Respiratory tract penetration of quinolone antimicrobials: a case in study

Antimicrobial lung penetration is thought to be predictive of efficacy in the treatment of lower respiratory tract infections. Lung penetration studies are commonly conducted with new antimicrobial agents to elucidate their potential utility in treating such infections. Although some very useful information may emerge, these studies are complicated by technical difficulties, theoretical assumptions, and numerous intricacies. Many studies describing quinolone penetration into saliva, sputum, bronchial secretions, and lung tissue have been published. In general, quinolone concentrations in lung tissue are 1.5-4 times the serum levels, whereas those in sputum and bronchial secretion are equal to or less than serum, and penetration into saliva is even less. The failure rate predicted from saliva, sputum, and bronchial secretion penetration and marginal in vitro activity of quinolones against streptococci does not consistently correlate with clinical efficacy data. In light of such conflicting data and the high lung tissue penetration of quinolones, the relevance of saliva, sputum, and bronchial secretion studies should be reevaluated. The utility of investigational quinolones in the treatment of lower respiratory tract infections can be determined only by well-designed clinical trials.     

Advanced-generation macrolides: tissue-directed antibiotics

The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as 'advanced-generation' macrolides compared with erythromycin, the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the beta-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.     

Bacampicillin, amoxycillin and talampicillin concentrations in bronchial secretions

There are references in the literature describing the influence of bronchial inflammation on the antibiotic concentration in bronchial secretions, including netilmicin concentrations in the bronchial secretion of patients undergoing tracheotomy. Three semi-synthetic penicillins are compared--bacampicillin, amoxicillin and talampicillin--administered frequently in the treatment of various respiratory infections. The three antibiotics were administered successively for two days each, in the same patient, irrespective of other drugs. At the same time the cytologic evaluation of the degree of bronchial inflammation was done. The antibiotic concentrations in bronchial secretions and in sera were measured at the same time. The results showed that the concentration of antibiotics in bronchial secretions of patients undergoing tracheotomy was proportional to the degree of bronchial inflammation. Among the semi-synthetic penicillins investigated the highest degree of concentration in the bronchial secretion was obtained after the bacampicillin.     

Pharmacokinetics and pharmacodynamics of newer oral cephalosporins: implications for treatment of community-acquired lower respiratory tract infections

Full knowledge of the inter-relationships between pharmacodynamics and pharmacokinetics is important in choosing an appropriate antibiotic, determining its optimal dosage regimen, and predicting which pharmacokinetic parameter(s) should best correlate with clinical efficacy in the treatment of community-acquired lower respiratory tract infections (LRTIs). Pharmacodynamics of antibiotics deal with the time-course of drug activity and mechanisms of action of drugs on bacteria. In particular, the bactericidal activity of beta-lactams such as the cephalosporins is dependent upon the time that serum concentrations remain above the minimum inhibitory concentration (MIC) of a given organism. A significant linear correlation exists between time above MIC (T > MIC) and time to eradication of bacteria from respiratory secretions. Therefore, the goal of a dosage regimen for antibiotics of this type is to maximise the time during which the organism is exposed to the drug, since the bactericidal activity correlates more with duration than with magnitude of dose. Most infections occur in tissue rather than in the blood. Thus, appropriate antibiotic therapy requires achievement of significant concentrations of antibiotics at the site of infection for long enough to eliminate the invading pathogen. At present, few data on the pulmonary disposition of newer oral cephalosporins are available in literature; they are generally limited to the evaluation of penetration of the antibiotic into the sputum and only for part of the dosage interval. The inadequacy of data limits the possibility of a pharmacodynamic investigation. The scarcity of data on the postantibiotic effect of these antimicrobial agents is also a problem. Therefore, at present, it is extremely difficult to prescribe a newer oral cephalosporin for the treatment of a LRTI in accordance with an authentic pharmacodynamic approach. This new approach, which results from the integration of bacteriological characteristics in in vivo pharmacokinetic studies, is extremely important in determining the choice of the appropriate antibiotic and the dosage regimen for treating LRTIs. An oral cephalosporin with good potency as well as a favourable pharmacokinetic profile and that permits concentrations higher than the MIC(90)s of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for almost the entire validated dosage interval in bronchial secretions, can potentially be considered the first choice.     

Comparison between penetration of amoxicillin combined with carbocysteine and amoxicillin alone in pathological bronchial secretions and pulmonary tissue

Patients with chronic bronchitis were treated orally with either amoxicillin (500 mg) alone or in combination with carbocysteine (150 mg), thrice daily for five days, in order to assess whether the combination allows higher antibiotic levels to be obtained in bronchial mucus than those obtained from amoxicillin alone. Serum and mucus levels were determined for each patient at first and fifth day of the two drug regimens. The levels of amoxicillin in the lung tissue collected in patients undergoing pulmonary surgery were also determined after a single oral dose of amoxicillin (1 g) or of amoxicillin (1 g) plus carbocysteine (300 mg). In the bronchial secretions, at the same plasma concentrations, amoxicillin levels were statistically higher after administration of combined substances. These findings indicate the presence of a pharmacokinetic synergism between these compounds, which allows amoxicillin to penetrate more easily through the hemato-bronchial barrier. The association of amoxicillin and carbocysteine, determining an increase of the quantitative levels of antibiotic in the bronchial secretion (also if it is purulent), performs a sterilizing action in a short time with significant therapeutic advantages.     

Relationship between chemical structure of antibiotics and pharmacokinetics

Modifications to the chemical structure of antibiotics can modify nearly all pharmacokinetic parameters: digestive absorption, half-life, protein binding, tissue distribution, metabolic biotransformation, biliary and renal elimination. Examples of increased oral bioavailability are given for beta-lactams, macrolides, tetracyclines, fosfomycin, quinolones and acyclovir. The structural modifications responsible for prolonged or shortened half-life, increased or decreased biliary excretion, increased or decreased renal clearance for the different families of antibiotics are reviewed.     

Drug treatment of pneumonia in the hospital. What are the choices?

Mortality and morbidity of nosocomial pneumonia remain high. Successful treatment of pulmonary infections depends on several factors including type of infection, offending pathogen, status of host defences, and adequate choice of antibiotic therapy. The physician's decision should aim at achieving antibiotic concentrations beyond the MIC at the site of infection. Gram-negative bacilli, notably Pseudomonos aeruginosa, Klebsiella pneumoniae and Escherichia coli, remain the most frequent agents in nosocomial pneumonia. Staphylococcus aureus and Streptococcus pneumoniae predominate among the Gram-positive cocci. Pneumocystis carinii predominates in immunocompromised patients. Protected sample bronchoscopy associated with quantitative cultures of samples, and quantification of intracellular microorganisms in cells recovered by broncho-alveolar lavage are two promising procedures which might replace previous, more aggressive methods. Penetration of antibiotics into lung tissue depends on physicochemical properties of the drug and the degree of inflammation of lung tissue. Quinolones, macrolides, tetracyclines and trimethoprim penetrate well into bronchial secretions. Penetration is moderate to low for aminoglycosides and beta-lactams. Fluoroquinolones and new beta-lactam agents, including third-generation cephalosporins imipenem, aztreonam and ticarcillin-clavulanate, showed comparative clinical efficacy in treatment of nosocomial pneumonia, with an efficacy rate close to 80%. Aminoglycosides should not be used alone. Combination therapy reduces but does not eliminate the risk of selection of Gram-negative resistant mutants. It should not be used routinely except for P. aeruginosa, Enterobacter cloacae and Serratia marcescens infections.     

Grepafloxacin: an overview of antibacterial activity, pharmacokinetics, clinical efficacy and safety

The treatment of respiratory tract infection is the most common reason for antibiotic prescribing. However, therapeutic options are diminishing as antibiotic resistance to penicillins and macrolides in key respiratory pathogens is increasing. As resistance increases, there are parallel rises in the number of treatment failures and the total cost of infection management. New generation broad-spectrum fluoroquinolones, such as grepafloxacin, have recently been recommended as a first-line treatment option in guidelines for lower respiratory tract infection. Grepafloxacin is an oral fluoroquinolone, with a microbiological and clinical profile that is particularly suited to the treatment of community-acquired respiratory infections. In vitro, it is rapidly bactericidal, and compared with earlier quinolones, its broad spectrum activity encompasses all important respiratory pathogens; Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila, including strains which are resistant to penicillin, other beta-lactam antibiotics and macrolides. In addition, grepafloxacin achieves high lung concentrations, and its long half-life (up to 15 h) enables once daily dosing. Overall, grepafloxacin combines the positive properties of the beta-lactam antibiotics against conventional Gram-positive and Gram-negative respiratory pathogens, with the activity of the macrolides against atypical pathogens. In patients with bacteriologically documented infections, clinical studies in community-acquired pneumonia have shown that treatment for 7-10 days once daily (o.d.) with approximately 600 mg is equivalent to that with either twice daily (b.i.d.) clarithromycin 250 mg, or three times daily (t.i.d.) cefaclor 500 mg, and superior to that with t.i.d. amoxycillin 500 mg. In these studies, grepafloxacin proved effective in the treatment of both typical and atypical pneumonia. In acute bacterial exacerbations of chronic bronchitis (ABECB), 7-10 days treatment with o.d. grepafloxacin 400 mg or 600 mg has been shown to be equivalent to that with either t.i.d. amoxycillin 500 mg, or b.i.d. ciprofloxacin 500 mg. In patients with a documented bacterial pathogen, microbiological success with both grepafloxacin dosage regimens was superior to amoxycillin 500 mg t.i.d. In addition, short course treatment of ABECB with 400 mg of grepafloxacin given o.d. for five days has been shown to be as effective, clinically and microbiologically as a ten-day course of the same dose. The safety profile of grepafloxacin has been well-characterised from data from over 12,000 patients treated in Phase II/III and post-marketing studies, and over 400,000 patients treated worldwide in routine clinical practice. The most commonly reported adverse events are gastrointestinal, mainly nausea and unpleasant taste. The potential for photosensitivity and central nervous system effects is low, and there have been no reports of convulsions. No unique or unexpected.     

The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview

The macrolide antimicrobial family is comprised of 14, 15 and 16 member-ringed compounds that are characterized by similar chemical structures, mechanisms of action and resistance, but vary in the different pharmacokinetic parameters, and spectrum of activity. The macrolides accumulate in many tissues such as the epithelial lining fluid and easily enter the host defense cells, predominantly macrophages and polymorphonuclear leukocytes (PMNs). Concentrations of the macrolides in respiratory tract tissues and extracellular fluids are in almost all cases higher than simultaneously measured serum concentrations, making them useful for respiratory tract infections. This review will focus on pharmacokinetic and pharmacodynamic aspects of the clinical relevant macrolides including azithromycin, clarithromycin, dirithromycin, erythromycin and roxithromycin.     

The pharmacokinetics of josamycin

Determination of the distribution coefficients in vitro demonstrates that josamycin (Wilprafen) is at least 15 times more lipophilic than erythromycin. On the other hand the distribution coefficients of penicillin G and of amoxicillin be in the hydrophilic range. The serum protein binding of josamycin is 15%, which is markedly less than with the other macrolides. These in vitro experiments show that small structural differences can alter the physicochemical and biological behaviour of an antibiotic, even when the molecules are closely related. A cross-over experiment with 12 volunteers and multiple application of 1 g of josamycin base or 1.175 g of erythromycin ethyl succinate showed that both macrolides are rapidly absorbed and reach their maximum within the first hour. In 21 patients the concentration of josamycin in lung tissue was 2 to 3 times that in the blood. The highest concentration of josamycin reached was 3.68 micrograms/g lung tissue (mean of 12 patients) and this was found for the group of patients from whom the tissue samples had been taken 2-3 h after the last administration of the drug. Lower mean concentrations of erythromycin were found in the serum and lung tissue of a similar group of 31 patients. The results indicate that the new macrolide antibiotic josamycin accumulates well in lung tissue and that the concentrations necessary for the treatment of infections (minimal inhibitory concentrations [MIC]) are rapidly reached also in the tissue.     

Penetration of garenoxacin into lung tissues and bone in subjects undergoing lung biopsy or resection

ABSTRACT

Objective: Concentrations of garenoxacin in plasma and samples of lung parenchyma, bronchial mucosa, and bone were determined following single-dose administration.

Research design and methods: Open-label, non-randomized study in which subjects undergoing invasive lung biopsy or resection were given a single 600?mg oral dose of garenoxacin. Lung parenchyma, and, if possible, bronchial mucosa and bone (i.e., flat bone with sinus mucosa or long bone from the lower legs) samples and corresponding plasma samples were obtained 2–4, 4–6, 10–12, or 20–24?h post-dose. Garenoxacin concentrations were measured using validated liquid chromatography with dual mass spectrometry. Safety was also assessed.

Results: Twenty-seven subjects enrolled and completed the study. Garenoxacin plasma concentrations (mean ± standard deviation) during the 24?h period ranged from 1.9 ± 1 to 7.4 ±3?µg/mL. Garenoxacin concentrations in lung tissue (15.2 ± 9?µg/g) peaked at 4–6?h and decreased to 3.7 ± 3?µg/g at 20–24?h. Mean ratios between bronchial mucosa and plasma ranged from 0.82 to 0.99 over a 24-h period. At 12?h, the mean ratio between bone and plasma was 0.56. Garenoxacin concentrations in lung tissue exceeded the MIC₉₀ for common respiratory pathogens by at least 61-fold. Garenoxacin was safe and well tolerated. Forty-five adverse events were reported by 26 subjects; none were determined to be attributable to garenoxacin by the investigators. Most of the adverse events were mild to moderate in severity.

Conclusions: Garenoxacin achieved 24-h concentrations in pulmonary tissues that exceeded the MIC₉₀ for common respiratory pathogens. A controlled study involving a larger number of lung and bone tissue samples is needed to further confirm these findings.     

Clinical results in the treatment of respiratory infections with moxifloxacin

Respiratory infections are a common source of morbidity and mortality, with pneumonia being the number one cause of death from infectious disease in Western industrialized countries. Initial antibiotic therapy of upper and lower respiratory infections is often empiric, being directed at the pathogens that are most likely to be present. Leading pathogens in respiratory infections are S. pneumoniae, H. influenzae and M. catarrhalis, which have developed considerable resistance problems against previous standard antibiotics like beta-lactams, macrolides and tetracyclines in the last decade. Newly developed quinolones such as moxifloxacin combine enhanced in vitro activity against Gram-positive bacteria with maintenance of activity against Gram-negative organisms. Three comparative, prospective, randomized, double-blind studies in the treatment of community acquired sinusitis, AECB and CAP demonstrated equal or higher efficacy of moxifloxacin in comparison to standard antibiotic therapies.     

Antimicrobial activity of thiamphenicol-glycinate-acetylcysteinate and other drugs against Chlamydia pneumoniae

Chlamydia pneumoniae is responsible for respiratory tract infections of both upper and lower respiratory tract. Although this bacterium is one of the most wide-spread pathogens of man, there are limited data on the antibiotic treatment of C. pneumoniae infections. The aim of this study has been to evaluate the in vitro activity of thiamphenicol glycinate acetylcysteinate (TGA, CAS 20192-91-0) in comparison with molecules with established activity against C. pneumoniae, as well as macrolides and quinolones. The results have shown that TGA and clarithromycin (CAS 81103-11-9) are the most active drugs tested, but it is important to underline that the minimal inhibitory concentration (MIC) ranges of TGA are very much lower than the breakpoint of thlamphenicol for the respiratory pathogens. In conclusion, the good antimicrobial in vitro activity of TGA against C. pneumoniae together with its in vivo characteristics, in particular the high concentration reached in lung and the combination with the mucolytic agent N-acetylcysteine (NAC, CAS 616-91-1), can make a valid choice in the treatment of respiratory tract infections caused by C. pneumoniae. These findings need further evaluation by clinical studies.     

Tissue pharmacokinetics of florfenicol in pigs experimentally infected with Actinobacillus pleuropneumoniae.

The aim of this study has been to determine the tissue pharmacokinetic parameters of florfenicol in the pigs experimentally infected with Actinobacillus pleuropneumoniae. 21 crossed-bred (Duroc x Landrace x Yorkshire) local species of pigs were infected experimentally with Actinobacillus pleuropneumoniae serotype 1 and confirmed as typical sub-acute pleuropneumonia. A single dose of 20 mg/kg body weight of florfenicol, a novel animal-using antibiotic, was administrated intramuscularly in the pigs and then samples of blood, lung, trachea with bronchi, liver, kidney and muscle were taken at scheduled time points. Drug concentrations were determined by high performance liquid chromatography (HPLC) with an ultraviolet detector via extraction with ethyl acetate under nitrogen flow. The statistic moment theory (SMT) mathematic package was applied to calculate the tissue pharmacokinetic parameters of florfenicol in the infected model. AUC of lung, trachea with bronchi, liver, kidney and muscle were 121.69, 79.37, 81.05, 181.2, and 94.07 mg/l x h, respectively, MRT were from 34.66 to 90.17 h, and t1/2beta from 24.75 to 69.34 h, respectively. CONCLUSIONS: Florfenicol was widely distributed in these tissues and maintained the effective therapeutic concentrations especially in the respiratory tract tissues that are the target organs of Actinobacillus pneuropneumoniae. CLINICAL SIGNIFICANCE: Tissue pharmacokinetic data could be evidence for regime designing of florfenicol in treatment of porcine pleuropneumonia.     

Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents

The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.     

PHARMACOKINETICS OF AZITHROMYCIN IN LUNG TISSUE, BRONCHIAL WASHING, AND PLASMA IN PATIENTS GIVEN MULTIPLE ORAL DOSES OF 500 AND 1000 MG DAILY

The present study compares the pharmacokinetics of azithromycin in plasma, lung tissue, and bronchial washing after oral administration of 500 mg (standard dose) versus 1000 mg daily for 3 days. Samples were taken during surgery for lung resection at various time points up to 204 h after the last drug dose, and azithromycin levels were analyzed by HPLC method. Azithromycin was widely distributed within the lower respiratory tract; sustained concentrations of the drug were detectable at the last sampling time (204 h) in lung tissue and bronchial washing, with long terminal half-lives of 132.86 and 74.32 h at 500 mg daily and 133.32 and 70.5 h at 1000 mg daily, respectively. Doubling the drug dose resulted in a remarkable increase in lung area under the curve (AUC, 1318 hx microg g(-1) vs 2502 hx microg g(-1)) and peak tissue concentration (9.13+/-0.53 microg g(-1) vs 17.85+/-2.4 microg g(-1)). In addition to this, enhanced azithromycin penetration from plasma into bronchial secretion and lung tissue was evidenced by the increase in the ratio of AUC(bronchial washing) versus AUC(plasma) (2.96 vs 5.27 at 500 and 1000 mg, respectively) and AUC(lung) versus AUC(plasma) (64.35 vs 97.73 at 500 and 1000 mg, respectively). In conclusion, the exposure of lung and bronchial washing to azithromycin is increased by doubling the dose, which results in favorable pharmacokinetic profile of the drug in the lower respiratory tract.     

Antibiotic safety assessment

Antibiotics usually have positive risk-benefit ratios, their adverse effects being generally mild and reversible on treatment cessation. However, severe adverse drug reactions (ADR), associated with significant mortality and morbidity have resulted in the withdrawal of several active antibiotics, including new fluoroquinolones. Adverse reactions to antibiotics are often poorly documented. The purpose of this article is to examine current tools for investigating and preventing antibiotic toxicity and to suggest future lines of investigation. Structure/ADR relationships have been investigated with various antibiotics (beta-lactams, macrolides, quinolones, etc.) in an attempt to reduce the risk of adverse reactions. Some reactions can be linked to the drug's stereochemical composition. In the case of quinolones for instance, particularly ofloxacin and its derivatives, experimental data show that individual enantiomers have different toxicities. Another major factor that influences the risk of ADRs in a given population is metabolic variability, due to genetic differences in the relevant drug-metabolizing enzymes. Idiosyncratic antibiotic toxicity can be caused by a chemically reactive metabolite. Recent advances in molecular biology, and especially in individual genomic characterization (DNA chip technology, etc.), could in future be useful for identifying patients who are at a special risk of ADR. Finally, certain pharmacokinetic parameters (AUC, Cmax, etc.) can be used to predict adverse effects.     

Potential role of antibiotics in the treatment of asthma

Although the role of antibiotic treatment in asthma is still disputed, clinical use of antimicrobials in this setting is more widespread than warranted on the basis of indications in the literature. Viral upper respiratory tract infections are known to be involved in asthma exacerbations. More recently, evidence of Mycoplasma pneumoniae and Chlamydia pneumoniae involvement in asthma attacks has been reported both in adult and paediatric populations. These pathogens are also involved in chronic asthma, and both in vitro and animal model studies indicate that atypical agents may play a role in the pathogenesis of the disease. Recent studies on asthma patients with evidence of atypical infection suggest that specific antimicrobial treatment (basically macrolides or fluoroquinolones) may confer additional advantages compared to standard therapy alone. Furthermore, a considerable amount of data has been gathered describing additional effects associated with macrolide treatment (reduced bronchial hyper-responsiveness, altered cytokine production, etc.). These non-antimicrobial effects have been defined as "anti-inflammatory activity". Should this information be confirmed, the use of macrolides in patients with asthma may be twofold: eradication of occult atypical infection; and reduction in the airway inflammation burden. Future lines of research in this field should attempt to determine whether specific antibiotic treatment may alter the natural history of asthma.     

Review of macrolides and ketolides: focus on respiratory tract infections

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.