was important or very important for 89.3%. When considering whether or not to prescribe HRT, 97.3% stated that breast cancer was an important or very important factor. When presented with hypothetical cases, 97.0% stated that they would prescribe combined estrogen-progestin for a symptomatic woman with an intact uterus; 13.6% stated that they would do so for a woman with no uterus. Most reported that they would prescribe HRT for 12 or more years (73.3%) and would follow up patients every 1 to 2 years (70.6%). INTERPRETATION: Despite controversy about HRT in the published literature, the Ontario physicians surveyed reported similar reasons and patterns of prescribing, pretreatment investigations, and surveillance of postmenopausal women using HRT. These results suggest that Ontario physicians'' knowledge about HRT is consistent with recommendations in the published literature.     

Factors associated with the use of evidence-based therapies after discharge among elderly patients with myocardial infarction

Background

In an accompanying article, we report moderate between-hospital variation in the postdischarge use of β-blockers, angiotensin-modifying drugs and statins by elderly patients who had been admitted to hospital with acute myocardial infarction. Our objective was to identify the characteristics of patients, physicians, hospitals and communities associated with differences in the use of these medications after discharge.

Methods

For this retrospective, population-based cohort study, we used linked administrative databases. We examined data for all patients aged 65 years or older who were discharged from hospital in 2005/06 with a diagnosis of myocardial infarction. We determined the effect of patient, physician, hospital and community characteristics on the rate of postdischarge medication use.

Results

Increasing patient age was associated with lower postdischarge use of medications. The odds ratios (ORs) for a 1-year increase in age were 0.98 (95% confidence interval [CI] 0.97–0.99) for β-blockers, 0.97 (95% CI 0.97–0.98) for angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers and 0.94 (95% CI 0.93–0.95) for statins. Having a general or family practitioner, a general internist or a physician of another specialty as the attending physician, relative to having a cardiologist, was associated with lower postdischarge use of β-blockers, angiotensin-modifying agents and statins (ORs ranging from 0.46 to 0.82). Having an attending physician with 29 or more years experience, relative to having a physician who had graduated within the past 15 years, was associated with lower use of β-blockers (OR 0.71, 95% CI 0.60–0.84) and statins (OR 0.81, 95% CI 0.67–0.97).

Interpretation

Patients who received care from noncardiologists and physicians with at least 29 years of experience had substantially lower use of evidence-based drug therapies after discharge. Dissemination strategies should be devised to improve the prescribing of evidence-based medications by these physicians.The use of medications such as acetylsalicylic acid (ASA), β-blockers, angiotensin-modifying drugs (angiotensin-converting-enzyme [ACE] inhibitors and angiotensin-receptor blockers) and statins is a mainstay of secondary prevention of myocardial infarction. In a companion study published in this issue of CMAJ, we report substantial increases in the use of evidence-based drug therapies after discharge among elderly patients with myocardial infarction over a 14-year period.¹ However, despite temporal improvements, the prescribing of evidence-based drug therapies differed among hospitals in 2005.Studies from the late 1980s to the mid-1990s showed that the prescribing of evidence-based drug therapies was influenced by patient characteristics.^2–6 However, the extent to which postdischarge prescribing is influenced by patient, physician, hospital and community characteristics has not been extensively explored.Our objective was to identify patient, physician, hospital and community characteristics associated with the use of of evidence-based drug therapies after discharge among patients with myocardial infarction.     

The solithromycin journey—It is all in the chemistry

The macrolide class of antibiotics, including the early generation macrolides erythromycin, clarithromycin and azithromycin, have been used broadly for treatment of respiratory tract infections. An increase of treatment failures of early generation macrolides is due to the upturn in bacterial macrolide resistance to 48% in the US and over 80% in Asian countries and has led to the use of alternate therapies, such as fluoroquinolones. The safety of the fluoroquinolones is now in question and alternate antibiotics for the outpatient treatment of community acquired bacterial pneumonia are needed. Telithromycin, approved in 2003, is no longer used owing to serious adverse events, collectively called the ‘Ketek effects’. Telithromycin has a side chain pyridine moiety that blocks nicotinic acetylcholine receptors. Blockade of these receptors is known experimentally to cause the side effects seen with telithromycin in patients use. Solithromycin is a new macrolide, the first fluoroketolide, which has been tested successfully in two Phase 3 trials and is undergoing regulatory review at the FDA. Solithromycin is differentiated from telithromycin chemically and biologically in that its side chain is chemically different and does not significantly block nicotinic acetylcholine receptors. Solithromycin was well tolerated and effective in clinical trials.     

Effects of perceived patient demand on prescribing anti-infective drugs

BACKGROUND: Although patient demand is frequently cited by physicians as a reason for inappropriate prescribing, the phenomenon has not been adequately studied. The objectives of this study were to determine the prevalence of perceived patient demand in physician-patient encounters; to identify characteristics of the patient, physician and prescribing situation that are associated with perceived demand; and to determine the influence of perceived demand on physicians'' prescribing behaviour. METHODS: An observational study using 2 survey approaches was conducted in February and March 1996. Over a 2-day period 20 family physicians in the Toronto area completed a brief questionnaire for each patient encounter related to suspected infectious disease. Physicians were later asked in an interview to select and describe 1 or 2 incidents from these encounters during which perceived patient demand influenced their prescribing (critical incident technique). RESULTS: Perceived patient demand was reported in 124 (48%) of the 260 physician-patient encounters; however, in almost 80% of these encounters physicians did not think that the demand had much influence on their decision to prescribe an anti-infective. When clinical need was uncertain, 28 (82%) of 34 patients seeking an anti-infective were prescribed one, and physicians reported that they were influenced either "moderately" or "quite a bit" by perceived patient demand in over 50% of these cases. Of the 35 critical prescribing incidents identified during the interviews, anti-infectives were prescribed in 17 (49%); the reasons for prescribing in these situations were categorized. INTERPRETATION: This study provides preliminary data on the prevalence and influence of perceived patient demand in prescribing anti-infectives. Patient demand had more influence on prescribing when physicians were uncertain of the need for an anti-infective.     

Peptide-mediated macrolide resistance reveals possible specific interactions in the nascent peptide exit tunnel

Expression of specific short peptides can render cells resistant to macrolide antibiotics. Peptides conferring resistance to structurally different macrolides including oleandomycin, azithromycin, azaerythromycin, josamycin and a ketolide cethromycin were selected from a random pentapeptide expression library. Analysis of the entire collection of the resistance peptides allowed their classification into five distinct groups according to their sequence similarity and the type of resistance they confer. A strong correlation was observed between the structures of macrolide antibiotics and sequences of the peptides conferring resistance. Such a correlation indicates that sequence-specific interactions between the nascent peptide and the macrolide antibiotic and/or the ribosome can occur in the ribosomal exit tunnel.     

Market penetration of new drugs in one United Kingdom region: implications for general practitioners and administrators.

OBJECTIVE--To determine the use of new drugs in one United Kingdom region. DESIGN--Examination of data on prescribing of angiotensin converting enzyme inhibitors, new broad spectrum antibiotics, and H2 receptor antagonists. Calculation of number of defined daily doses prescribed each month. SETTING--All general practices in Northern Ireland. MAIN OUTCOME MEASURES--Drug use index and market share of each drug. RESULTS--During 1988-91 prescribing of angiotensin converting enzyme inhibitors increased by 126%, of H2 receptor antagonists by 46%, and of new antibiotics by 207%. The first drug on the market usually retained the largest market share. Use of oral antibiotics increased threefold irrespective of the reporting policy of the general practitioners'' local laboratory. CONCLUSIONS--The increase in prescribing of these drugs seems to be greater than can be accounted for by an increase in patients with specific indications for these drugs. This suggests that the profession has not instituted effective checks to ensure that the legitimate promotion of new products does not lead to inappropriate and wasteful use.     

How Physician Obesity Specialists Use Drugs to Treat Obesity

Specialist physicians may have prescribing habits that are different from nonspecialist physicians. Little is known about the prescribing habits of physicians specializing in the treatment of obesity. An anonymous survey was given to the physician members of the American Society of Bariatric Physicians (ASBP). There was a 35% response rate (266 physicians) to the questionnaire that was represented nationally. Almost all prescribed medications and all of them recommended phentermine. The average maximal dose of phentermine was above that approved in the package insert, and these physicians disagreed with the National Institutes of Health (NIH) Obesity Treatment Guidelines. Phendimetrazine, metformin, and phentermine plus l ‐5‐hydroxytryptophan (5‐HTP) with carbidopa were all used more frequently than either orlistat or sibutramine. The combination of sibutramine and orlistat as well as 5‐HTP/carbidopa were prescribed by 14 and 20%, respectively. As 5‐HTP‐carbidopa was a combination not previously reported for the treatment of obesity, a retrospective chart review was performed in a single obesity practice, which may not be representative. Twenty‐two subjects had a 16% weight loss with phentermine over 6 months and an additional 1% weight loss with the addition of 5‐HTP/carbidopa for an additional 6 months. One subject who started on 5‐HTP/carbidopa alone lost 24.4% of initial body weight over 6 months. This questionnaire revealed that 20% of the obesity specialists responding to the survey used phentermine plus of 5‐HTP/carbidopa, an unreported combination. A controlled, randomized, clinical trial to evaluate the safety and efficacy of this combination in treating obesity should be considered.