Macrolide Antibacterials Research Articles

Motilin receptor in GtoPdb v.2023.1

Motilin receptors (provisional nomenclature) are activated by motilin, a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide. There are significant species differences in the structure of motilin and its receptor, and in the functions of motilin. In humans and large mammals such as dog, activation of these receptors by motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. In humans and other mammals drugs and other non-peptide compounds which activate the motilin receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote upper gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibacterials (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea.

Nonantimicrobial Actions of Macrolides: Overview and Perspectives for Future Development.

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. SIGNIFICANCE STATEMENT: Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.

Immunotherapy in Elderly Transplant Recipients

Currently, >50% of candidates for solid organ transplantation in Europe and the US are aged >50 years while approximately 15% of potential recipients are aged >or=65 years. Elderly transplant candidates are characterized by specific co-morbidity profiles that compromise graft and patient outcome after transplantation. The presence of coronary artery or peripheral vascular disease, cerebrovascular disease, history of malignancy, chronic obstructive lung disease or diabetes mellitus further increases the early post-transplant mortality risk in elderly recipients, with infections and cardiovascular complications as the leading causes of death. Not only are elderly patients more prone to developing drug-related adverse effects, but they are also more susceptible to pharmacokinetic and pharmacodynamic drug interactions because of polypharmacy. The majority of currently used immunosuppressant drugs in organ transplantation are metabolized by cytochrome P450 (CYP) or uridine diphosphate-glucuronosyltransferases and are substrates of the multidrug resistance (MDR)-1 transporter P-glycoprotein, the MDR-associated protein 2 or the canalicular multispecific organic anion transporter, which predisposes these immunosuppressant compounds to specific interactions with commonly prescribed drugs. In addition, important drug interactions between immunosuppressant drugs have been identified and require attention when choosing an appropriate immunosuppressant drug regimen for the frail elderly organ recipient. An age-related 34% decrease in total body clearance of the calcineurin inhibitor ciclosporin was observed in elderly renal recipients (aged >65 years) compared with younger patients, while older recipients also had 44% higher intracellular lymphocyte ciclosporin concentrations. Similarly, using a Bayesian approach, an inverse relationship was noted between sirolimus clearance and age in stable kidney recipients. Ciclosporin and tacrolimus have distinct pharmacokinetics, but both are metabolized by intestinal and hepatic CYP3A4/3A5 and transported across the cell membrane by P-glycoprotein. The most common drug interactions with ciclosporin are therefore also observed with tacrolimus, but the two drugs do not interact identically when administered with CYP3A inhibitors or inducers. The strongest effects on calcineurin-inhibitor disposition are observed with azole antifungals, macrolide antibacterials, rifampicin, calcium channel antagonists, grapefruit juice, St John's wort and protease inhibitors. Drug interactions with mycophenolic acids occur mainly through inhibition of their enterohepatic recirculation, either by interference with the intestinal flora (antibacterials) or by limiting drug absorption (resins and binders). Rifampicin causes a reduction in mycophenolic acid exposure probably through induction of uridine diphosphate-glucuronosyltransferases. Proliferation signal inhibitors (PSIs) such as sirolimus and everolimus are substrates of CYP3A4 and P-glycoprotein and have a macrolide structure very similar to tacrolimus, which explains why common drug interactions with PSIs are comparable to those with calcineurin inhibitors. Ciclosporin, in contrast to tacrolimus, inhibits the enterohepatic recirculation of mycophenolic acids, resulting in significantly lower concentrations and hence risk of underexposure. Therefore, when switching from tacrolimus to ciclosporin and vice versa or when reducing or withdrawing ciclosporin, this interaction needs to be taken into account. The combination of ciclosporin with PSIs requires dose reductions of both drugs because of a synergistic interaction that causes nephrotoxicity when left uncorrected. Conversely, when switching between calcineurin inhibitors, intensified monitoring of PSI concentrations is mandatory. Increasing age is associated with structural and functional changes in body compartments and tissues that alter absorptive capacity, volume of distribution, hepatic metabolic function and renal function and ultimately drug disposition. While these age-related changes are well-known, few specific effects of the latter on immunosuppressant drug metabolism have been reported. Therefore, more clinical data from elderly organ recipients are urgently required.

Azithromycin Treatment Modulates Cytokine Production in Chlamydia trachomatis Infected Women

Chlamydial infection of the lower genital tract usually spreads to the upper genital tract and is then responsible for more serious consequences of chlamydial infection, such as infertility, ectopic pregnancy, pelvic pain and pelvic inflammatory disease [1]. Genital infection with Chlamydia trachomatis and the resulting cytokine environment largely determines the outcome of infection and disease [2–7]. Chlamydial infections are usually treated with Azithromycin or Doxycycline [8]. The immunomodulatory effects of macrolides have mainly been shown in vitro or in animal experiments. It has been reported that macrolide antibiotics can interfere with cytokine production in vitro [9–11]. Azithromycin has also been reported to inhibit the production of pro-inflammatory cytokines [12–17]. There is little evidence from the clinical arena that these immunomodulatory actions of antibiotics play a role in terms of outcome. Therefore, further studies to investigate the potential usefulness of azithromycin are necessary to elucidate its mechanism of action. The direct relevance of these findings for the treatment of infectious and inflammatory diseases will have to be tested in patients. The results of clinical trials have suggested that antibacterial activity of azithromycin is efficacious in the treatment of chlamydial cervical infection [18–20]. However, there are no human studies that have assessed antibacterial as well as anti-inflammatory effects of azithromycin treatment in different clinical conditions associated with the chlamydial infections. In a recent study on a Macaque model, azithromycin effectively prevented the progression of inflammation and fibrosis in both the lower and upper reproductive tract after repeated chlamydial infections suggesting that azithromycin may provide anti-inflammatory as well as antimicrobial properties and this combined activity may be particularly well-suited for the treatment of chlamydial infection [21]. Therefore, it might be possible that in immunopathological conditions like infertility and pelvic inflammatory disease, the anti-inflammatory property of azithromycin may act in the eradication of infection and disease. Hence, in the present study in order to examine the anti-inflammatory effects of azithromycin, we investigated the levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) in women representing different clinical conditions, that is, Chlamydiapositive fertile and infertile women with genital tract infection of C. trachomatis before and after treatment with azithromycin.

The Potential for Interaction between Warfarin and Coprescribed Medication

Warfarin is commonly involved in drug-related hospital admissions. The drug is most commonly prescribed to elderly patients in whom polypharmacy is common and, when administered in combination with other drugs such as NSAIDs, aspirin (acetylsalicylic acid) or macrolide antibacterials, is associated with increased bleeding risk. The aim of this study was to investigate the prevalence of prescriptions that might give rise to clinically relevant drug-drug interactions in a warfarinized population. Primary care prescribing of warfarin and potentially interacting medicines was assessed between 1 April 2005 and 31 March 2006 using computerized prescribing data retrieved from 321 primary care practices in Scotland. A total of 17,861 registered patients were prescribed warfarin in the study year, of whom 68% (n=12,107) were concomitantly issued with a prescription for at least one potentially interacting medicine. For short-term use, 'one-off' prescriptions for antibacterials (sulfonamides, ciprofloxacin, and macrolides), nonselective NSAIDs and antithrombotics (fibrinolytics) were the most frequently prescribed drug groups with potential for interaction, being prescribed to 12.7%, 5.3%, and 1.4% of warfarinized patients, respectively. Macrolide antibacterials were prescribed in significantly fewer warfaranized patients than standardized population (3.84% vs 4.41%; p<0.001). For long-term use, nonselective NSAIDs and antithrombotics were the most frequently prescribed drug groups, being prescribed to 21.0% and 21.1% of warfarinized patients, respectively. When compared with a standardized population, NSAIDs and antithrombotics were prescribed to a significantly smaller proportion of the warfarin population, whereas selective cyclo-oxygenase 2 inhibitors were prescribed to a significantly greater proportion. Nevertheless for the whole warfarinized population 26.3% were prescribed nonselective NSAIDs and 22.5% antithrombotic agents. The lower 'one off' use of macrolide antibacterials and long-term use of antithrombotics and NSAIDs in warfarinized patients observed in this study might suggest awareness among general practitioners of the increased risks for bleeding associated with concomitant use of these agents with warfarin therapy. However, despite this, the majority of warfarinized patients in this study were issued with a repeat prescription for at least one potentially interacting medicine.

Clinical??Relevance??of??Pharmacokinetics and??Pharmacodynamics??in Cardiac??Critical??Care??Patients

Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (beta-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur.

Secondary Prevention of Coronary Heart Disease in Elderly Patients Following Myocardial Infarction

Cardiovascular disease remains the leading cause of mortality in elderly patients. While coronary heart disease (CHD) morbidity and mortality have decreased over the last 25 years, the percentage reduction in elderly patients is nearly 50% lower than that for the general adult population. Therefore, aggressive primary and secondary prevention of CHD is imperative for our society, and hyperlipidaemia remains the major modifiable risk factor in the elderly population. However, there appears to be a reluctance among practitioners to treat hyperlipidaemia in elderly patients, a bias that is particularly important given the absolute benefits of treating such patients. While many of the major clinical trials involving HMG-CoA reductase inhibitors (statins) in patients with CHD focused on younger individuals, subsequent subgroup analyses of elderly patients have shown consistent reductions in all-cause mortality, major CHD events and numbers of revascularization procedures. Intensive statin therapy in the setting of acute myocardial infarction (MI) has also been shown to reduce the risk of death, MI, unstable angina, revascularization and stroke in elderly patients. Furthermore, three recent articles that have evaluated intensive lipid-lowering in the elderly population have extended the known benefits of such therapy to elderly patients with acute coronary syndrome and stable CHD.Elderly patients often take multiple medications and are at significant risk of drug-drug interactions. Several available statin medications are metabolized by cytochrome P450 (CYP) 3A4 and can therefore interact with commonly used medications such as amiodarone, macrolide antibacterials, calcium channel antagonists, fibric acid derivatives and ciclosporin. These interactions can result in an increased frequency of statin-related hepatotoxicity and myopathy.There are currently six commercially available statin medications on the US market, three of which, lovastatin, simvastatin and pravastatin, are available in generic formulations, and are thus less expensive. Of the commercially available statins, rosuvastatin, atorvastatin and simvastatin have the highest potency. While rosuvastatin currently lacks clinical event data, atorvastatin has the most clinical event data for CHD and even stroke prevention. Although pravastatin has lower potency than other described statins, it also has the lowest risk of drug-drug interactions involving CYP.

Direct Costs in Patients Hospitalised with Community-Acquired Pneumonia After Non-Response to Outpatient Treatment with Macrolide Antibacterials in the US

Antibacterial cost-containment programmes emphasise the use of narrow-spectrum generic agents whenever possible. The use of these agents is driven by their lower purchase prices; the consequences of treatment failure are rarely considered. This study was conducted to identify the costs of treating patients hospitalised with community-acquired pneumonia (CAP) associated with Streptococcus pneumoniae following failure to respond to outpatient treatment with macrolide antibacterials. A multicentre, retrospective, observational study was performed in patients with CAP due to S. pneumoniae who were admitted to 31 North American hospitals following a lack of response to >or=2 days of outpatient treatment with a macrolide antibacterial. Direct medical costs (year 2004 values) of infection-related hospital resources, including antibacterials (purchase, preparation, dispensing, administration and monitoring), diagnostic tests, therapeutic procedures, treatment of adverse events and therapeutic failures, and hospitalisation per diem (ward, critical care and ventilator days), were analysed. Total hospital costs were then compared with standard diagnosis-related group (DRG) reimbursement. A total of 122 patients were enrolled. Patients were frequently bacteraemic (52%) and infected with macrolide-resistant strains of S. pneumoniae (71%). Initial inpatient antibacterial treatment was not successful in 17 patients (14%) and seven patients (5.7%) died. The mean length of stay was 8.7 days (SD 7) including 1.3 days (SD 2.9) in a critical care unit and 1.4 days (SD 4.4) of mechanical ventilation. The mean cost of hospitalisation was US dollars 12,678 (SD 13 346) but standard DRG reimbursement averaged only US dollars 8,634. Patients who do not respond to outpatient treatment with a macrolide antibacterial and who are subsequently hospitalised with CAP caused by S. pneumoniae are likely to be infected with a non-susceptible strain, are frequently bacteraemic, are at an increased risk for mortality compared with previously published estimates in patients with CAP due to S. pneumoniae, and incur hospital costs that far exceed standard DRG reimbursement for CAP.

Cethromycin

Cethromycin [ABT 773, A-195773, Abbott-195773, A-1957730, A-195773-0] is a once-daily ketolide antibiotic that originated from Abbott Laboratories' research into next-generation compounds to the macrolide antibacterial, clarithromycin. The aim of the research programme was to maintain the positive attributes of clarithromycin and to add the property of efficacy against macrolide-resistant organisms. Cethromycin acts by binding to the 23S molecule of the 50S ribosomal subunit. Advanced Life Sciences is conducting multinational, pivotal phase III trials of cethromycin for the treatment of mild-to-moderate community-acquired pneumonia, phase II/III trials for treatment of acute bacterial sinusitis, as well as preclinical trials for the treatment of anthrax. Advanced Life Sciences plans to advance discussions with prospective commercialisation partners for cethromycin during 2006. Abbott Laboratories and Taisho Pharmaceutical entered a collaboration to develop and commercialise new macrolide antibacterials in October 1997. Each company brought its existing macrolides into the collaboration and both companies were to jointly develop novel new macrolides. Abbott was to have exclusive marketing, manfacturing and supply rights worldwide (except in Japan) to any compounds resulting from this collaboration. Taisho was to receive royalties on Abbott's sales in consideration of granted rights. In Japan, the two companies were to co-market any resulting macrolide antibacterials. This agreement extended to the development of cethromycin; however, the agreement was suspended in April 2004 and appears to have been terminated. Abbott exclusively licensed cethromycin to Advanced Life Sciences worldwide excluding Japan in December 2004. Advanced Life Sciences initiated commercial manufacturing agreements for cethromycin with DSM and Cardinal Health in May 2006. In March 2006, Advanced Life Sciences completed private placement of $US36 million from which the net proceeds will be used to advance development of cethromycin. The company plans to submit an NDA for cethromycin in 2007. In Japan, phase II trials were being conducted with Abbott's partner, Taisho Pharmaceutical. Although development in the US had been put on hold, Abbott was to continue to support product development in Japan by Taisho. However, in April 2004, Taisho and Abbott Japan decided to suspend co-development activities for cethromycin. A patent has been granted for cethromycin (US patent number 5 866 549) that expires in September 2016.

Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice

Macrolide antibacterials inhibit the production of various cytokines and the migration of inflammatory cells. These anti-inflammatory actions of macrolides may be beneficial in attenuating inflammatory processes involved in bacterial sepsis. Therefore, we investigated the ability of azithromycin to attenuate the deleterious effects of lipopolysaccharide (LPS), in three different LPS-induced inflammatory models. Our results show that azithromycin (10 and 100 mg/kg) significantly attenuated the intraperitoneal LPS-induced increase in plasma TNF-α concentration. It also increased survival rate in a septic shock model in mice challenged with intravenous LPS. Oral treatment with azithromycin (up to 300 mg/kg) was less effective in suppressing neutrophil infiltration into the lungs 24 h after intranasal LPS challenge, possibly because of a slower onset of action or inadequate dosing. In the same model, azithromycin given intraperitoneally significantly improved inflammatory markers (total cell number, neutrophil percentage and MIP-2 concentration) in bronchoalveolar lavage fluid. In conclusion, azithromycin exhibits significant anti-inflammatory properties but the potency of such effects varies depending on the experimental model and route of administration.

Antimicrobial therapy in childhood asthma and wheezing.

There is an increasing number of viral and bacterial pathogens suspected of contributing to asthma pathogenesis in childhood, making it more difficult for the practitioner to make specific therapy decisions. This review discusses the role of viruses, e.g. respiratory syncytial virus, human metapneumovirus, influenza viruses and rhinoviruses, as well as the role of the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae, as contributors to childhood asthma. Diagnosis, prevention, and therapy are discussed, including a summary of drugs, i.e. macrolide antibacterials, antivirals, and vaccine regimens already available, or at least in clinical trials. For the practitioner dealing with patients every day, drug regimens are assigned to the individual pathogens and an algorithm for the management of atypical infections in patients with asthma or recurrent wheezing is presented.

Therapeutic implications of macrolide resistance in pneumococcal community-acquired lower respiratory tract infections.

Macrolide anti-bacterials are widely used for the empirical treatment of lower respiratory tract infections (RTIs) due to their activity against Streptococcus pneumoniae and other common respiratory pathogens and good safety/tolerability profile. However, the prevalence of macrolide resistance, particularly pneumococcal macrolide resistance, is increasing all around the world. The mechanisms underlying macrolide resistance include efflux pump, methylase activity and, less commonly, ribosomal mutation, which produce differing levels of resistance. Growth in macrolide resistance has been linked to the increased use of these agents, and several risk factors for the development of resistance have been identified. There are emerging data to suggest that in vitro macrolide resistance may increase the likelihood of treatment failure in patients with lower RTIs. However, at present, treatment failure is rare and randomised; intervention-based trials investigating the impact of anti-bacterial resistance on clinical outcomes are lacking. Strategies to promote appropriate use of macrolides and other anti-bacterials are needed, both to maximise therapeutic impact and to minimise the development of resistance. Furthermore, there is a need for alternative anti-bacterial agents which have high efficacy against respiratory pathogens (including resistant strains) and a low potential to induce resistance.

Semisynthetic macrolide antibacterials derived from tylosin. Synthesis and structure-activity relationships of novel desmycosin analogues.

A series of 20-O-substituted and 3,20-di-O-substituted derivatives of desmycosin were synthesized and their biological properties were evaluated. In particular, we have synthesized numerous side chain modified analogues of desmycosin as well as some analogues possessing a combination of modified side chain and alternative C-3 substituents. Thus, alpha,beta-unsaturated analogues of desmycosin (2), tylosin (1), 10,11,12,13-tetrahydrotylosin (11), and 2,3-didehydrodesmycosin (13) were prepared from the corresponding aldehydes by a Wittig reaction with the stabilized ylides (a-d), generating a trans-double bond, followed by modified Pfitzner-Moffat oxidation of the C-3 hydroxyl group. To evaluate the importance of the C-3 position of desmycosin for biological activity, the C-3 substituted derivatives were synthesized by a standard sequence of protective group chemistry followed by Wittig reaction and esterification as the key steps. For the attachment of the C-3 ester functionality, a mixed anhydride protocol was adopted. Reaction proceeded smoothly to give corresponding esters in yields ranging from 70 to 80%. Base- and acid-catalyzed rearrangement products including desmycosin 8,20-aldols (24a and 24b) and desmycosin 3,19-aldol (25) are also described. Parallel array synthesis and purification techniques allowed for the rapid exploration of structure-activity relationships within this class and for the improvement in potency. In vitro evaluation of these derivatives demonstrated good antimicrobial activity against Gram-positive bacteria for most of the compounds. The present derivatives of 16-membered macrolides were active against MLS(B)-resistant strains that were inducibly resistant, but not those constitutively resistant to erythromycin.

A guide to selection and appropriate use of macrolides in skin infections.

Dermatologists must be aware of the adverse effects of antimicrobial agents as well as various drug interactions that may influence the choice of drug as well as specific drug schedules. The development of modern antibacterials has improved the treatment of cutaneous bacterial infections. Macrolide antibacterials continue to be an important therapeutic class of drugs with established efficacy in a variety of skin infections. All macrolides inhibit protein synthesis by reversibly binding to the 23S ribosomal RNA in the 50S-subunit. Erythromycin, the prototype of macrolide antibacterials, was isolated from the metabolic products of a strain of Streptomyces erytherus in 1952. Originally, erythromycin was introduced as an alternative to penicillin because of its activity against the Gram-positive organisms. Numerous studies have demonstrated the efficacy and safety of erythromycin for various infectious diseases. Unfortunately, erythromycin is associated with a number of drawbacks including a narrow spectrum of activity, unfavorable pharmacokinetic properties, poor gastrointestinal tolerability, and a significant number of drug-drug interactions. Newer macrolides have been developed to address these limitations. The pharmacokinetics of azithromycin and clarithromycin allow for shorter dosing schedules because of prolonged tissue levels. The efficacy of azithromycin for the treatment of skin and soft tissue infections in adults and children is well established. The unique pharmakinetics of azithromycin makes it a suitable agent for the treatment of acne. Clarithromycin represents a clear advance in the macrolide management of patients with leprosy and skin infections with atypical mycobacteria. Dirithromycin and roxithromycin display no clinical or bacteriological adcantage over erythromycin despite a superior pharmacokinetic profile. An area of concern is the increasing macrolide resistance that is being reported with some of the common pathogens which may limit the clinical usefulness of this class of antimicrobial agents in future.

Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview.

The long and growing list of non-antiarrhythmic drugs associated with prolongation of the QT interval of the electrocardiogram has generated concern not only for regulatory interventions leading to drug withdrawal, but also for the unjustified view that QT prolongation is usually an intrinsic effect of a whole therapeutic class [e.g. histamine H(1) receptor antagonists (antihistamines)], whereas, in many cases, it is displayed only by some compounds within a given class of non-antiarrhythmic drugs because of an effect on cardiac repolarisation. We provide an overview of the different classes of non-antiarrhythmic drugs reported to prolong the QT interval (e.g. antihistamines, antipsychotics, antidepressants and macrolides) and discusses the clinical relevance of the QT prolonging effect. Drug-induced torsade de pointes are sometimes considered idiosyncratic, totally unpredictable adverse drug reactions, whereas a number of risk factors for their occurrence is now recognised. Widespread knowledge of these risk factors and implementation of a comprehensive list of QT prolonging drugs becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia, hypocalcaemia), impaired hepatic/renal function, concomitant treatment with other drugs with known potential for pharmacokinetic/pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class I or III antiarrhythmic agents). This review provides insight into the strategies that should be followed during a drug development program when a drug is suspected to affect the QT interval. The factors limiting the predictive value of preclinical and clinical studies are also outlined. The sensitivity of preclinical tests (i.e. their ability to label as positive those drugs with a real risk of inducing QT pronglation in humans) is sufficiently good, but their specificity (i.e. their ability to label as negative those drugs carrying no risk) is not well established. Verapamil is a notable example of a false positive: it blocks human ether-a-go-go-related (HERG) K(+) channels, but is reported to have little potential to trigger torsade de pointes. Although inhibition of HERG K(+) channels has been proposed as a primary test for screening purposes, it is important to remember that several ion currents are involved in the generation of the cardiac potential and that metabolites must be specifically tested in this in vitro test. At the present state of knowledge, no preclinical model has an absolute predictive value or can be considered as a gold standard. Therefore, the use of several models facilitates decision making and is recommended by most experts in the field.

Commonly used antibacterial and antifungal agents for hospitalised paediatric patients: implications for therapy with an emphasis on clinical pharmacokinetics.

Due to normal growth and development, hospitalised paediatric patients with infection require unique consideration of immune function and drug disposition. Specifically, antibacterial and antifungal pharmacokinetics are influenced by volume of distribution, drug binding and elimination, which are a reflection of changing extracellular fluid volume, quantity and quality of plasma proteins, and renal and hepatic function. However, there is a paucity of data in paediatric patients addressing these issues and many empiric treatment practices are based on adult data. The penicillins and cephalosporins continue to be a mainstay of therapy because of their broad spectrum of activity, clinical efficacy and favourable tolerability profile. These antibacterials rapidly reach peak serum concentrations and readily diffuse into body tissues. Good penetration into the cerebrospinal fluid (CSF) has made the third-generation cephalosporins the agents of choice for the treatment of bacterial meningitis. These drugs are excreted primarily by the kidney. The carbapenems are broad-spectrum beta-lactam antibacterials which can potentially replace combination regimens. Vancomycin is a glycopeptide antibacterial with gram-positive activity useful for the treatment of resistant infections, or for those patients allergic to penicillins and cephalosporins. Volume of distribution is affected by age, gender, and bodyweight. It diffuses well across serous membranes and inflamed meninges. Vancomycin is excreted by the kidneys and is not removed by dialysis. The aminoglycosides continue to serve a useful role in the treatment of gram-negative, enterococcal and mycobacterial infections. Their volume of distribution approximates extracellular space. These drugs are also excreted renally and are removed by haemodialysis. Passage across the blood-brain barrier is poor, even in the face of meningeal inflammation. Low pH found in abscess conditions impairs function. Toxicity needs to be considered. Macrolide antibacterials are frequently used in the treatment of respiratory infections. Parenteral erythromycin can cause phlebitis, which limits its use. Parenteral azithromycin is better tolerated but paediatric pharmacokinetic data are lacking. Clindamycin is frequently used when anaerobic infections are suspected. Good oral absorption makes it a good choice for step-down therapy in intra-abdominal and skeletal infections. The use of quinolones in paediatrics has been restricted and most information available is in cystic fibrosis patients. High oral bioavailability is also important for step-down therapy. Amphotericin B has been the cornerstone of antifungal treatment in hospitalised patients. Its metabolism is poorly understood. The half-life increases with time and can be as long as 15 days after prolonged therapy. Oral absorption is poor. The azole antifungals are being used increasingly. Fluconazole is well tolerated, with high bioavailability and good penetration into the CSF. Itraconazole has greater activity against aspergillus, blastomycosis, histoplasmosis and sporotrichosis, although it's pharmacological and toxicity profiles are not as favourable.

Clinically significant drug interactions with agents specific for migraine attacks.

The drugs which provide specific relief from migraine attacks, the ergopeptides (ergotamine and dihydroergotamine) and the various 'triptans' (notably sumatriptan), are often prescribed for persons already taking various migraine preventative agents, and sometimes drugs for other indications. As a result, migraine-specific drugs may become involved in drug-drug interactions. The migraine-specific drugs all act as agonists at certain subclasses of serotonin (5-hydroxytryptamine; 5-HT) receptor, particularly those of the 5-HT1D subtype, and produce vasoconstriction through these receptor-mediated mechanisms. The oral bioavailabilities of these drugs, particularly those of the ergopeptides, are often incomplete, due to extensive presystemic metabolism. As a result, if migraine-specific agents are coadministered with drugs with vasoconstrictive properties, or with drugs which inhibit the metabolism of the migraine-specific agents, there is a risk of interactions occurring which produce manifestations of excessive vasoconstriction. This can also occur through pharmacodynamic mechanisms, as when ergopeptides or triptans are coadministered with methysergide or propranolol (although a pharmacokinetic element may apply in relation to the latter interaction), or if one migraine-specific agent is used shortly after another. When ergopeptide metabolism is inhibited by the presence of macrolide antibacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene. Similar pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably apply to combination of the ergopeptides with HIV protease inhibitors (indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may raise circulating triptan concentrations, although this does not yet seem to have led to reported clinical problems. Caffeine may cause increased plasma ergotamine concentrations through an as yet inadequately defined pharmacokinetic interaction. However, a direct antimigraine effect of caffeine may contribute to the claimed increased efficacy of ergotamine-caffeine combinations in relieving migraine attacks. Serotonin syndromes have been reported as probable pharmacodynamic consequences of the use of ergots or triptans in persons taking serotonin reuptake inhibitors. There have been two reports of involuntary movement disorders when sumatriptan has been used by patients already taking loxapine. Nearly all the clinically important interactions between the ergopeptide antimigraine agents and currently marketed drugs are likely to have already come to notice. In contrast, new interactions involving the triptans are likely to be recognised as additional members of this family of drugs, with their different patterns of metabolism and pharmacokinetics, are marketed.

Drug interactions with cisapride: clinical implications.

Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend avoiding coadministration of cisapride with amiodarone, cimetidine (alternatives are famotidine, nizatidine, ranitidine or one of the proton pump inhibitors), diltiazem and verapamil (the dihydropyridine calcium antagonists are alternatives), grapefruit juice, isoniazid, metronidazole, quinine, quinupristin/dalfopristin and zileuton (montelukast is an alternative). Pharmacodynamic interactions with cisapride involve drugs that have the potential to have additive effects on the QT interval. We do not recommend use of cisapride with class Ia and III antiarrhythmic drugs or with adenosine, bepridil, cyclobenzaprine, droperidol, haloperidol, nifedipine (immediate release), phenothiazine antipsychotics, tricyclic and tetracyclic antidepressants or vasopressin. Vigilance is advised if anthracyclines, cotrimoxazole (trimethoprim-sulfamethoxazole), enflurane, halothane, isoflurane, pentamidine or probucol are used with cisapride. In addition, uncorrected electrolyte disturbances induced by diuretics may increase the risk of torsade de pointes. Patients receiving cisapride should be promptly treated for electrolyte disturbances.

Limited transplacental transfer of macrolide antibacterials

Limited transplacental transfer of macrolide antibacterials

QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience.

Evidence has accrued that several non-cardiac drugs may prolong cardiac repolarisation (hence, the QT interval of the surface electrocardiogram) to such a degree that potentially life-threatening ventricular arrhythmias (e.g. torsades de pointes) may occur, especially in case of overdosage or pharmacokinetic interactions. This has fostered discussion on the molecular mechanisms underlying the class-III antiarrhythmic effect shared by apparently disparate classes of drugs, on the clinical relevance of this side effect and on possible guidelines to be followed by drug companies, ethics committees and regulatory agencies in the risk-benefit assessment of new and licensed drugs. This review provides an update on the different classes of non-cardiac drugs reported to prolong the QT interval (e.g. histamine H1-receptor antagonists, antipsychotics, antidepressants and macrolides), on the possible underlying molecular mechanisms and on the clinical relevance of the QT prolonging effect. Identification and widespread knowledge of risk factors that may precipitate prolongation of the QT interval into life-threatening arrhythmias becomes an important issue. Risk factors include congenital long QT syndrome, clinically significant bradycardia or heart disease, electrolyte imbalance (especially hypokalaemia, hypomagnesaemia), impaired hepatic/renal function and concomitant treatment with other drugs with known potential for pharmacokinetic/ pharmacodynamic interactions (e.g. azole antifungals, macrolide antibacterials and class-I or -III antiarrhythmic agents). Future perspectives for drug research and development are also briefly outlined.