Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine

Importance of the field: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients.

Areas covered in this review: This review describes the development (2003 – 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston^®), an aerosolized formulation of the monobactam antibiotic aztreonam.

What the reader will gain: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV₁), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine ‘on/off’ courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 – 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System?, which provides appropriate particle size and small airway deposition, and has excellent portability.

Take home message: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV₁ in patients with CF.     

Aerosolized antibiotics: the past,present and future,with a special emphasis on inhaled colistin

Inhaled antibiotics, such as TOBI (a tobramycin solution), gentamicin, colistin and aztreonam lysine (Cayston) have been effectively administered with safety and efficacy in patients with cystic fibrosis and bronchiectasis. In addition, inhaled antibiotics have been administered with safety and efficacy for the prevention and treatment of patients with ventilator-associated tracheobronchitis or pneumonia due to multidrug-resistant Gram-negative bacteria (mainly Pseudomonas aeruginosa or Acinetobacter baumannii). Original studies showed that inhaled colistin resulted in treatment success of nosocomial pneumonia or ventilator-associated pneumonia (VAP) due to multidrug-resistant Gram-negative bacteria. However, although aerosolized colistin seems to be safe and effective for the eradication of P. aeruginosa and the management of pneumonia in cystic fibrosis patients, hospital-acquired pneumonia and VAP due to multidrug-resistant Gram-negative bacteria, it is still unclear if it provides additional benefit in all-cause hospital mortality, or VAP-related mortality rates. For this reason, randomized controlled trials (RCTs) are necessary to validate the efficacy and safety of aerosolized colistin, mainly in patients with nosocomial pneumonia or VAP. In addition, RCTs are necessary to determine the appropriate inhaled colistin dose and the optimal delivery device.     

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.     

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV₁%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden.

Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications.

Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.     

Early antibiotic treatment of pseudomonas aeruginosa colonisation in cystic fibrosis: a critical review of the literature

Aim To assess the evidence supporting early antibiotic treatment in asymptomatic cystic fibrosis (CF) patients colonised by Pseudomonas aeruginosa (PA).Methods We carried out a computerised (Medline, Embase) and hand search of journals for suitable publications. All English-language clinical studies regarding the efficacy of early antibiotic treatment on PA colonisation in asymptomatic patients were considered. Each eligible publications fitting these criteria were assessed for the following outcome measures: frequency of positive PA cultures; serum level of precipitating antibodies; lung function; survival; number of hospitalisations; adverse effects and resistance to antibiotics.Results Of the 11 studies eventually considered, 3 were randomised—2 versus placebo— and 8 were cohort studies—2 of which had historical controls. Overall, 309 patients (population range 7–91 patients) were recruited. There was a high variability between the individual studies for age, outcome measures, duration of follow-up (1 to 44 months) and treatment (three studies used only aerosol tobramycin, one colistin, four aerosol colistin plus oral ciprofloxacin, one used intravenous treatment and two miscellaneous therapy). An overall evaluation indicated that early antibiotic treatment can reduce the number of positive cultures and the anti-PA antibody titre. In one study, FEV1 was better in the treated group (oral ciprofloxacin and nebulised colistin) than in historical controls, while in one placebo-controlled trial, no effect on lung function was shown after 1 year of tobramycin inhalation. Collateral effects and bacterial resistance were not increased. The short follow-up did not allow definite conclusions with regard to the long-term progression of respiratory insufficiency or survival.Conclusions Evidence was found that antibiotic treatment can reduce the rate of positive cultures and of anti-PA antibody titres in asymptomatic CF patients with newly isolated PA. Different therapeutic options have not been directly compared: a multi-centre comparative study needs to be carried out.     

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.     

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.     

Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study

Objective: Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year.

Research design and methods: This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV₁ ≥25%–≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV₁% predicted, and change in sputum Pa density (log₁₀ colony forming units/g sputum).

Results: A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (<4?minutes) and decreased over the course of the study, possibly due to patients becoming more experienced with the administration of TIP. The post-inhalation events resolved without intervention in most cases. FEV₁% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = ?1.9% [14.55]; P?=?0.199).

Conclusions: This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.     

Tobramycin for the treatment of bacterial pneumonia in children

INTRODUCTION: Common etiological agents for community-acquired lower respiratory tract infection (LRTI) include Streptococcus pneumoniae, Hemophilus influenzae and Mycoplasma pneumoniae and can be easily managed with oral or intravenous antibiotics. However, LRTI in patients with underlying illnesses, such as cystic fibrosis (CF) and immune deficiency, or on ventilator support is difficult to manage because these are caused by Gram-negative bacilli. Tobramycin has been shown to be effective in the management of these patients. AREAS COVERED: Information about the antimicrobial activity, pharmacological aspects (including pharmacokinetics and pharmacodynamics), clinical efficacy, safety and side effects of tobramycin have been covered in this review. EXPERT OPINION: A major advance for the use of tobramycin has occurred with its use by the inhalational route, in children with CF. The inhalation route provides the advantage of ease of administration for prolonged periods at home and allows use of very high doses. Systematic reviews suggest that tobramycin inhalation improves outcome, decreases the need for hospitalization and decreases the need for use of frequent systemic antibiotics in CF patients colonized with pseudomonas. Data on the efficacy of inhaled tobramycin in non-CF bronchiectasis are scarce, as are data on the prevention and treatment of ventilator-associated pneumonia, and on the role of combining inhaled tobramycin with systemic tobramycin. Despite limitations, this drug has the potential to be used in various conditions other than CF.     

Réévaluation de la colistine

Colistin (polymyxin E) designates two different drugs, colistin sulfate, an oral digestive decontaminant, and colismethate sodium (CMS) intended for intravenous, intrathecal/intraventricular, or inhaled therapy. Colistin interferes with bacterial membranes creating cytoplasmic leaks lethal to bacteria through interactions with membrane proteins and phospholipids (including LPS). This mechanism of action confers bactericidal activity to colistin on frequently multiresistant pathogens such as Acinetobacter spp., P. aeruginosa, and Klebsiella spp. It also leads to specific resistance mechanisms, which arise from modifications in bacterial membrane proteins. New methods applied to pharmacokinetic studies of colistin take into account the in-solution and plasmatic hydrolysis of CMS, the inactive prodrug, into active compounds among which colistin. These studies show that current therapeutic regimens may be optimized. Colistin being a concentration dependent bactericidal antibiotic, the area under the curve (AUC)/MIC was proven the best PK/PD parameter associated with in vivo efficacy, opening new perspectives in alternate dosing regimens. Nephrotoxicity occurs at a rate comparable to aminoglycosides and neurotoxicity is more often benign; both being reversible upon discontinuation of therapy. In multiresistant Gram negative, mostly A. baumanii or P. aeruginosa, nosocomial infections as well as in chronic P. aeruginosa infections and exacerbations in cystic fibrosis patients, the efficacy of colistin has been demonstrated within the limitations inherent to studies of an antibiotic which can only be used after determination of susceptibility in severe infections nonetheless requiring urgent adequate therapy. Further clarifications are required concerning the added benefit of combination with antibiotics considered as synergistic such as rifampicin and carbapenems.     

Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial

Abstract

Background:

Tobramycin inhalation powder (TIP) was reported to be effective in two Phase III studies in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa (Pa). The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6–21 years.     

Aspects of pulmonary drug delivery strategies for infections in cystic fibrosis – where do we stand?

Introduction: Cystic fibrosis (CF) is the most common life-shortening hereditary disease among Caucasians and is associated with severe pulmonary damage because of decreased mucociliary clearance and subsequent chronic bacterial infections. Approximately 90% of CF patients die from lung destruction, promoted by pathogens such as Pseudomonas aeruginosa. Consequently, antibiotic treatment is a cornerstone of CF therapy, preventing chronic infection and reducing bacterial load, exacerbation rates and loss of pulmonary function. Many drugs are administered by inhalation to achieve high pulmonary concentration and to lower systemic side effects. However, pulmonary deposition of inhaled drugs is substantially limited by bronchial obstruction with viscous mucus and restrained by intrapulmonary bacterial biofilms.

Areas covered: This review describes challenges in the therapy of CF-associated infections by inhaled antibiotics and summarizes the current state of microtechnology and nanotechnology-based pulmonary antibiotic delivery strategies. Recent and ongoing clinical trials as well as experimental approaches for microparticle/nanoparticle-based antibiotics are presented and their advantages and disadvantages are discussed.

Expert opinion: Rapidly increasing antimicrobial resistance accompanied by the lack of novel antibiotics force targeted and more efficient use of the available drugs. Encapsulation of antimicrobials in nanoparticles or microparticles of organic polymers may have great potential for use in CF therapy.     

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.     

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.     

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.     

High-dose tobramycin inhibits lipopolysaccharide-induced MUC5AC production in human lung epithelial cells

Tobramycin inhalation therapy is an effective therapy for cystic fibrosis as well as severe bronchiectasis that is colonized with Pseudomonas aeruginosa. The mechanism responsible for the efficacy of tobramycin in the treatment of severe chronic infectious diseases has not been elucidated. We demonstrate that high-dose tobramycin decreases MUC5AC gene expression and protein production in NCI-H292 cell stimulated with lipopolysaccharide of P. aeruginosa. MUC5AC protein of NCI-H292 cell stimulated by lipopolysaccharide was analyzed by an enzyme-linked immunosorbent assay and MUC5AC expression at the mRNA level was analyzed by RT-PCR. Western blot was performed to examine a potential role for the signaling molecules upstream of NFκB. High-dose tobramycin (500 μg/ml) decreased the level of MUC5AC protein released into the supernatant of the NCI-H292 cell line at 24 h after lipopolysaccharide stimulation (P < 0.001). The tobramycin treatment also inhibited MUC5AC mRNA expression at 12 h after lipopolysaccharide stimulation (P < 0.05) and suppressed NFκB activation 60 min after lipopolysaccharide stimulation (P < 0.001). Tobramycin suppressed the phosphorylation of extracellular signal-regulated protein kinase, p38 MAP kinase. These results suggest that high-dose tobramycin, such as inhalation therapy, can inhibit MUC5AC gene expression and MUC5AC protein production in NCI-H292 cells, in part through the mitogen-activated protein kinase pathway. Thus, the activation of TLR4 and the subsequent immune/inflammatory responses induced by chronic infections such as P. aeruginosa might be modulated by tobramycin. Our data may reveal one of the mechanisms responsible for the clinical effect of tobramycin inhalation therapy against severe chronic respiratory diseases due to P. aeruginosa.     

Inhaled or nebulised ciprofloxacin for the maintenance treatment of bronchiectasis

Introduction: Inhaled or nebulised antibiotics are a major topic of ongoing research interest in reducing exacerbations in bronchiectasis. There are no licenced inhaled or nebulised antibiotics currently in bronchiectasis.

Areas covered: Inhaled or nebulised ciprofloxacin as a long-term treatment in bronchiectasis.

Expert opinion: Results from the Phase III ongoing trials on inhaled or nebulised ciprofloxacin will be key for the outcome of the drugs but additionally, cost-effectiveness and longer-term studies will be necessary to determine the viability of the drug. Head to head studies are needed to decide on the optimum inhaled or nebulised antibiotic and their place with or without long term macrolide therapy. It is also important to determine what treatment is viable for acute exacerbations due to P. aeruginosa. Ciprofloxacin is the only currently available oral agent for exacerbations due to P. aeruginosa. The concern is that using inhaled or nebulised ciprofloxacin will prevent the use and efficacy of its oral equivalent, by developing resistance.     

Inhaled colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria: A real-life experience in tertiary care hospitals in Saudi Arabia

BackgroundNosocomial pneumonia (NP) due to multidrug-resistant (MDR) Gram-negative pathogens, has continued to rise over the last several decades. Parenteral administration of colistin results in poor alveolar penetration and subtherapeutic concentration; therefore, direct drug deposition at site of infection may improve the effectiveness while minimizing the systemic exposure. The aim of this study is to describe the safety and effectiveness of inhaled colistin for the treatment of NP caused by MDR Gram-negative pathogens.MethodPatients who received inhaled colistin from May 2015 to May 2019 at 2 different tertiary care hospitals in Riyadh, Saudi Arabia were identified from pharmacy databases and their charts were retrospectively reviewed.Results86 patients were enrolled in this study. The mean age was 56 ± 20 years. The mean Acute Physiology and Chronic Health Evaluation (APACHE II) was 17 ± 5. The responsible pathogens for NP were Pseudomonas aeruginosa (60%) Acinetobacter baumannii (28%), and Klebsiella pneumoniae (9%). Most patients (76/86) received concomitant intravenous antibiotics. Mean colistin total daily dose was 6 ± 3 million international units divided into 2–3 doses. Mean inhaled colistin duration of therapy was 11 ± 6 days. Favorable clinical outcome was achieved in 51 (59%) patients while favorable microbiological outcome occurred in 29 (34%) patients. Death due to all causes was noted in 39 (45%) cases. Renal injury occurred in 19 (22%) patients, all received concomitant intravenous colistin.ConclusionInhaled colistin can be considered as salvage therapy as adjunct to intravenous administration for treatment of patients with NP due to MDR Gram-negative pathogens.     

呼吸系统疾病治疗用雾化吸入抗菌药物的研究进展

传统的抗菌药物给药方式(口服或静脉注射)由于药物的理化性质和宿主解剖学特点,感染部位往往达不到有效的抗菌浓度,导致了治疗的失败。雾化吸入疗法因药物直接作用于靶器官,具有起效迅速、疗效佳、全身不良反应少、不需要患者刻意配合等优势,成为治疗呼吸系统相关疾病较为理想的给药方法。目前抗菌药物吸入制剂只有妥布霉素、氨曲南和多黏菌素,正在研制的有环丙沙星、左氧氟沙星、阿米卡星、两性霉素B、万古霉素等。国外在20世纪40年代开始对吸入抗菌药物进行研究,相对国外的研究,国内的相关报道还较少,因此,为给呼吸系统疾病的防治带来临床新路径,对近年来国内外雾化吸入抗菌药物的药效/药动学研究进展进行综述。     

Estimating in vivo airway surface liquid concentration in trials of inhaled antibiotics.

Antibiotic drugs exhibit concentration dependence in their efficacy. Therefore, ensuring appropriate concentration of these drugs in the relevant body fluid is important for obtaining the desired therapeutic and physiological action. Until recently there had been no suitable method available to measure or estimate concentration of drugs in the human airways resulting from inhaled aerosols or to determine the amount of inhaled antibiotics required to ensure minimum inhibitory concentration of a drug in the airway surface liquid (ASL). In this paper a numerical method is used for estimating local concentration of inhaled pharmaceutical aerosols in different generations of the human tracheobronchial airways. The method utilizes a mathematical lung deposition model to estimate amounts of aerosols depositing in different lung generations, and a recent ASL model along with deposition results to assess the concentration of deposited drugs immediately following inhalation. Examples of concentration estimates for two case studies: one for the antibiotic tobramycin against Pseudomonas aeruginosa, and another for taurolidine against Burkholderia cepacia are presented. The aerosol characteristics, breathing pattern and properties of nebulized solutions were adopted from two recent clinical studies on efficacy of these drugs in cystic fibrosis (CF) patients and from other sources in the literature. While the clinically effective tobramycin showed a concentration higher than the required in vivo concentration, that for the ineffective taurolidine was found to be below the speculated required in vivo concentration. Results of this study thus show that the mathematical ASL model combined with the lung deposition model can be an effective tool for helping decide the optimum dosage of inhaled antibiotic drugs delivered during human clinical trials.