Macrolides: A Canadian Infectious Disease Society position paper

Since the introduction of erythromycin in 1965, no new compounds from the macrolide antimicrobial class were licensed in Canada until the 1990s. Clarithromycin and azithromycin, since their introduction, have become important agents for treating a number of common and uncommon infectious diseases. They have become prime agents in the treatment of respiratory tract infections, and have revolutionized the management of both genital chlamydial infections, by the use of single-dose therapy with azithromycin, and nontuberculous mycobacterial infections, by the use of clarithromycin. The improvement of clarithromycin and azithromycin over the gastrointestinal intolerability of erythromycin has led to supplanting the use of the latter for many primary care physicians. Unfortunately, the use of these agents has also increased the likelihood for misuse and has raised concerns about a resultant increase in the rates of macrolide resistance in many important pathogens, such as Streptococcus pneumoniae. This paper reviews the pharmacology and evidence for the current indications for use of these newer agents, and provides recommendations for appropriate use.Key Words: Azithromycin, Clarithromycin, Erythromycin, Macrolides, Review, Therapeutic useErythromycin A is a naturally occurring, microbiologically active compound of the macrolide class of antibiotics. Chemical modification of erythromycin A''s 14-membered lactone ring has led to the formation of semisynthetic derivatives with not only improved bioavailability and tolerability, but also expanded spectrums of microbiological activity and improved pharmacokinetic profiles. Such modifications produced clarithromycin, classified as a macrolide because it retains the central 14-membered lactone ring (1,2), and azithromycin, classified as an azalide due to its 15-membered aglycone ring (1). The latter two compounds are the newest agents in the macrolide class licensed for use in Canada. Roxithromycin and dirithromycin are available in other countries.These compounds are clinically active against Gram-positive and Gram-negative cocci, and Gram-negative bacilli (primarily Haemophilus influenzae, Legionella species, Moraxella catarrhalis, Campylobacter jejuni, Bordatella pertussis and Helicobacter pylori). Azalides such as azithromycin have exhibited superior activity against Gram-negative pathogens and are generally less active against Gram-positive pathogens. Intracellular pathogens such as Chlamydia species, Mycoplasma species, Ureaplasma species, Borrelia species and nontuberculous mycobacteria species show varying susceptibilities. On the basis of their microbial activity, both the macrolides and azalides have been shown to be clinically useful in the treatment of uncomplicated skin and soft tissue infections, upper and lower respiratory tract infections, sexually transmitted Chlamydia trachomatis infection and peptic ulcer disease. Additionally, the improved pharmacokinetic profiles and acid stability exhibited by the newer agents may lead to enhanced patient adherence through less frequent dosing and improved bioavailability in the presence of food.     

Regional oxygen supply and consumption balance in experimental left ventricular hypertrophy

Summary The aim of the present study was to determine if the relationship between myocardial O₂ supply and O₂ consumption was preserved after prolonged pressure overload due to aortic valve stenosis. This was examined in anesthetized open-chest dogs in which the aortic valve was plicated 6 months previously. We measured coronary blood flow with radioactive microspheres and regional small vessel O₂ saturation with microspectrophotometry, to obtain O₂ supply, and O₂ consumption. Regional O₂ consumption was calculated as the product of flow and O₂ extraction. The left ventricular weight/body weight ratio was 81% greater in the dogs with aortic valve stenosis. There were no hemodynamic differences between the groups except that left ventricular systolic pressure was 38±22 mm Hg greater than aortic in the hypertrophied group. Coronary blood flow did not differ between the control and hypertrophied groups nor were there subepicardial vs subendocardial differences. When maximal coronary flow was determined with chromonar (10 mg/kg), the flow increase was significantly attenuated in the hypertrophied subendocardium (242.1±82.3 (hypertrophy) vs 512.4±204.1 ml·min^–1·100 g^–1 (control)). There were no significant differences in O₂ extraction or O₂ consumption/g between control and hypertrophied animals. There was a significantly lower O₂ supply/consumption ratio in the subendocardium compared to the subepicardium of both groups. However, the O₂ supply/consumption ratio was not decreased by hypertrophy. Thus, despite significant hypertrophy, a loss of flow reserve and a high left ventricular pressure, O₂ supply/consumption balance is preserved in valvular aortic stenosis at rest.     

Acromiohumeral Distance During Neuromuscular Electrical Stimulation of the Lower Trapezius and Serratus Anterior Muscles in Healthy Participants

Context

Compromise to the acromiohumeral distance has been reported in participants with subacromial impingement syndrome compared with healthy participants. In clinical practice, patients with subacromial shoulder impingement are given strengthening programs targeting the lower trapezius (LT) and serratus anterior (SA) muscles to increase scapular posterior tilt and upward rotation. We are the first to use neuromuscular electrical stimulation to stimulate these muscle groups and evaluate how the muscle contraction affects the acromiohumeral distance.

Objective

To investigate if electrical muscle stimulation of the LT and SA muscles, both separately and simultaneously, increases the acromiohumeral distance and to identify which muscle-group contraction or combination most influences the acromiohumeral distance.

Design

Controlled laboratory study.

Setting

Human performance laboratory.

Patients or Other Participants

Twenty participants (10 men and 10 women, age = 26.9 ± 8.0 years, body mass index = 23.8) were screened.

Intervention(s)

Neuromuscular electrical stimulation of the LT and SA.

Main Outcome Measure(s)

Ultrasound measurement of the acromiohumeral distance.

Results

Acromiohumeral distance increased during contraction via neuromuscular electrical stimulation of the LT muscle (t₁₉ = −3.89, P = .004), SA muscle (t₁₉ = −7.67, P = .001), and combined LT and SA muscles (t₁₉ = −5.09, P = .001). We observed no differences in the increased acromiohumeral distance among the 3 procedures (F_2,57 = 3.109, P = .08).

Conclusions

Our results supported the hypothesis that the muscle force couple around the scapula is important in rehabilitation and scapular control and influences acromiohumeral distance.Key Words: subacromial impingement syndrome, real-time ultrasound, rehabilitation

Key Points

• Acromiohumeral distance increased during neuromuscular electrical stimulation of the lower trapezius muscle, serratus anterior muscle, and combined lower trapezius and serratus anterior muscles.
• The increase in acromiohumeral distance was not different among the 3 neuromuscular electrical-stimulation procedures.
• The muscle force couple around the scapula is important in rehabilitation and scapular control and influences acromiohumeral distance.

Optimal upper limb function depends on the ability to statically and dynamically position the shoulder girdle in an optimal coordinated fashion.^1,2 Suboptimal motor control is considered a risk factor for developing shoulder subacromial impingement syndrome.^3–14 Alterations in scapular motion have been linked to a decrease in serratus anterior (SA) muscle activity, an increase in upper trapezius muscle activity, and an imbalance of forces between the upper and lower parts of the trapezius muscle.¹⁵ This may adversely affect scapular positioning, resulting in reduced scapular upward rotation, increased anterior scapular tilt, and scapular winging.^4,9,16 In turn, scapular upward rotation and posterior tilt are considered vital for elevating the acromion and, hence, widening the subacromial space, thereby preventing impingement of the subacromial tissues.^17,18 Atalar et al¹⁹ suggested that reduced scapular mobility led to a decrease in acromiohumeral distance (AHD) during upper extremity abduction. Therefore, when developing rehabilitation strategies for patients with subacromial impingement syndrome, correcting neuromuscular control of the SA and trapezius muscles is important.^20,21Overall, researchers^22,23 have supported the theory that altered activity in the scapular rotator muscles is present in patients with subacromial impingement syndrome and have highlighted the role of scapular rotator muscle training as an essential component of shoulder rehabilitation. A clinical practice strategy, supported by research data, recommends that patients who have subacromial shoulder impingement and present with primary movement dysfunction of the scapula should be given strengthening programs targeting the lower trapezius (LT) and SA muscles.^24,25 The LT muscle is reported to increase posterior scapular tilt, and the SA muscle is believed to increase upward rotation of the scapula.² In turn, posterior scapular tilt and upward scapular rotation are associated with increased AHD.^17,18Authors^9,23,26–29 of electromyographic (EMG) studies have tested muscle activity in participants with subacromial impingement syndrome and in healthy persons. In patients with subacromial impingement syndrome, when the upper extremity was at rest and during flexion and abduction, the EMG signal amplitude of the upper trapezius muscle increased, whereas the EMG signal amplitude of the LT and SA muscles decreased.^30,31 These researchers have considered the immediate changes in the surface EMG activity of the scapular rotator muscles. However, to our knowledge, we are the first to use neuromuscular electrical stimulation (NMES) to stimulate the muscle groups of the LT and SA and evaluate the effect of muscle contraction in these muscles on the AHD. Neuromuscular electrical stimulation is used for various medical applications and is a common intervention during rehabilitation to improve function and motor control,³² prevent and treat shoulder pain,³³ increase range of motion,³⁴ and facilitate changes in muscle action and performance.³⁵ Therefore, the purpose of our study was to investigate whether stimulation of the LT and the SA muscles (separately and simultaneously) with NMES would increase the AHD and to investigate which muscle-group contraction or combination most influenced the AHD.     

Health anxiety disorders in older adults: Conceptualizing complex conditions in late life

Health anxiety disorders (e.g., hypochondriasis) are prevalent but understudied in older adults. Existing research suggests that severe health anxiety has a late age of onset, perhaps because of comorbidity with physical health conditions that are more likely to occur with aging. Despite being under diagnosed in later life due to a lack of age-appropriate diagnostic criteria, significant positive associations with age suggest that health anxiety disorders are more prevalent in older than younger adults. Preliminary research also highlights the complexity of these disorders in older adults and the potential importance of medical morbidity as a risk factor. This review explores the complexities of health anxiety disorders in later life with a focus on understanding defining features, prevalence rates, correlates, assessment, diagnosis, and treatment. We offer a theoretical model of the development of severe health anxiety among older adults to encourage further research on this important and under-studied topic.     

Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine–glycine–glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.