Nebulized antibiotics in cystic fibrosis

Nebulization is a useful administration route in cystic fibrosis (CF) as it delivers antibiotics directly to the endobronchial site of infection and is associated with decreased toxicity because of limited systemic absorption. It is assumed that the concentration of antibiotics in bronchial secretions should be as high as 10 times the minimum inhibiting concentration to allow penetration of antibiotics into biofilms, suppress inhibitory factors and promote bactericidal effectiveness. However, effective aerosol delivery is compromised by nebulizers with limited capacity to produce particles of a size in the respirable range. Three antibiotics are commonly used for inhalation: tobramycin, amikacin and colistin (colomycin). Placebo-controlled studies evaluating antibiotic aerosol maintenance in stable patients chronically infected with Pseudomonas aeruginosa indicate a significant improvement of lung function and a reduction of the number of hospital admissions for an acute exacerbation of CF. TOBI is a recently marketed preservative- and sulfate-free formula of tobramycin, specially designed for diffusion in the bronchioles and optimal tolerance. A wide-scope study involving 520 patients compared TOBI (300 mg twice daily; n = 258) with placebo (n = 262) for three 28-day cycles with each cycle separated by a 28-day period of no treatment. Respiratory function was significantly improved as early as in the second week and remained so for the rest of the trial even during periods without aerosol treatment. There was also a parallel decrease in the relative risk of hospitalization, the number of days of hospitalization and the number of days on intravenous antipyocyanic treatment. Toxicity studies carried out so far have shown no renal or ototoxicity with nebulized tobramycin. Introduction or selection of resistant bacteria is relatively rare but remains a matter of concern. Aerosol maintenance treatment with an appropriate antibiotic in a high enough dosage can be recommended for patients with CF who are chronically infected with P. aeruginosa.     

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.     

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.     

Antimicrobial use and Pseudomonas aeruginosa susceptibility profile in a cystic fibrosis centre

The susceptibility patterns of 1315 mucoid and non-mucoid Pseudomonas aeruginosa strains from 224 patients were determined along with antibiotic utilisation in a Cystic Fibrosis Centre from 1993 to 1997. Ceftazidime was the most active agent (86.0% sensitive isolates), followed by piperacillin-tazobactam (81.7%), aztreonam (80.3%), imipenem (80%), piperacillin (76.8%), tobramycin (76.5%), ciprofloxacin (73.7%), ticarcillin (72.4%), ticarcillin-clavulanic acid (70.2%), amikacin (69.5%), netilmicin (56.5%), meropenem (79%) and imipenem (75.5%). The most frequently used compounds were nebulized colistin (mean+/-S.D., 109+/-45 defined daily doses per 1000 patients per day), followed by ciprofloxacin (98+/-8), tobramycin (55+/-9), ceftazidime (31+/-8) and amikacin (55+/-9). The mean antibiotic consumption by our CF patients was 413+/-47 defined daily doses per 1000 patients per day. Trend testing showed a significant decline of susceptibility to aminoglycosides, imipenem and ciprofloxacin, while the susceptibility of P. aeruginosa to piperacillin and ceftazidime was stable.     

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.     

Successful Use of Ceftolozane‐Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug‐Resistant Pseudomonas aeruginosa

Ceftolozane‐tazobactam, a novel β‐lactam/β‐lactamase inhibitor, was recently approved for the treatment of complicated urinary tract and intraabdominal infections, as monotherapy and in combination with metronidazole, respectively. Ceftolozane‐tazobactam exhibits a wide spectrum of activity against both gram‐positive bacteria, gram‐negative bacteria including multidrug‐resistant (MDR) Pseudomonas aeruginosa, and some anaerobic bacteria. Although not currently approved for any pulmonary indication, studies have demonstrated excellent distribution to epithelial lining fluid, indicating that it may be an alternative agent to use in the treatment of respiratory tract infections caused by MDRP. aeruginosa. Unfortunately, data are lacking regarding the use of ceftolozane‐tazobactam in the treatment of respiratory tract infections including patients with cystic fibrosis (CF). We describe the first case report, to our knowledge, of a 25‐year‐old white man successfully treated with ceftolozane‐tazobactam for a pulmonary exacerbation of his CF caused by MDRP. aeruginosa. He was admitted for his fourth hospitalization in 7 months for a pulmonary exacerbation of his CF. After blood and sputum were cultured, prednisone, cefepime, inhaled tobramycin, and intravenous ciprofloxacin were started. On day 4, after no signs of clinical improvement, respiratory cultures revealed nonmucoid MDRP. aeruginosa, susceptible only to colistin. β‐Lactam therapy was subsequently changed to ceftolozane‐tazobactam 3 g intravenously every 8 hours while continuing ciprofloxacin and inhaled tobramycin. Ceftolozane‐tazobactam susceptibility was determined by the Etest method (minimum inhibitory concentration 1.5 μg/ml). By day 3 of therapy, the patient showed signs of clinical improvement and was discharged after completion of a 12‐day course of antibiotics. Until additional research is available, we hope this evidence will provide consideration of ceftolozane‐tazobactam for this novel off‐label indication.     

Effect of antibiotic co-administration on young and mature biofilms of cystic fibrosis clinical isolates: the importance of the biofilm model

The prognosis of patients with cystic fibrosis (CF) has improved dramatically over the last three decades although the majority of patients still die in early adulthood. Infection with Pseudomonas aeruginosa has generally been associated with declining lung function and increased mortality in patients. This study aimed to investigate the in vitro activity of tobramycin/clarithromycin combination on biofilms of clinical isolates of P. aeruginosa, meticillin-susceptible and -resistant Staphylococcus aureus, and Burkholderia cepacia. First, the impact of antibiotic co-administration on biofilms at different stages of maturation, i.e. during early formation and on 24-h-old and 12-day-old biofilms, was compared. The 24-h-old biofilms were found to behave differently compared with those aged 12 days, which were more resistant to antibiotics. A kinetic study of antibiotic co-administration twice a day for 9 days on 12-day-old P. aeruginosa biofilms was then performed to simulate the effect of treatment of CF patients by inhaled tobramycin through aerosolisation (TOBI). The results obtained support a synergistic activity of tobramycin/clarithromycin combination on biofilms of P. aeruginosa PY02 and PA01, with a logarithmic bacterial decrease of 3.37 and 3.96, respectively. On the other hand, increased resistance to each of the antibacterial agents used alone was observed. This study highlights the importance of the biofilm stage for in vitro investigations and enabled the development of an in vitro model of mature biofilm that is more appropriate to mimic in vivo conditions in CF patients.     

The Delivery of High-Dose Dry Powder Antibiotics by a Low-Cost Generic Inhaler

The routine of loading multiple capsules for delivery of high-dose antibiotics is time consuming, which may reduce patient adherence to inhaled treatment. To overcome this limitation, an investigation was carried out using four modified versions of the Aerolizer® that accommodate a size 0 capsule for delivery of high payload formulations. In some prototypes, four piercing pins of 0.6 mm each were replaced with a single centrally located 1.2-mm pin and one-third reduced air inlet of the original design. The performance of these inhalers was evaluated using spray-dried antibiotic powders with distinct morphologies: spherical particles with a highly corrugated surface (colistin and tobramycin) and needle-like particles (rifapentine). The inhalers were tested at capsule loadings of 50 mg (colistin), 30 mg (rifapentine) and 100 mg (tobramycin) using a multistage liquid impinger (MSLI) operating at 60 L/min. The device with a single pin and reduced air inlet showed a superior performance than the other prototypes in dispersing colistin and rifapentine powders, with a fine particle fraction (FPF wt% <5 μm in the aerosol) between 62 and 68%. Subsequently, an Aerolizer® with the same configuration (single pin and one-third air inlet) that accommodates a size 00 capsule was designed to increase the payload of colistin and rifapentine. The performance of the device at various inspiratory flow rates and air volumes achievable by most cystic fibrosis (CF) patients was examined at the maximum capsule loading of 100 mg. The device showed optimal performance at 45 L/min with an air volume of 1.5–2.0 L for colistin and 60 L/min with an air volume of 2.0 L for rifapentine. In conclusion, the modified size 00 Aerolizer® inhaler as a low-cost generic device demonstrated promising results for delivery of various high-dose formulations for treatment of lung infections.     

Inhaled antibiotics for the treatment of chronic bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis: systematic review of randomised controlled trials

Introduction: Inhaled antibiotics are probably the safest and most effective therapy for Pseudomonas aeruginosa chronic lung infection in cystic fibrosis (CF) patients.

Areas covered: To summarise the available evidence, a systematic review of the three currently available inhaled antibiotics (aztreonam lysine (AZLI), colistin (COL) and tobramycin (TOB)) was performed. The three AZLI placebo-controlled studies showed that the improvements in FEV₁ and mean sputum P. aeruginosa density were statistically significant better than with placebo. The two COL placebo-controlled studies involved few patients but showed that COL was better than placebo in terms of maintenance of some pulmonary function parameters. The tobramycin inhalation solution (TIS) and tobramycin inhalation powder studies showed that the efficacy of both formulations was similar but significantly better than placebo. In the comparative studies, TIS showed more efficacy than COL solution, colistin inhalation powder showed non-inferiority to TIS and AZLI was superior to TIS.

Expert opinion: Placebo-controlled and comparative clinical trials have shown that clinical evidence of inhaled antibiotics is very different. The choice of treatment for each individual CF patient must be based on the features of the drug (clinical evidence on efficacy and safety), the inhalation system and the patient characteristics. Development of new inhaled antibiotics will allow new end points of efficacy and therapy regimens to be assessed.     

Aerosolization of low phase transition temperature liposomal tobramycin as a dry powder in an animal model of chronic pulmonary infection caused by Pseudomonas aeruginosa

Eradication of mucoid Pseudomonas aeruginosa in an animal model of chronic pulmonary infection has been previously demonstrated following the intratracheal administration of Fluidosomes, a low phase transition temperature (low T(C)) liposomal tobramycin preparation administered in liquid form (Beaulac et al., Antimicrob. Agents Chemother., 40, 665-669, 1996). In the present work, the same liposomal formulation was administered as a dry powder aerosol to an animal model of chronic pulmonary infection in view of a possible clinical development in cystic fibrosis patients. Chronic infection was established by intratracheal administration of 10(5) cfu of a mucoid variant of P. aeruginosa, PA 508, prepared in agar beads. Sixteen hours after one aerosol treatment, the cfu counts performed on lungs (pair) treated with liposomal tobramycin were of 4.31x10(5) cfu/lungs comparatively to 1.32x10(8) and 3.02x10(8) cfu/lungs respectively in untreated and in lungs treated with free antibiotic. Considering the quantity of liposome-tobramycin that has reached the lungs, the results suggest that aerosolization of low T(C) liposomal tobramycin used as a dry powder preparation could be an effective way of treating chronic pulmonary infection caused by Pseudomonas.     

Dry powder inhalation of antibiotics in cystic fibrosis therapy, part 1: development of a powder formulation with colistin sulfate for a special test inhaler with an air classifier as de-agglomeration principle.

The aim of this study was to investigate the pulmonary administration of antibiotics as dry powder to patients with cystic fibrosis (CF), as an alternative for nebulization. This part of the study describes the development of a powder formulation with colistin sulfate as model substance. The aim of the new dosage form was to increase pulmonary deposition, therapeutic efficiency and, by that, compliance by the CF patients. A physical powder mixture of colistin and a size fraction of lactose (106-150 microm) was prepared and the mixture was optimized with respect to colistin content (83.3%) for use in a special test inhaler. A laser diffraction apparatus with special inhaler adapter was applied for analysis of the size distribution of the aerosol cloud from the inhaler. The size distributions of the aerosol clouds from the test inhaler at flow rates between 30 and 60 l/min for the optimized formulation showed nearly the same median diameter as that for the primary drug particles. But the X(100)-value was much lower, because of an effective large particle separation from the inspiratory air by an air classifier in the test inhaler. The results suggest that dry powder inhalation might be a suitable and highly efficient alternative for nebulization of antibiotic drugs in CF therapy.     

Systemic colistin use in children without cystic fibrosis: a systematic review of the literature

The increasing incidence of multidrug-resistant (MDR) Gram-negative infections necessitates the use of neglected antibiotics such as colistin, even in the paediatric field. The objective of this review was to evaluate the available clinical evidence regarding the effectiveness and safety of systemic colistin in children without cystic fibrosis (CF). Relevant articles were identified from PubMed, Cochrane and Scopus databases. Ten case series and fifteen case reports, including a total of 370 children, were eligible for inclusion in this systematic review. Only 17 of the children were included in studies published after 1977. A total of 326 children received colistin for the treatment of infections and 44 for surgical prophylaxis or prophylaxis of infections in burns patients. Regarding the clinical outcome, 271 of 311 children included in the identified cases series were evaluable. From these 271 children, 235 (86.7%) were cured of the infection, 10/271 (3.7%) improved, 6/271 (2.2%) deteriorated and 20/271 (7.4%) died. Fourteen (70%) of the 20 deaths were attributed to the infection. No infection occurred in the 44 reported children with burns or surgical morbidity who received colistin for prophylaxis. Of these 44 children, 9 (20.5%) died; all deaths were attributed to co-morbidity. Nephrotoxicity occurred in 10/355 (2.8%) of the evaluable children in cases series included in this review. Most of the identified relevant case reports focused on treatment complications. The available evidence, mainly from old case series, suggests that systemic colistin is an effective and acceptably safe option for the treatment of children without CF who have MDR Gram-negative infections.     

Dry powder inhalation of colistin sulphomethate in healthy volunteers: A pilot study

BACKGROUND: Pulmonary administration of the antimicrobial drugs colistin sulphomethate and tobramycin has been shown to be effective in slowing down pulmonary deterioration in cystic fibrosis (CF) patients. Both drugs are administered by liquid nebulisation, a technique known to have disadvantages. Dry powder inhalation may be an attractive alternative. We investigated inhalation of colistin sulphomethate dry powder using a newly developed Twincer device in healthy volunteers. METHODS: Eight healthy volunteers inhaled a single dose of 25mg colistin sulphomethate dry powder each, using the Twincer inhaler. The median diameter (X(50)) of the dry powder was 1.6 microm (X(10)=0.7 microm, X(90)=3.1 microm), measured by laser diffraction technique. Pulmonary function tests were performed before, 5 and 30 min after inhalation. Serum samples were drawn at t=15 min, 45 min, 1.5h, 2.5h, 3.5h, 5.5h, 7.5h and 24h after inhalation. RESULTS: The colistin sulphomethate dry powder inhaler was well tolerated: no clinically relevant effect on FEV(1) was observed nor did the volunteers experience adverse effects. CONCLUSION: Dry powder inhalation of colistin sulphomethate using the Twincer inhaler is well tolerated by healthy volunteers. A pilot study in cystic fibrosis patients is therefore considered safe in developing a dry powder inhalation of colistin for everyday CF treatment.     

Aerosolization of Low Phase Transition Temperature Liposomal Tobramycin as a Dry Powder in an Animal Model of Chronic Pulmonary Infection Caused by Pseudomonas aeruginosa

Abstract

Eradication of mucoid Pseudomonas aeruginosa in an animal model of chronic pulmonary infection has been previously demonstrated following the intratracheal administration of Fluidosomes, a low phase transition temperature (low T_c) liposomal tobramycin preparation administered in liquid form (Beaulac et al., Antimicrob. Agents Chemother., 40, 665–669, 1996). In the present work, the same liposomal formulation was administered as a dry powder aerosol to an animal model of chronic pulmonary infection in view of a possible clinical development in cystic fibrosis patients. Chronic infection was established by intratracheal administration of 10⁵ cfu of a mucoid variant of P. aeruginosa, PA 508, prepared in agar beads. Sixteen hours after one aerosol treatment, the cfu counts performed on lungs (pair) treated with liposomal tobramycin were of 4.31 × 10⁵ cfu/lungs comparatively to 1.32 × 10⁸ and 3.02 × 10⁸ cfu/lungs respectively in untreated and in lungs treated with free antibiotic. Considering the quantity of liposome-tobramycin that has reached the lungs, the results suggest that aerosolization of low T_c liposomal tobramycin used as a dry powder preparation could be an effective way of treating chronic pulmonary infection caused by Pseudomonas.     

常见革兰氏阴性菌耐药性动态变化特征及分析

目的 分析本地区2003年1月～2006年6月期间最常见革兰氏阴性茵(大肠埃希茵、肺炎克雷伯菌、铜绿假单胞菌和鲍曼不动杆菌)耐药性的变化,为指导临床合理使用抗菌素提供可靠依据.方法 应用回顾性调查分析方法对我院该期间临床标本分离的大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌和鲍曼不动杆菌的药敏试验进行对比统计分析.结果 近4年来,该4种细菌对常用抗菌药物的耐药率总体呈上升趋势.大肠埃希茵对头孢呋辛、头孢他啶、头孢噻肟、头孢吡肟耐药率变化显著,对大肠埃希茵保持较强抗茵活性而耐药率＜30%的抗菌药物有阿莫西林-克拉维酸、哌拉西林-三唑巴坦、亚胺培南、美诺培南、阿米卡星;肺炎克雷伯茵对哌拉西林、替卡西林-克拉维酸、头孢他啶、头孢噻肟、头孢呋辛、环丙沙星耐药率变化显著,对肺炎克雷伯菌保持较强抗菌活性而耐药率＜30%的抗菌药物有阿莫西林-克拉维酸、哌拉西林-三唑巴坦、亚胺培南、美诺培南、阿米卡星、奈替米星、妥布霉素;铜绿假单胞菌对妥布霉素、阿米卡星、庆大霉素、环丙沙星耐药率变化显著,对铜绿假单胞菌保持较强抗菌活性而耐药率＜30%的抗菌药物有替卡西林-克拉维酸、哌拉西林-三唑巴坦、头孢他啶、亚胺培南、美诺培南、阿米卡星、庆大霉素、妥布霉素、环丙沙星、多粘菌素E;对鲍曼不动杆菌保持较强抗茵活性而耐药率＜30%的抗茵药物有哌拉西林-三唑巴坦、头孢他啶、亚胺培南、美诺培南、阿米卡星.结论 本地区大肠埃希菌、肺炎克雷伯茵、铜绿假单胞菌和鲍曼不动杆菌对常用抗菌药物耐药率高,多重耐药现象严重,根据药敏结果选择抗菌药物,可有效控制和减缓细茵耐药性的增长.     

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.     

In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy

Pseudomonas aeruginosa causes severe nosocomial pneumonia in Intensive Care Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals (110 non-duplicate initial isolates; 62 clonal pairs of initial and last isolates during treatment). Minimum inhibitory concentrations (MICs) were determined for amikacin, ciprofloxacin, meropenem, piperacillin/tazobactam (TZP), cefepime and ceftazidime (used in therapy) as well as five reporter antibiotics (aztreonam, colistin, gentamicin, piperacillin and ticarcillin) using Clinical and Laboratory Standards Institute (CLSI) methodology. Susceptibility was assessed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI breakpoints. Resistance rates prior to treatment exceeded 25% for cefepime, ceftazidime, piperacillin, ticarcillin and aztreonam (EUCAST and CLSI) and for gentamicin, TZP and colistin (EUCAST only). The highest rates of cross-resistance were noted for ceftazidime and cefepime and the lowest rate for amikacin. Mean MIC values were systematically higher in isolates from patients previously exposed (1 month) to the corresponding antibiotic. For clonal pairs, a systematic increase in MIC between initial and last isolates (significant for amikacin, cefepime, meropenem and TZP) was noted. There was a significant correlation between the use of antibiotics (adjusted for respective proportional use of each drug) and loss of susceptibility at the population level when using EUCAST breakpoints. The high level of resistance of P. aeruginosa in ICU patients with nosocomial pneumonia as well as its further increase during treatment severely narrows the already limited therapeutic options. Further observational studies and the development of early diagnosis for resistant isolates are warranted.     

Evaluation of long-term co-administration of tobramycin and clarithromycin in a mature biofilm model of cystic fibrosis clinical isolates of Pseudomonas aeruginosa

Pseudomonas aeruginosa colonisation and chronic lung infection associated with biofilm formation is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. There is thus an urgent need to develop alternative ways to treat biofilm-associated clinical infections. A kinetic study of twice-daily co-administration of the antibiotics tobramycin and clarithromycin was performed over 28 days on 12-day-old mature P. aeruginosa biofilms formed on microplate pegs for 23 clinical isolates of various phenotypes and genotypes to simulate the treatment of CF patients with inhaled tobramycin through aerosolisation (TOBI^®). Drug activity was assessed by enumeration of persistent bacteria before, during and after treatment. A mature (12-day-old) biofilm model was chosen because a previous study suggested that such a biofilm was a more realistic in vitro model than a 24-h-old biofilm. Synergistic activity of the drug combination was confirmed on biofilms of 9/23 P. aeruginosa isolates. Of these nine isolates, total destruction of the biofilm was observed for five of them. Combination treatment was superior or equivalent to treatment with tobramycin alone, as activity was observed on 47.8% of the isolates with the combination versus 26.1% with tobramycin alone. No correlation was observed between drug susceptibility profiles and the phenotype or genotype of the isolates.     

Pseudomonas aeruginosa biofilms are more susceptible to ciprofloxacin than to tobramycin

The objective of this study was to determine and compare the biofilm elimination concentrations (BEC: the concentration which reduced the viability of biofilm organisms by at least 99.9%) of ciprofloxacin and tobramycin for Pseudomonas aeruginosa, a common cause of nosocomial biomaterial-related infections. Bacterial biofilms were produced in the modified. Robbins device using continuous culture flow at 60 ml/h for 40–44 h, and the sessile organisms were then exposed to either ciprofloxacin or tobramycin at a range of concentrations for 12 or 36h. The BEC of ciprofloxacin was 5 μg/ml for the 12 and 36 h treatments, a value 10 × greater than the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). In contrast, the BEC of tobramycin was > 100 μ/ml after 12h and 75 ug/ml following 36 h of drug exposure, that is 75–100 × the MIC and MBC. The results demonstrated that the BEC is a more suitable indicator of the antibiotic susceptibility of P. aeruginosa biofilms than the MIC and MBC. Ciprofloxacin was significantly more effective than tobramycin in the treatment of P. aeruginosa adherent to biomaterials. With respect to clinical application, if the intention of antibiotic use is to eradicate bacteria adherent to devices, only biofilm-active agents should be used.