Tobramycin solution for inhalation in cystic fibrosis patients: a review of the literature

Cystic fibrosis patients suffer increased sputum production and a notable decline in respiratory function throughout the progression of their disease. Patients are left vulnerable to respiratory colonization/infection from a number of pathogens, including Pseudomonas aeruginosa. At present, the only antibiotic formulation that is FDA approved for aerosolized delivery is tobramycin solution for inhalation (TSI). TSI allows for targeted antibiotic delivery to the lungs and is indicated for maintenance therapy in cystic fibrosis patients infected with P. aeruginosa. Studies demonstrate that cyclical treatment with TSI is associated with an increase in respiratory function and a decrease in sputum density in cystic fibrosis patients. Additional benefits include fewer hospitalizations and a decreased need for systemic antibiotics. However, because of the need for chronic administration, issues such as emergence of resistant organisms and toxicity are a potential concern and have also been evaluated. This review details the pharmacology of TSI and literature involving its use in cystic fibrosis patients.     

Macrolides as immunomodulatory medications for the therapy of chronic lung diseases

Macrolide antibiotics have potent immunomodulatory activity. The spectrum of action of these antibiotics extends to regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation, and modulation of host defense mechanisms. Macrolides are now being used or investigated to treat chronic lung inflammatory diseases, including diffuse panbronchiolitis (DPB), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Intense research is ongoing to further elucidate the targets and mechanism/s of action of macrolides in eukaryotic cells. In this paper, we review recent findings on novel effects of macrolides on epithelial barrier function and resolution of inflammation, which may shed light on the mechanisms underlying the beneficial effects of macrolides in the clinic.     

Inhaled colistin for lower respiratory tract infections

INTRODUCTION: Lower respiratory tract infections, due to Pseudomonas aeruginosa or Acinetobacter baumannii, are frequently encountered in patients with cystic fibrosis (CF) or in patients developing nosocomial pneumonias. Both of these conditions bear a high mortality risk and aggressive antibiotic therapy is necessary. Inhaled antibiotics might represent an effective therapeutic approach for these diseases as it has demonstrated good bactericidal efficacy and safety in both preclinical and clinical studies. This colistin formulation might be useful particularly in patients with respiratory tract infections due to multidrug-resistant Gram-negative bacteria. Its main advantages are a better safety profile with a minimal or absent risk of nephrotoxicity. AREAS COVERED: This paper discusses the available systemic formulations of colistin, with pharmacokinetic and safety profiles, followed by an overview of inhaled antibiotics in lower respiratory tract infections. EXPERT OPINION: Inhaled colistin should be used selectively as monotherapy in chronic infections with P. aeruginosa in CF patients, whereas in patients with hospital/ventilator-acquired pneumonia (HAP/VAP), it should be used in a combined regimen with systemic antibiotics.     

Prospects for the prevention and control of pseudomonal infection in children with cystic fibrosis

Most patients with cystic fibrosis (CF) experience recurrent and chronic endobronchial Pseudomonas aeruginosa infections. It is possible to prevent or delay the onset of these chronic infections in most patients with CF by eliminating cross-infection and by early aggressive antibiotic treatment of the first positive sputum culture and of subsequent intermittent colonisation. Lung tissue damage is caused by activation of the immunologically specific inflammatory defence mechanisms of the lungs, which are initiated by the antibody response and dominated by polymorphonuclear neutrophil leucocytes and their proteolytic and oxidative products. This inflammation induces a phenotypic shift from nonmucoid to mucoid, alginate-producing phenotypes of P. aeruginosa which then grow, endobronchially, as a biofilm. Such biofilms are impossible to eradicate with antibiotics. By using chronic suppressive antibiotic maintenance therapy and anti-inflammatory drugs it is however, possible to maintain the lung function of these patients for a number of years.     

The treatment of respiratory pseudomonas infection in cystic fibrosis: what drug and which way?

Pseudomonas aeruginosa is a non-capsulate and non-sporing gram-negative bacillus that most commonly affects the lower respiratory system in humans. Burkholderia (previously Pseudomonas) cepacia has emerged as an important respiratory pathogen in patients with cystic fibrosis (CF). The ability of P. aeruginosa to persist and multiply in moist environments and equipment, such as humidifiers in hospital wards, bathrooms, sinks and kitchens, maybe of importance in cross-infection. P. aeruginosa infections of the lower respiratory tract can range in severity from colonisation (without an immunological response) to a severe necrotising bronchopneumonia. Infection is seen in patients with CF and other chronic lung diseases such as non-CF bronchiectasis. In patients with CF, once P. aeruginosa is established in the airways it is almost impossible to eradicate, but prior to this, aggressive treatment can delay the development of chronic infection. 30 to 40% of the present paediatric population with CF will have chronic pseudomonal infection. B. cepacia has a particular predisposition to infect patients with CF and may be distinguished from P. aeruginosa by accelerated lung disease in about one- third of patients. Overwhelming septicaemia and necrotising pneumonia are well described (cepacia syndrome); events that are rare with P. aeruginosa. With the propensity for social cross-infection, segregation policies have been accepted as means of controlling outbreaks. A number of antipseudomonal agents are available. The most commonly used are the extended-spectrum penicillins, aminoglycosides, cephalosporins, fluoroquinolones, polymixins and the monobactams. An aminoglycoside with a beta-lactam penicillin is usually considered to be the first line treatment. No trial has shown any significant clinical advantage of any particular combination regimen over another. The emergence of resistance continues to be a concern. Pipericillin, piperacillin/tazobactam and meropenem have good but equivalent antibacterial activity against P. aeruginosa. However, B. cepacia is characterised by in vitro resistance to colistin (colomycin), aminoglycosides and ciprofloxacin but better susceptibility to ceftazidime. Nebulised delivery of antipseudomonal antibiotics is thought to prevent recurrent exacerbations, reduce antibiotic usage and maintain lung function, particularly in patients with CF. Colistin, tobramycin and gentamicin are currently the most commonly prescribed nebulised antibiotics. Much effort is directed at treating chronic P. aeruginosa infection but as chronic infection is seldom if ever eradicated when first established, prevention is preferable. Early intensive treatment for P. aeruginosa infection is advocated in order to maintain pulmonary function and postpone the onset of chronic P. aeruginosa infection.     

Anti-inflammatory capabilities of macrolides

Macrolide antibiotics play a significant role in clinical practise due not only to their antibacterial activity, but also to their accompanying anti-inflammatory effect that is independent of their antibiotic action. Several studies reported in literature show that macrolides affect several inflammatory processes, such as migration of neutrophils, the oxidative burst in phagocytes and production of pro-inflammatory cytokines, although the precise mechanisms are not clear. They also inhibit eosinophilic inflammation and may be useful in the treatment of patients with steroid-dependent asthma. Macrolides are also effective in diffuse panbronchiolitis, chronic sinusitis and inflammatory skin diseases.     

Aerosolized antibiotics for non-cystic fibrosis bronchiectasis

There are strong data supporting using the use of aerosolized antibiotics for the treatment of Gram-negative infections in patients with cystic fibrosis (CF). The regular use of aerosol tobramycin or colistin can decrease exacerbations of lung disease, decrease bacteria counts, and improve pulmonary function in persons with CF and Pseudomonas aeruginosa airway infection. Bronchiectasis is caused by reoccurring or continuous presence of bacteria in association with airway obstruction. Although CF is the most common cause of childhood bronchiectasis, there are many other causes. Because secretions in the bronchiectasis airway are similar to the pus found in the CF airway, and because pulmonary complications and progression of disease in non-CF bronchiectasis is similar to CF bronchiectasis, many centers treat patients with bronchiectasis using aerosolized tobramycin solution for inhalation (TSI). There have been only a few small studies of aerosolized antibiotics to treat pseudomonas infection in subjects with non-CF bronchiectasis. Unlike the CF experience, there does not seem to be an improvement of pulmonary function after treatment with aerosol tobramycin in this population despite a decreased sputum bacterial density and a trend toward a decrease in risk of hospitalization. Furthermore, the risk of adverse events such as bronchospasm may be more common in adults with non-CF bronchiectasis than reported in the CF population.     

Inhaled gentamicin in non-cystic fibrosis bronchiectasis: effects of long-term therapy

Bronchiectasis is a disease state defined by irreducible dilations of the airways. If they occur in diseases other than cystic fibrosis they are termed non-CF bronchiectasis. The common denominator is the increased risk of recurrent infections with bacteria, such as Staphylococcus aureus or Pseudomonas aeruginosa. Such infections are difficult to eradicate with systemic antibiotics because the structural abnormalities in the bronchial wall reduce their bactericidal effect at this level. An alternative to systemic antibiotics might be represented by inhaled formulations, which can be given in much lower doses and can be more effective. Previous studies demonstrated that inhaled gentamicin can reduce bacterial load and local infection in both cystic fibrosis and non-CF bronchiectasis. The study discussed in this paper demonstrates that long-term therapy with inhaled gentamicin can eradicate the infection or reduce the bacterial load, decrease the risk of subsequent infections and improve the quality of life in patients with non-CF bronchiectasis with a minimal risk of side effects.     

Tobramycin for nebulisation: new formulation. A high price for a small improvement in formulation

(1) In patients with cystic fibrosis, chronic bronchial infection with Pseudomonas aeruginosa is a major factor in the development of chronic respiratory failure and premature death. (2) Over the last two decades, such patients have commonly received long-term treatment with antibiotic aerosols (mainly tobramycin or colistin, in off-licence uses). (3) Tobramycin solution for nebulisation is the first antibiotic preparation to be licensed in the EU for this indication. (4) Comparative evaluation of antibiotic aerosol therapy for chronic bronchial infections due to P. aeruginosa includes two large trials of nebulised tobramycin. (5) A combined analysis of these two placebo-controlled trials, both lasting 20 weeks, showed that tobramycin aerosol delayed the deterioration of respiratory function and reduced the number of hospitalisations. However, an increase in P. aeruginosa resistance to tobramycin was reported. (6) The file on tobramycin includes no precise criteria for stopping treatment, and no data on the long-term impact of the observed increase in bacterial resistance. (7) The main adverse effects of tobramycin aerosol are tinnitus and voice changes. Deafness has also been reported. (8) The available assessment file does not show whether the risk-benefit ratio of tobramycin aerosol differs from that of other nebulised antibiotics used (off-licence) in this setting. However, tobramycin is the best-assessed nebulised antibiotic for this indication. (9) In practice, tobramycin solution for nebulisation may be considered the reference long-term treatment for chronic pulmonary infections due to P. aeruginosa in patients with cystic fibrosis. Assessment should continue, however, especially regarding the possible impact on mortality and the selection of resistant strains.     

Tobramycin solution for inhalation in cystic fibrosis patients: a review of the literature

Cystic fibrosis patients suffer increased sputum production and a notable decline in respiratory function throughout the progression of their disease. Patients are left vulnerable to respiratory colonization/infection from a number of pathogens, including Pseudomonas aeruginosa. At present, the only antibiotic formulation that is FDA approved for aerosolized delivery is tobramycin solution for inhalation (TSI). TSI allows for targeted antibiotic delivery to the lungs and is indicated for maintenance therapy in cystic fibrosis patients infected with P. aeruginosa. Studies demonstrate that cyclical treatment with TSI is associated with an increase in respiratory function and a decrease in sputum density in cystic fibrosis patients. Additional benefits include fewer hospitalizations and a decreased need for systemic antibiotics. However, because of the need for chronic administration, issues such as emergence of resistant organisms and toxicity are a potential concern and have also been evaluated. This review details the pharmacology of TSI and literature involving its use in cystic fibrosis patients.     

N'-substituted-2'-O,3'-N-carbonimidoyl bridged macrolides: novel anti-inflammatory macrolides without antimicrobial activity

Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.     

Antibiotics as immunomodulant agents in COPD

It is widely accepted that some antibiotics have activities beyond their direct antibacterial effects. Macrolide is the antibiotic class with more convincing studies and evidence on its immunomodulatory and anti-inflammatory activities. Different clinical studies have shown that macrolide prophylaxis in patients with moderate-severe chronic obstructive pulmonary disease (COPD) can have a significant impact on the exacerbation rate reducing morbidity and, potentially, mortality of the disease. Other antibiotics, such as fluoroquinolones, demonstrate a variety of immunomodulatory effects but only few clinical data are available in COPD. New macrolide derivatives devoid of antibacterial activity have been synthetized. This review analyses the relevance of immunomodulatory and anti-inflammatory effects of antibiotics in the management of COPD.     

Mucoid and pigmentation characters can be suppressed by non-anti-Pseudomonas aeruginosa antibiotics in cystic fibrosis: a report of promising preliminary results

In an effort to develop new strategies, the authors are exploring the hypothesis that non-anti-Pseudomonas aeruginosa antibiotics can affect some major virulence factors in cystic fibrosis P. aeruginosa. Recent samples (127) of P. aeruginosa isolated from the sputum of cystic fibrosis patients and manifesting a mucoid growth were stored at -70 degrees C until experimentation. The mucoid character was retested after thawing and one 24-h in-vitro passage at 37 degrees C onto 100-mm blood agar plates to prepare a bacterial suspension for inoculation (Steers or MIC-2000 plus replicator) and cultivation (48 h, 37 degrees C) onto different 100-mm or 150-mm Mueller-Hinton agar plates containing either no antibiotics or antibiotics alone, and antibiotic combinations without presumed anti-P. aeruginosa activity. Some isolates (49, 38.6%) of P. aeruginosa expressed again the mucoid character on antibiotic-free Mueller-Hinton agar and growth was prevented by antibiotics in a number of them: 7 with doxycycline (16.0 micrograms/ml), 2 with rifampicin (16.0 micrograms/ml), 6 with roxithromycin-sulfamethoxazole (16.0-304.0 micrograms/ml) and 23 with trimethoprim-sulfamethoxazole. In the remaining evaluable isolates, the mucoid was modified towards the rough character in 36 out of 42 with doxycyline, 36 out of 47 with rifampicin, 31 out of 43 with roxithromycin-sulfamethoxazole and 20 out of 26 with trimethoprim-sulfamethoxazole. In parallel, the pigmentation was lost in the presence of antibiotics in those P. aeruginosa isolates having manifested this character on Mueller-Hinton agar. These results suggest that non-anti-P. aeruginosa antibiotics can modify the in vitro markers of virulence in cystic fibrosis P. aeruginosa and that they merit further investigation.     

Effects of five antibiotics on adhesion and haemagglutinating properties of Pseudomonas aeruginosa isolated from cystic fibrosis patients

The aim of this study was to evaluate the in vitro effect of five antibiotics at sub-inhibitory concentrations on the adhesive and haemagglutinating properties of Pseudomonas aeruginosa isolated from cystic fibrosis sputa. Eleven isolates (mucoid and non-mucoid) from cystic fibrosis, and four isolates (mucoid and non-mucoid) from other chronic respiratory infections were tested. The adhesion test was performed on human lymphoblastoid cell-lines; the haemagglutination test used human O+ and guinea-pig erythrocytes. The antibiotics were tested at six sub-inhibitory concentrations, from MIC/2 to MIC/64. Among the five antibiotics, cefsulodin and pefloxacin were the most active in decreasing the adhesive properties: this effect was statistically significant at MIC/2 and MIC/4 for cefsulodin and at all sub-inhibitory concentrations for pefloxacin. No differences appeared between mucoid and non-mucoid strains, and no correlation was noted with their clinical origins. The three other antibiotics (ceftazidime, latamoxef and imipenem) had no significant effect on the adhesion of all the strains tested, but their effect was rather strain-dependent. This fact and the heterogeneity found in adherence and haemagglutinating activity of each strain suggest that the adhesins and the haemagglutinins of P. aeruginosa are very complex structures.     

Macrolide antibiotics in food-animal health

Several 14- and 16-membered-ring macrolide antibiotics have acquired important roles in the modern production of food animals. Macrolide antibiotics exhibit many similar antimicrobial properties whether used in veterinary or human medicine. In addition to their direct inhibitory action on micro-organisms, macrolides exert a variety of subinhibitory concentration (sub-MIC) effects that are being increasingly recognised as important factors in the explanation of therapeutic results. Macrolides achieve wide tissue distribution and high intracellular concentrations that contribute prominently to their efficacy. Another important factor governing efficacy is the complex interaction between macrolides, micro-organisms, and phagocytes that may enable the host defence system to enhance the antibiotic's inhibitory action. A potential role for macrolides in modulating inflammatory processes has also been recognised. In both sub-MIC effects and interactions with the host immune system, different macrolides exert different responses that may reinforce or oppose each other. This complexity of responses requires additional studies in appropriate disease states and animal species in order to elucidate a more comprehensive understanding and explanation of in vivo outcomes.     

Changes in strategies for optimal antibacterial therapy in cystic fibrosis

Aggressive antibiotic therapy of bacterial airway infection is one of the main reasons for the dramatic increase in life expectancy over the last few decades. Staphylococcus aureus and Haemophilus influenzae are the predominant pathogens in younger patients, but the choice of antibiotic therapy against these pathogens remains highly controversial. There is general agreement that patients with pulmonary exacerbations should be treated and many cystic fibrosis (CF) centres will also try to eradicate bacteria in the absence of symptoms. Prophylactic antibiotic therapy, with anti-staphylococcal medications started at the time of diagnosis, is advocated by some groups but its positive effect remains unproven. In fact, recent studies have suggested that continuous prophylactic treatment with anti-staphylococcal antibiotics may increase the risk of early colonisation with Pseudomonas aeruginosa. P. aeruginosa is the main pathogen in older children with CF. While chronic airway infection with mucoid P. aeruginosa is considered irreversible, both the combination of oral ciprofloxacin with inhaled colistin and inhaled tobramycin alone has been used successfully in the early phase of colonisation. In patients chronically infected with P. aeruginosa, standard treatment of pulmonary exacerbations consists of intravenous combination therapy for 2-3 weeks. Controversy exists whether this treatment should be performed routinely every 3 months or only in the presence of a pulmonary exacerbation. Inhaled antibiotics such as tobramycin have been shown to improve lung function and reduce sputum density of P. aeruginosa, but both the optimal dose and the duration of therapy are unclear at the present time.     

New developments in inhaled antibiotics for the treatment of Pseudomonas aeruginosa

The field of inhaled antibiotics that target Pseudomonas aeruginosa infections has made substantial contributions to the health, disease management, and life expectancies of individuals with cystic fibrosis (CF) over the last three decades. This paper reviews some of the recent clinical developments in the field of inhaled antibiotics for CF and briefly describes formulations and ongoing developments for US and/or European regulatory approvals. Lung delivery technologies, in regards to inhaled antibiotics for CF, are also reviewed.     

Antibacterial activity of liposomal gentamicin against Pseudomonas aeruginosa: a time-kill study

Cystic fibrosis (CF) is a common and lethal genetic disorder with a carrier frequency of 1 in 29 Caucasians. Chronic respiratory infections with Pseudomonas aeruginosa are the leading cause of morbidity and mortality in individuals with CF. Aminoglycoside antibiotics, including gentamicin, are highly effective against P. aeruginosa, but severe toxicity limits their use. One potential strategy for avoiding this problem is to encapsulate aminoglycosides in liposomes. In this study, we compared the bactericidal capacity of liposome-encapsulated gentamicin with that of free antibiotic against clinical isolates of P. aeruginosa. Liposome size, encapsulation efficiency and minimal inhibitory concentrations (MICs) of the free and liposomal gentamicin against gentamicin-sensitive and -resistant strains of P. aeruginosa were determined. In vitro time-kill studies were performed using free and liposomal gentamicin at 1, 2 or 4 times the MICs. The average liposomal size was 426.25 +/- 13.56 nm, with a gentamicin encapsulation efficiency of 4.51 +/- 0.54%. The MICs for liposomal gentamicin were significantly lower than those of corresponding free gentamicin. In addition, the time-kill values for liposomal gentamicin were either equivalent to or better than those of the free antibiotic. In conclusion, our liposomal gentamicin formulation is a more potent antipseudomonal drug with an improved killing time and prolonged antimicrobial activity.     

Macrolide antibiotics in food-animal health

Several 14- and 16-membered-ring macrolide antibiotics have acquired important roles in the modern production of food animals. Macrolide antibiotics exhibit many similar antimicrobial properties whether used in veterinary or human medicine. In addition to their direct inhibitory action on micro-organisms, macrolides exert a variety of subinhibitory concentration (sub-MIC) effects that are being increasingly recognised as important factors in the explanation of therapeutic results. Macrolides achieve wide tissue distribution and high intracellular concentrations that contribute prominently to their efficacy. Another important factor governing efficacy is the complex interaction between macrolides, micro-organisms, and phagocytes that may enable the host defence system to enhance the antibiotic’s inhibitory action. A potential role for macrolides in modulating inflammatory processes has also been recognised. In both sub-MIC effects and interactions with the host immune system, different macrolides exert different responses that may reinforce or oppose each other. This complexity of responses requires additional studies in appropriate disease states and animal species in order to elucidate a more comprehensive understanding and explanation of in vivo outcomes.     

Nebulized tobramycin in patients with chronic respiratory infections during clinical evolution of Wegener's granulomatosis

Aminoglycosides are effective against Pseudomonas aeruginosa but with intravenous administration there are only very low concentrations achieved in sputum; therefore in order to obtain therapeutic levels in patients with endobronchial infections should be administered high doses with increased likelihood to produce both nephrotoxic and ototoxic effects. Direct aerosol delivery of aminoglycosides to the lower respiratory tract has the advantage to achieve high antibiotic sputum concentrations in the infected area with reduced risk of systemic toxic reactions because of minimal absorption into the circulation. Nowadays, except for patients suffering from cystic fibrosis and bronchiectasis, the administration of antibiotics through inhalers is not very much in use. The aim of this study was to administer nebulized tobramycin in chronic respiratory infections developed during the evolution of Wegener's Granulomatosis in order to obtain data concerning the safety and efficacy of inhaled aminoglycosides. The results obtained underlined an improvement in FEV1, FEF75 and PaO2. The aerosolized tobramycin administered in 300 mg doses three times per day for four weeks, showed itself to be effective and safe, not causing any undesirable clinical or microbiological side-effects. Moreover, a long term treatment has been shown to control the Pseudomonas aeruginosa infection on the bronchial system in Wegener's granulomatosis and reduce the frequency of exacerbations in chronic patients.