The Clinical Pharmacology Research Center and Department of Adult and Pediatric Medicine, Bassett Healthcare, Cooperstown, NY, USA
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Abstract |
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Aims of this review: This review aims: to give the reader information on the background areas described, as well as related areas; to review the CAP benefits with macrolides and how they may be related to the immunomodulatory properties they demonstrate, albeit in a shorter period of time than previously demonstrated with chronic pulmonary disorders; to use ex vivo data to support these extrapolations.
Literature search: A literature search using Medline was conducted from 1966 onwards, searching for articles with relevant key words such as macrolide, diffuse panbronchiolitis, community-acquired pneumonia, biofilm, immunomodulation, cystic fibrosis, erythromycin, clarithromycin, roxithromycin and azithromycin, bronchiectasis and asthma. When appropriate, additional references were found from the bibliographies of identified papers of interest. Any relevant scientific conference proceedings or medical texts were checked when necessary.
Conclusions: (1) Research into macrolide immunomodulation for chronic pulmonary disorders demonstrates consistent positive effects, although of types other than seen with diffuse panbronchiolitis. These effects, together with their inhibitory activity on biofilms, have the potential to make them a useful option. (2) The benefits for CAP are consistent, and higher when a macrolide is given with another atypical agent than if the other atypical agent is given alone, suggesting a non-antibacterial benefit. (3) Recent research of the immunomodulatory properties of azithromycin imply that azithromycin may have a previously unknown short-term biphasic effect on inflammation modulation: enhancement of host defence mechanisms shortly after initial administration followed by curtailment of local infection/inflammation in the following period. (4) Additional in vivo research is needed prior to developing any firm conclusions.
Keywords: azithromycin , clarithromycin , erythromycin , pneumonia , diffuse panbronchiolitis
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Macrolide benefits beyond antimicrobial activity: early observations |
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Immunomodulation by macrolides of chronic inflammatory pulmonary disorders |
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DPB is a chronic, obstructive pulmonary disease that is found almost exclusively in Japan. At presentation, patients have dyspnoea upon exertion, a productive cough, wheezing, weight loss and potentially sputum that is colonized with one or more pathogens. They also typically have a history of several years of chronic sinusitis. Prior to discovering the benefits of chronic low-dose erythromycin therapy (which was recently reviewed in this journal in detail)6 the 5 year mortality from DPBonce a patient became colonized with P. aeruginosawas >90%. The non-antibacterial benefits from 14- and 15-membered macrolides on an inflamed DPB pulmonary system appear to be multifaceted. First, animal studies demonstrated that chronic erythromycin dosing resulted in decreased sputum/mucus production in a dose-dependent fashion. This occurred secondary to the binding of the macrolide to the epithelial cell chloride channelswhich in turn blocked the channelsplus the inhibition of water secretion that moves with the chloride ions across the cell membrane.7,8 This blockade results in a decrease of hypersecretion and has been demonstrated to occur in humans during chronic lower and upper airway inflammatory conditions when clarithromycin is administered as a long- (8 weeks) and short-term (7 days) regimen.911
There is no doubt that decreased secretions would result in a better quality of life (QOL) for patients with these chronic respiratory diseases, especially those with high secretion output volumes. However, the ability to decrease the ceaseless inflammatory processes that perpetuate the ongoing pulmonary damage would also be advantageous. This has been demonstrated for macrolides during investigations into their mechanism of action in DPB patients, as detailed in Table 112,13 and a recent review article.6 As noted from the results of the two DPB studies described in Table 1 as well as the 17 others described in the recent review, no matter which macrolide (erythromycin, clarithromycin, roxithromycin and azithromycin) was utilized for DPB treatment the impact they had on the pulmonary inflammatory process was very consistent. When administered chronically in low doses, the macrolides are able to suppress the overabundance of neutrophils (PMNs) present in the lungs. This is effected by reducing their chemotaxis to the lungs by diminishing the responsible cytokines [i.e. interleukin (IL)-8]. As such, months after the start of macrolide therapy, a sputum differential would be more likely to be consistent with that of a healthy volunteer or of a patient with non-inflammatory pulmonary disease, in whom there is always a higher percentage of alveolar macrophages (AMs) than of PMNs. The suppression of the acute inflammatory process is likely to result in other secondary benefits, such as improved pulmonary function and decreased incidence of acute exacerbations, both of which would be a significant clinical improvement for DPB patients. However, there is inconsistence as to when these effects occur upon starting macrolide therapy: the studies in Table 1 and the review note highly variable times to onset of clinical benefitanywhere from a few months to 16 months.6 Although it would be advantageous to identify the source of this variance, this is less pressing, as long as the population consistently benefits from the macrolides some time after commencing treatment.
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Other inflammatory pulmonary disorders |
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Asthma
As an example, the study investigating the impact of clarithromycin on mild to moderate bronchial asthma not only had no healthy volunteers as a control, but had a defined dosing period of 8 weeks rather than dosing to effect, as had been the method in the DPB studies.14 Whereas the lack of healthy volunteers is unlikely to be important, the discontinuation of dosing at 8 weeks may have been shortsighted, since it took between 516 months in the DPB studies for clinical end-points to be reached. Nevertheless, there were significant decreases in: serum and sputum eosinophil counts; eosinophilic cationic protein; patient symptom score (based on incidence of asthma attacks, amount of disability during attacks and amount of nocturnal asthma) (P < 0.05); and increases in PC20. The fact that there were no changes in pulmonary function tests may be merely a function of the mild to moderate severity of the asthma of patients in the study, as opposed to a more severe obstructive form, in which there may be more likelihood of change. The authors' conclusions were that beyond clarithromycin's antibacterial effects, there were also anti-asthmatic effects not related to bronchodilation. There was also an eosinopenic effect, through a mechanism that is probably related to eosinophil cytokine expression.14 However, one thing cannot be ignored: like the DPB trials, this study has too small a sample size. This means that more research is necessary before this treatment modality can be accepted widely.
Bronchiectasis
Studies investigating prolonged administration of low-dose macrolides in the treatment of bronchiectasis had contrasting designs as compared to the DPB studies, as well as amongst each other. This subsequently resulted in the outcomes contrasting to those of the DPB studies, as well as each other.15,16 Whereas the first was a study of bronchietatic children with increased airway responsiveness (AR), the latter study was of adult patients with idiopathic bronchiectasis. Whereas the DPB patients were dosed with macrolides until clinical response, the children were dosed with roxithromycin for 12 weeks and the adults with erythromycin for 8 weeks. Although the DPB patients underwent baseline and follow-up BALs (where BAL stands for bronchoalveolar lavage) to collect respiratory secretion samples for white blood cell (WBC) differentials and cytokine measurements, both bronchiectasis studies used either expectorated or induced sputum samples. Even though expectorated sputum in this case should be reflective of the diseased pulmonary area, the BAL would have been definitive proof and should have been an option in case the patient was not productive or serially produced contaminated samples. The fact that there was no change in pathogen, WBC or cytokine densities in the adult study leads one to wonder whether their results would have differed if more disease-specific specimenstaken by means of BALhad been analysed. Although the non-DPB studies have been investigating standard pulmonary function test (PFT) results before and after initiating treatment to discover potential differences, results have been very mixed, as was seen with these two studies, which had contrasting outcomes. However, in addition to PFTs, airway responsiveness testing was conducted in these more recent trials. As such, even though, as with the paediatric trial, the PFT changes may be insignificant, there may be significant AR decreases. These were measured by high-dose methacholine challenge tests before and after treatment. The maximal response and provocative cumulative dose of methacholine that produced a 20% fall in FEV1 were used as the two indices of AR.15 The data are strong and promising and should lead to additional research in this population with this class of drugs. However, these studies also suffer from being too small.
Bronchiolitis obliterans syndrome
In an open label pilot study, azithromycin 250 mg was administered three times a week to six lung transplant patients with stage 1 or greater bronchiolitis obliterans syndrome (BOS) to see if pulmonary function improved or not.17
After an average of 14 weeks, patients had a mean increase of 17% (P
0.05) in FEV1, as compared with baseline, together with an absolute FEV1 increase of 0.50 L on average. The authors concluded that there was a potential role for macrolides as part of the maintenance therapy in lung transplant patients with BOS.17
The ability to discover a significant change with so few patients would seem unlikely, especially with PFTs over such a relatively short period of time. In this case, it is apparent that the macrolide was producing the effect, rather than other concurrent medication, because azithromycin was the only new medication. For a regular medication to have caused an improvement in PFTs, there would have to have been an increase in dose or exposure to it, such as would happen in a drug interaction. However, since azithromycin lacks any significant drug interactionsincluding against the anti-rejection agents the patients were receivingit seems highly unlikely the improvement was due to anything except azithromycin. Unfortunately, as a pilot study, markers of pulmonary inflammation were not conducted at baseline and repeated throughout to try to correlate the change in PFTs with a decrease in pulmonary inflammation or other physiological change(s). However, these six patients provide a stimulus for additional work with this diagnosis.
Cystic fibrosis
As seen in Table 1 and the recent review mentioned earlier,6 larger trials have been conducted in cystic fibrosis (CF). To date, three relatively large trials have been conducted: one in children (n=41),18 one in adults (n=60)19 and one in both age groups (n=185).20 Each of these trials utilized azithromycin, as this was most likely to minimize any drugdrug interactions with the numerous concurrent drugs administered in CF. As noted in Table 1, all three of the studies had the same basic outcomes: decreased incidence of antibiotic requiring exacerbations and improvement or stabilization of PFTs while on azithromycin, as compared with worsening of both while on placebo. As the mixed age group study demonstrated, daily dosing with azithromycin did not appear to be necessary regardless of age. The study showed that by only giving azithromycin three times a week the results were the same as the other CF trials.1820 Further study is required to find out whether an even smaller regimen would obtain the same results.
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Chronic airway inflammation, P. aeruginosa and biofilms |
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To date, although the 14- and 15-membered macrolides have demonstrated a variety of benefits, as demonstrated in the sections above and in Table 1, they also provide added benefits once pulmonary conditions such as DPB, cystic fibrosis or bronchiectasis progress to a stage when infection/colonization with these mucoid strains of P. aeruginosa occur. Probably the most commonly identified benefit to date is the ability of the 14- and 15-membered macrolides to break down, as well as prevent further development of the biofilms protecting the mucoid P. aeruginosa strains. This ability affects isolates that attach to either the natural airways of the patient or the synthetic material used for endotracheal/tracheostomy tubes, and occurs at subminimal inhibitory concentrations of the macrolides.2429 Once exposed to these low macrolide concentrations, there is a decrease in the amount of alginate and hexose in the biofilm and also most likely the overall amount of polysaccharides. This decrease leads to an eradication of the membranous structures of the biofilm, thereby letting in concurrently administered anti-pseudomonal antibiotics, as well as acute reactant phagocytes, such as neutrophils, to eradicate the once shielded pathogens.2429 In addition, although acutely absent of any inherent anti-pseudomonal activity, as P. aeruginosa accumulates the macrolides intracellularly with continued dosing, there is a resultant inhibition of protein synthesis. As the exposure and inhibition goes on, there is eventual bactericidal activity by the macrolides against the P. aeruginosa, even though the extracellular concentrations were below the MIC for the isolates of the macrolides.30 The other main effect that macrolides have on P. aeruginosa, especially mucoid strains, is an attenuation of various virulence factors that are essential for its pathogenesis. Azithromycin, for example, has been demonstrated to inhibit the quorum-sensing circuitry of P. aeruginosa by decreasing the production of autoinducers, which subsequently decreases virulence factors (autoinducer 3-oxo-C12-HSL is suppressed which leads to decreased IL-8 production) and pulmonary morbidity.3133 Although all of the macrolides share these anti-virulence-factor properties, it has been demonstrated that azithromycin has the highest potency of the 14- and 15-membered macrolides and would therefore be the most effective option for those seeking this effect.32 By using the macrolides in cystic fibrosis, DPB or bronchiectasis patients who are infected/colonized with P. aeruginosa it is obvious from these data that it may be possible to not only potentially eradicate them when previously it was not possible to, but also, alter them so that they cause much less damage to the pulmonary tree. Evidence to date that these in vitro and other data are clinically applicable to humans is indirectly available in the DPBmacrolide literature. The fact that chronic low-dose macrolides have improved the 5 year survival rate from <10% once patients were colonized with P. aeruginosa to >90% demonstratesat least for this conditionthat these in vitro and murine data are most likely to be duplicated clinically as well. If this is true for DPB then it is probably true for other chronic pulmonary inflammatory diseases.
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Other types of mucoid disease |
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Implications of short-term macrolide therapy for CAP |
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Clinical evidence of macrolide activities beyond antimicrobial activity |
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Source of CAP benefits? Immunomodulatory pharmacodynamic aspects of macrolides |
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In order to identify what the macrolide was inducing in the short-term in relation to a CAP regimen of a macrolide, the first studies have been conducted ex vivo using healthy volunteers. In one study, 12 healthy volunteers were administered the standard European adult CAP 3 day regimen of oral azithromycin (500 mg/day) and had blood samples drawn both prior to therapy and 2.5 and 24 h and 28 days after the end of therapy to measure drug effects on various neutrophil functions and circulating inflammatory mediators.57
Healthy volunteers were chosen for this initial study to assure that the harvested neutrophils were neither primed nor defective secondary to an inflammatory condition. Ex vivo analyses of the subjects' neutrophils demonstrated an initial neutrophil degranulating effect of azithromycin, which was reflected by rapid decreases in azurophilic granule enzyme activities in the cells and corresponding increases in the serum. The oxidative burst response to a particulate stimulus was also acutely enhanced. These actions both occurred when serum and neutrophil azithromycin concentrations were generally higher, being maximal at the 24 h time point and gradually decreasing over the subsequent 27 days to a point where they were less than those at baseline. In addition, a continuous fall in chemokine (IL-8 and human growth related oncogene-) and IL-6 serum concentrations, within the non-pathological range, accompanied a down-regulation of the oxidative burst and an increase in neutrophil apoptosis up to 28 days after the end of dosing. Neutrophils harvested at the 28 day time-point still contained measurable azithromycin concentrations, which indicated that transfer of the drug from other types of cells (e.g. fibroblasts) to rapidly replaced neutrophils had occurred. The authors concluded that the neutrophil degranulation and oxygen burst in response to particulate matter, which occurs immediately following initiation of azithromycin dosing, may enhance endogenous host defence mechanisms to complement the direct antibacterial activity of the drug itself. In the weeks that follow the completion of the azithromycin regimen, sufficient drug from other secondary or tertiary physiological compartments is available and continually transferred to local or circulating neutrophils, and is then able to inhibit neutrophil activity, including enhancement of neutrophil apoptosis. This more prolonged process would lead to a curtailment of local inflammation and subsequently help to clear tissues from potentially damaging mediators, subsequent to the resolution of the infection.57
Although it is unclear whether these latter effects are secondary to intracellular azithromycin, the release of anti-inflammatory cytokines, such as IL-1ra as was demonstrated in CAP patients,58
or a combination of the two, an in vitro study59
provides support for the above described study57
and actually sheds light on how the introduction of a common community-acquired respiratory tract infection (RTI) pathogen modifies, yet supports, the results demonstrated in healthy volunteers.
The aim of the study was to determine the effects of azithromycin on neutrophil apoptosis, oxidative function and IL-8 production in the presence or absence of Streptococcus pneumoniae (its lysate), in comparison with penicillin, erythromycin, dexamethasone or phosphate-buffered saline.59
Neutrophils utilized were collected from healthy volunteers. The results of the study showed that the level of apoptosis noted after 1 h of exposure to azithromycin was similar to the level of apoptosis demonstrated after the neutrophils were incubated for 3 h with tumour necrosis factor (TNF). However, if S. pneumoniae lysate was present, azithromycin was unable to induce neutrophil apoptosis and this finding was verified via an experiment with a system that detects late-stage apoptosis. After 6 h of incubation, even though azithromycin-induced apoptosis could be verified after 1 min when the lysate was not present, it was again prevented if the bacterial lysate was co-incubated. Penicillin, dexamethasone and erythromycin had no effect on apoptosis. After 1 h of incubation, the testing for oxidative function did not show a change in function when neutrophils were incubated with any of the drugs, whether the bacterial lysate was present or not. Although in vitro exposure of the neutrophils to the S. pneumoniae lysate did indeed induce IL-8 synthesis, penicillin, erythromycin and azithromycin did not affect its production, whether the bacterial lysate was present or not. In contrast, dexamethasone significantly inhibited IL-8 production.59
The authors concluded that azithromycin-induced neutrophil apoptosis may be detected in the absence of any effect on neutrophil function, and the pro-apoptotic properties of azithromycin are inhibited in the presence of S. pneumoniae. Although at face value the results seem to conflict with the results of the first study57
and would indicate that there is only benefit in healthy volunteers, and that those with pneumococcal CAP would only benefit from azithromycin's antibacterial properties, the results actually support the benefits that macrolides can produce in CAP patients. When comparing the two studies it is important to remember that they are not very different and are both representative of the acute period of an infection as well as the phase when the body is cleaning up the infection, and the host's response to it. As the two studies demonstrate, if a patient presented with pneumococcal CAP, the ability of the body to attract more neutrophils to the site will probably not be affected to a point that would impair it, due to no or minimal acute suppression of IL-8. This is in stark contrast to the highly immunosuppressive effects noted with the corticosteroid, dexamethasone. Once the neutrophils reach the infection site, their ability to react to the bacterial stimulants is not adversely affected by azithromycin and actually may induce a reaction that would enhance the bactericidal effects of the neutrophils. Once the bacteria have been killed and cleared, azithromycin is able to induce apoptosis, regardless of whether there is any residual IL-8 present or not, and thereby allow the body to clear these apoptotic neutrophils without them spilling their pro-inflammatory products in the process. This latter ability minimizes, if not suppresses, any further inflammation that may cause ongoing local and/or systemic damage. The fact that azithromycin was able to induce apoptosis at concentrations even lower than erythromycin, suggests that, due to its prolonged tissue half-life, azithromycin will continue to induce local apoptosis and minimize any further inflammation once the bacteria are cleared for the large proportion of the time that it may take to free the leftover inflammation from a case of CAP.57,59
Whether the beneficial biphasic effects demonstrated in these studies with azithromycin are equally present if other macrolides are used is unclear. Despite the differences noted in the latter study between azithromycin and erythromycin,59
the benefits noted in RTIs have been described with a variety of macrolides, and the benefits of one versus the other has yet to be discerned from RTI study results. In fact, as demonstrated in the literature, as long as the drug is present locally, erythromycin and roxithromycin demonstrate similar induction of neutrophil apoptosis, and in vitro investigations with clarithromycin have also noted this biphasic effect with clarithromycin and human THP-1 monocytes.60,61
A small number of studies is hardly sufficient to lead to any definitive conclusions. However, the findings to date, especially from the azithromycin study, which was dosed analogously to a common CAP regimen, are intriguing and leave one with the ability to begin to formulate extrapolations of their in vivo/ex vivo immune response effects and the improved outcomes described earlier. The enhancement of the antibacterial effects of neutrophils immediately upon the start of an azithromycin regimen may be the mechanism by which the use of a macrolide as monotherapy, or in combination with a ß-lactam or fluoroquinolone, consistently appears to result in more rapid resolution of the signs/symptoms of CAP, thereby allowing for earlier hospital discharges and decreased mortality rates. Although the anti-inflammatory effects of macrolides have been established for over two decades, measurements of these effects have been typically conducted weeks to months after the start of therapy. The fact that these anti-inflammatory effects begin to manifest at such an early time-point after the start of a treatment regimen also theoretically correlates with the improved outcomes noted in CAP patients. Not only does the patient receive the benefit of a period of antibacterial enhancement, but also a relatively rapid quashing of the inflammatory response, which in most cases will help prevent any perpetuation of the inflammatory cascade and subsequent tissue damage that may result in slower resolution of the infectious process.
However, these benefits will remain only educated extrapolations until research is undertaken to try to document this biphasic effect of macrolides in the treatment of CAP in in vivo systems, such as animal models or even humans. Although a cold comment, an immunocompetent animal model of CAP, or any infection for that matter, would be ideal to demonstrate this benefit, as animals could be sacrificed serially to document the biphasic effect. Once infected and the infection has proceeded to a pre-determined pathogen load, sampled animals could be sacrificed to measure baseline infection site cell differentials, cytokine/chemokine contents and the viability of the acute reactant phagocytes. The remaining animals could then be dosed with a macrolide (± another antibiotic) and then serially sacrificed for repeat measurements of the same parameters, during which time an infection would be considered to be in its acute phase. This process could be repeated later, at which time the host would be considered to be in a convalescent phase, with the site cleansed of the inflammatory milieu of the infection. Although it would be ideal to do this in humans, the serial site sampling that would be necessary would limit the types of patients appropriate for such a study. To assure maximal collection techniques the best human model may be intubated pneumonia patients whose deep pulmonary secretions could be obtained for testing, as the infection devolves secondary to antibiotic treatment.
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Short-term immunomodulation in non-infectious conditions |
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Conclusions |
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Footnotes |
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References |
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2 . Kudoh, S. & Kimura, H. (1984). Clinical effect of low-dose long-term administration of macrolides on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 254, Suppl., 254.
3 . Kudoh, S., Azuma, A., Yamamoto, M. et al. (1998). Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. American Journal of Respiratory and Critical Care Medicine 157, 182932.[ISI][Medline]
4 . Kudoh, S., Uetake, T., Hagiwara, K. et al. (1987). Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 25, 63242.[Medline]
5 . Yamamoto, M., Kondo, A., Tamura, M. et al. (1990). Long-term therapeutic effects of erythromycin and new quinolone antibacterial agents on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 28, 130513.[Medline]
6
.
Schultz, M. J. (2004). Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. Journal of Antimicrobial Chemotherapy 54, 218.
7 . Goswami, S. K., Kivity, S. & Marom, Z. (1990). Erythromycin inhibits respiratory glycoconjugate secretion from human airways in vitro. American Review of Respiratory Diseases 141, 728.
8 . Tamaoki, J., Isono, K., Sakai, N. et al. (1992). Erythromycin inhibits Cl secretion across canine tracheal epithelial cells. European Respiratory Journal 5, 2348.[Abstract]
9 . Tamaoki, J., Takeyama, K., Tagaya, E. et al. (1995). Effect of clarithromycin on sputum production and its rheological properties in chronic respiratory tract infections. Antimicrobial Agents and Chemotherapy 39, 168890.[Abstract]
10
.
Tagaya, E., Tamaoki, J., Kondo, M. et al. (2002). Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest 122, 2138.
11 . Rubin, J.-I, Druce, H., Ramirez, O. E. et al. (1997). Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis. American Journal of Respiratory and Critical Care Medicine 155, 201823.[Abstract]
12 . Kadota, J.-I., Sakito, O., Kohno, S. et al. (1993). A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. American Review of Respiratory Diseases 147, 1539.
13
.
Sakito, O., Kadota, J.-I., Kohno, S. et al. (1996). Interleukin 1ß, tumor necrosis factor and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration 63, 428.[ISI][Medline]
14 . Amayasu, H., Yoshida, S., Ebana, S. et al. (2000). Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Annals of Allergy, Asthma, & Immunology 84, 5948.[ISI]
15
.
Koh, Y. Y., Lee, M. H., Sun, Y. H. et al. (1997). Effect of roxithromycin on airway responsiveness in children with bronchiectasis: a double-blind, placebo-controlled study. European Respiratory Journal 10, 9949.
16
.
Tsang, K. W. T., Ho, P.-I., Chan, K.-n. et al. (1999). A pilot study of low-dose erythromycin in bronchiectasis. European Respiratory Journal 13, 3614.
17
.
Gerhardt, S. G., McDyer, J. F., Girgis, R. E. et al. (2003). Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. American Journal of Respiratory and Critical Care Medicine 168, 1215.
18 . Equi, A., Balfour-Lynn, I. M., Bush, A. et al. (2002). Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 360, 97884.[CrossRef][ISI][Medline]
19
.
Wolter, J., Seeney, S., Bell, S. et al. (2002). Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 57, 2126.
20
.
Saiman, L., Marshall, B. C., Mayer-Hamblett, N. et al. (2003). Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. Journal of the American Medical Association 290, 174956.
21
.
Howe, R. A. & Spencer, R. C. (1997). Macrolides for the treatment of Pseudomonas aeruginosa infections. Journal of Antimicrobial Chemotherapy 40, 1535.
22 . Kobayashi, H. (1995). Biofilm disease: its clinical manifestation and therapeutic possibilities of macrolides. American Journal of Medicine 99, Suppl. 6A, 26S30S.[CrossRef][Medline]
23 . Kobayashi, H. (2001). Airway biofilm disease. International Journal of Antimicrobial Agents 17, 3516.[CrossRef][ISI][Medline]
24 . Yasuda, H., Ajiki, Y., Koga, T. et al. (1993). Interaction between biofilms formed by Pseudomonas aeruginosa and clarithromycin. Antimicrobial Agents and Chemotherapy 37, 174955.[Abstract]
25 . Vranes, J. (2000). Effect of subminimal inhibitory concentrations of azithromycin on adherence of Pseudomonas aeruginosa to polystyrene. Journal of Chemotherapy 12, 2805.[ISI][Medline]
26 . Ichimiya, T., Yamasaki, T. & Nasu, M. (1994). In-vitro effects of antimicrobial agents on Pseudomonas aeruginosa biofilm formation. Journal of Antimicrobial Chemotherapy 34, 33141.[Abstract]
27
.
Bui, K. Q., Banevicius, M. A., Nightingale, C. H. et al. (2000). In vitro and in vivo influence of adjunct clarithromycin on the treatment of mucoid Pseudomonas aeruginosa. Journal of Antimicrobial Chemotherapy 45, 5762.
28 . Takeoka, K., Ichimiya, T., Yamasaki, T. et al. (1998). The in vitro effect of macrolides on the interaction of human polymorphonuclear leukocytes with Pseudomonas aeruginosa in biofilm. Chemotherapy 44, 1907.[CrossRef][ISI][Medline]
29
.
Yanagihara, K., Tomono, K., Sawai, T. et al. (2000). Combination therapy for chronic Pseudomonas aeruginosa respiratory infection associated with biofilm formation. Journal of Antimicrobial Chemotherapy 46, 6972.
30 . Tateda, K., Ishii, Y., Matsumoto, T. et al. (1996). Direct evidence for antipseudomonal activity of macrolides: exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin. Antimicrobial Agents and Chemotherapy 40, 22715.[Abstract]
31
.
Tateda, K., Comte, R., Pechere, J.-C. et al. (2001). Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 45, 19303.
32 . Molinari, G., Guzmán, C. A., Pesce, A. et al. (1993). Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. Journal of Antimicrobial Chemotherapy 31, 6818.[Abstract]
33 . Nguyen, T., Louie, S. G., Beringer, P. M. et al. (2002). Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease. Current Opinion in Pulmonary Medicine 8, 5218.[CrossRef][ISI][Medline]
34
.
Yoshii, I., Nishimura, H., Yoshikawa, T. et al. (2001). Therapeutic possibilities of long-term roxithromycin treatment for chronic diffuse sclerosing osteomyelitis of the mandible. Journal of Antimicrobial Chemotherapy 47, 6317.
35
.
Heffelfinger, J. D., Dowell, S. F., Jorgensen, J. H. et al. (2000). Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Archives of Internal Medicine 160, 1399408.
36
.
Macfarlane, J., Boswell, T., Douglas, G. et al. (2001). BTS guidelines for the management of community acquired pneumonia in adults. Thorax 56, Suppl. IV, iv164.
37 . Memish, Z. A., Shibl, A. M., Ahmed, Q. A. A. et al. (2002). Guidelines for the management of community-acquired pneumonia in Saudi Arabia: a model for the Middle East region. International Journal of Antimicrobial Agents 20, Suppl. 1, S112.[ISI][Medline]
38
.
Pallares, R., Linares, J., Vadillo, M. et al. (1995). Resistance to penicillin and cephalosporins and mortality from severe pneumococcal pneumonia in Barcelona, Spain. New England Journal of Medicine 333, 47480.
39 . Mandell, L. A., Bartlett, J. G., Dowell, S. F. et al. (2003). Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clinical Infectious Diseases 37, 140533.[CrossRef][ISI][Medline]
40 . Jung, S., Song, J., Oh, W. et al. (2002). Clinical outcomes of pneumococcal pneumonia by antibiotic-resistant strains in Asian countries; the Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract L-991, p. 360. American Society for Microbiology, Washington, DC, USA.
41
.
Amsden, G. W., Baird, I. M., Simon, S. et al. (2003). Efficacy and safety of azithromycin versus levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis. Chest 123, 7727.
42 . Lode, H., File, T. M., Jr, Mandell, L. et al. (2002). Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability. Clinical Therapeutics 24, 191536.[CrossRef][ISI][Medline]
43
.
Stahl, J. E., Barza, M. D., Desfardin, J. et al. (1999). Effect of macrolides as part of initial empiric therapy on length of stay in patients hospitalized with community-acquired pneumonia. Archives of Internal Medicine 159, 257680.
44 . Mufson, M. A. & Stanek, R. J. (1999). Bacteremic pneumococcal pneumonia in one American city: a 20-year longitudinal study, 19781997. American Journal of Medicine 107, 34S43S.[Medline]
45 . Martinez, J. A., Horcajada, J. P., Almela, M. et al. (2003). Addition of a macrolide to a ß-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clinical Infectious Diseases 36, 38995.[CrossRef][ISI][Medline]
46 . Weiss, K., Cortes, L., Beaupre, A., et al. (2002). Clinical characteristics, initial presentation and impact of treatment on mortality in bacteremic Streptococcus pneumoniae pneumonia (BSPP). In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract L-987, p. 359. American Society for Microbiology, Washington, DC, USA.
47 . Gupta, A. K., Rai, S., Farag, B. et al. (2002). Comparative analysis of levofloxacin (LV) vs ceftriaxone (CX)/azithromycin (AZ) in the treatment of community-acquired pneumonia (CAP): length of stay. In Abstracts of the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 2002. Abstract L-981, p. 357. American Society for Microbiology, Washington, DC, USA.
48
.
Gleason, P. P., Meehan, T. P., Fine, J. M. et al. (1999). Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Archives of Internal Medicine 159, 256272.
49
.
Brown, R. B., Iannini, P., Gross, P. et al. (2003). Impact of initial antibiotic choice on clinical outcomes in community-acquired pneumonia: analysis of a hospital claims-made database. Chest 123, 150311.
50 . Lonks, J. R., Garau, J., Gomez, L. et al. (2002). Failure of macrolide antibiotic treatment in patients with bacteremia due to erythromycin-resistant Streptococcus pneumoniae. Clinical Infectious Diseases 35, 55664.[CrossRef][ISI][Medline]
51 . Trowbridge, J. F., Artymowicz, R. J., Lee, C. E. et al. (2002). Antimicrobial selection and length of hospital stay in patients with community-acquired pneumonia. Journal of Clinical Outcomes Management 9, 6139.
52 . Lentino, J. R. & Krasnicka, B. (2002). Association between initial empirical therapy and decreased length of stay among veteran patients hospitalized with community acquired pneumonia. International Journal of Antimicrobial Agents 19, 616.[CrossRef][ISI][Medline]
53 . Meehan, T. P., Fine, M. J., Krumholz, H. M. et al. (1997). Quality of care, process, and outcomes in elderly patients with pneumonia. Journal of the American Medical Association 278, 20804.[Abstract]
54
.
Battleman, D. S., Callahan, M. & Thaler, H. T. (2002). Rapid antibiotic delivery and appropriate antibiotic selection reduce length of hospital stay of patients with community-acquired pneumonia: link between quality of care and resource utilization. Archives of Internal Medicine 162, 6828.
55 . Lehtomaki, K. (1988). Clinical diagnosis of pneumococcal, adenoviral, mycoplasmal and viral pneumonia in young men. European Respiratory Journal 1, 3249.[Abstract]
56 . Jay, S. J., Johnson, W. G., Jr & Pierce, W. K. (1991). The radiographic resolution of Streptococcus pneumoniae pneumonia. New England Journal of Medicine 293, 798801.
57
.
uli
, O., Erakovi
, V.,
epelak, I. et al. (2002). Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. European Journal of Pharmacology 450, 27789.[CrossRef][ISI][Medline]
58
.
Kolling, U. K., Hansen, F., Braun, J. et al. (2001). Leucocyte response and anti-inflammatory cytokines in community acquired pneumonia. Thorax 56, 1215.
59
.
Koch, C. C., Esteban, D. J., Chin, A. C. et al. (2000). Apoptosis, oxidative metabolism and interleukin-8 production in human neutrophils exposed to azithromycin: effects of Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 46, 1926.
60 . Inamura, K., Ohta, N., Fukase, S. et al. (2000). The effects of erythromycin on human peripheral neutrophil apoptosis. Rhinology 38, 1249.[ISI][Medline]
61 . Ives, T. J., Schwab, U. E., Ward, E. S. et al. (2001). Disposition and functions of clarithromycin in human THP-1 monocytes during stimulated and unstimulated conditions. Research Communications in Molecular Pathology & Pharmacology 110, 183208.
62
.
Chow, L. W. C., Yuen, K-Y., Woo, P. C. Y. et al. (2000). Clarithromycin attenuates mastectomy-induced acute inflammatory response. Clinical and Diagnostic Laboratory Immunology 7, 92531.