colistin and Lung-Diseases

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

Topics: Administration, Inhalation; Anti-Bacterial Agents; Aztreonam; Chronic Disease; Colistin; Cystic Fibrosis; Humans; Lung Diseases; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Pseudomonas aeruginosa colonisation has a negative effect on pulmonary function in cystic fibrosis patients. The organism can only be eradicated in the early stage of colonisation, while reduction of bacterial density is desirable during chronic colonisation or exacerbations. Monthly, or at least 3-monthly, microbiological culture is advisable for patients without previous evidence of P. aeruginosa colonisation. Cultures should be performed at least every 2-3 months in patients with well-established colonisation, and always during exacerbations or hospitalisations. Treatment of patients following the first isolation of P. aeruginosa, but with no clinical signs of colonisation, should be with oral ciprofloxacin (15-20 mg/kg twice-daily for 3-4 weeks) plus inhaled tobramycin or colistin (intravenous treatment with or without inhaled treatment can be used as an alternative), while patients with acute infection should be treated for 14-21 days with high doses of two intravenous antimicrobial agents, with or without an inhaled treatment during or at the end of the intravenous treatment. Maintenance treatment after development of chronic P. aeruginosa infection/colonisation (pathogenic colonisation) in stable patients (aged>6 years) should be with inhaled tobramycin (300 mg twice-daily) in 28-day cycles (on-off) or, as an alternative, colistin (1-3 million units twice-daily). Colistin is also a possible choice for patients aged<6 years. Treatment can be completed with oral ciprofloxacin (3-4 weeks every 3-4 months) for patients with mild pulmonary symptoms, or intravenously (every 3-4 months) for those with severe symptoms or isolates with ciprofloxacin resistance. Moderate and serious exacerbations can be treated with intravenous ceftazidime (50-70 mg/kg three-times-daily) or cefepime (50 mg/kg three-times-daily) plus tobramycin (5-10 mg/kg every 24 h) or amikacin (20-30 mg/kg every 24 h) for 2-3 weeks. Oral ciprofloxacin is recommended for patients with mild pulmonary disease. If multiresistant P. aeruginosa is isolated, antimicrobial agents that retain activity are recommended and epidemiological control measures should be established.

Topics: Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Bronchopneumonia; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Humans; Inhalation; Injections, Intravenous; Lung Diseases; Pneumonia, Bacterial; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Topics: Animals; Antibodies, Bacterial; Antineoplastic Agents; Arthritis, Infectious; Bone Diseases; Burns; Carbenicillin; Carrier State; Colistin; Cross Infection; Cystic Fibrosis; Disease Models, Animal; Drug Therapy, Combination; Gentamicins; Humans; Immunologic Deficiency Syndromes; Leukemia; Lung Diseases; Pneumonia; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Therapy; Skin Diseases, Infectious; Surgical Wound Infection; Transplantation, Homologous

The clinical course of cystic fibrosis (CF) is characterised by chronic bronchial infection with Pseudomonas aeruginosa. Therapy with inhaled aminoglycosides was introduced to decrease the rate of infectious exacerbations and to delay pulmonary progression. However, development of resistance to aminoglycosides is frequent. Few investigations are available into the resistance profile under treatment with colistin. Antibiotic resistance to colistin was analysed in 44 adult CF patients treated with inhaled colistin. Resistance to aminoglycosides was observed in 86% of cases (38/44) before therapy and decreased to 43% (19/44) under treatment with colistin. Five patients (11%) developed polymyxin resistance. After cessation of therapy pseudomonas became sensitive to polymyxin within a few months and enabled colistin to be reintroduced. In addition, we performed a pilot study analysing the effect of inhaled colistin on the growth of pseudomonas. The number of Pseudomonas aeruginosa decreased from 16.7 million (CFU) bacteria per ml sputum to 2.9 million under therapy with colistin. There was a more than tenfold increase in bacterial counts after inhaled colistin was stopped. Genotyping revealed no change in the type of pseudomonas strains.. Development of resistance to polymyxin is not rare under long-term treatment with inhaled colistin and requires temporary interruption of therapy. Sputum cultures should therefore be tested regularly for polymyxin resistance in patients treated with inhaled colistin.

Topics: Administration, Inhalation; Adult; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Drug Resistance, Microbial; Female; Humans; Lung Diseases; Male; Pilot Projects; Polymyxins; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum

Chronic pulmonary infection with Pseudomonas aeruginosa (PA) develops in most patients with cystic fibrosis (CF) and is associated with a poor prognosis. Much effort has been directed toward treating the chronic infection, but it is almost impossible to eradicate it once established; therefore, prevention is preferable. Since 1989 CF patients at the Danish CF Center in Copenhagen have been treated with an intensive three-step-protocol consisting of colistin inhalations and oral ciprofloxacin at the time of initial PA colonization. This study compares 48 patients treated according to this intensive protocol with 43 historic controls. The study was carried out over 44 months and included 218 patient-years. Only 16% of the treated patients developed chronic PA infection after 3 1/2 years compared with 72% of the control patients (Kaplan Meier estimate, P < 0.005, log rank test). This indicates that aggressive treatment prevented or delayed chronic PA infection in 78% of the patients for 3 1/2 years. Furthermore, aggressive treatment maintained or increased pulmonary function (forced vital capacity and forced expiratory volume in 1 second in percent of predicted values) during the year after inclusion compared with the control group, in which pulmonary function declined (P < 0.01, Mann-Whitney test). Although some of the treated patients eventually developed chronic PA infection, these patients had significantly better pulmonary function at the onset of chronic PA infection compared with control patients (P < 0.001, Mann-Whitney test). When the different steps in the intensive three-step-protocol were analyzed, there was a trend suggesting that 3 months of high-dose treatment with colistin inhalation and oral ciprofloxacin produced the best results in terms of postponement or prevention of chronic PA infection (P < 0.05).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Carrier State; Child; Child, Preschool; Chronic Disease; Ciprofloxacin; Colistin; Cystic Fibrosis; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Infant; Lung Diseases; Male; Proportional Hazards Models; Pseudomonas aeruginosa; Pseudomonas Infections; Statistics, Nonparametric; Vital Capacity

The objective of this study was to quantify the deposition in the lung of a Colistine aerosol generated using a pneumatic nebuliser (Pari LL(R) equipped with a Pari Master, Pari, Germany) and to compare this with the results obtained with an ultrasonic nebuliser (DP100, DP Medical, France) in four subjects suffering from cystic fibrosis being colonised with Pseudomonas aeruginosa. To quantify the pulmonary deposition of the aerosols we have used an indirect isotopic method which consists in assimilating the kinetics of the molecules studied with a serum albumin tagged with Technetium 99m (Tc99mm) and added to a preparation of Colistine. We have previously verified that the addition of a radioactive tracer does not change the normal distribution or dynamics of the medication within the aerosol and the radioactive counter linked to the tracer reflects the mass of the medicament. The pulmonary deposition was expressed as a percentage of the nebuliser dose. A regional analysis of the deposition (central, peripheral, superior and inferior) was carried out and in central deposition compared to the periphery (C/P) and superior compared to inferior (S/I) were calculated. With the DP100 nebuliser the pulmonary deposition of the aerosol was very reproducible from one patient to another, varying only between 9.5 to 14 percent of the nebuliser dose. With the Pari LL the fraction deposited varied more from one patient to another from 5.6 to 27% of the nebuliser dose. In three of four patients, the pulmonary deposition was superior or equal to that obtained with the ultrasonic nebuliser. The patients whose pulmonary deposition was inferior, using the pneumatic nebuliser, was the youngest in the group and co-ordinately poorly the triggering of the nebuliser with the beginning of inspiration. With the two nebulisers, the pulmonary deposition of Colisitine was very heterogeneous throughout the pulmonary parenchyma. The mean of the ratio C/P and S/I obtained in all four patients was identical (1.35 an 0.86 respectively), indicating a deposition of the aerosol which was predominantly central and inferior but was distributed equally in the peripheral parts of the lung. Pneumatic nebulisers offer a reliable alternative notably for domiciliary treatment for Colistine aerosols in patients suffering from cystic fibrosis. In younger patients who have not yet acquired good motor co-ordination, nebulisers which function continuously or are triggered by inspiration seem to be the pr

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Anti-Bacterial Agents; Child; Colistin; Cystic Fibrosis; Equipment Design; Female; Humans; Lung Diseases; Male; Nebulizers and Vaporizers; Pseudomonas Infections; Tissue Distribution

Forty patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection entered a prospective double-blind placebo-controlled study of colistin inhalation. Active treatment consisted of inhalation of colistin one million units twice daily for three months and was compared to placebo inhalations of isotonic saline. Significantly more patients in the colistin inhalation group completed the study as compared to the placebo group (18 versus 11). Colistin treatment was superior to placebo treatment in terms of a significantly better clinical symptom score, maintenance of pulmonary function and inflammatory parameters. We recommend colistin inhalation therapy for cystic fibrosis patients with chronic P. aeruginosa lung infection as a supplementary treatment to frequent courses of intravenous anti-pseudomonas chemotherapy.

Topics: Administration, Inhalation; Adolescent; Adult; Child; Chronic Disease; Clinical Trials as Topic; Colistin; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Lung Diseases; Male; Pseudomonas Infections; Vital Capacity

Acinetobacter baumannii has emerged as a major cause of nosocomial infections. Various resistance mechanisms of A. baumannii against antibiotics have transformed it into a successful nosocomial pathogen. Because of the limited number of available antibiotics, we used a medicinal plant with an antibacterial effect. Zataria multiflora Boiss (ZMB) extract and its components were used for the treatment of pneumonic mice infected with A. baumannii. The biological effects of this extract and the regulation of the outer membrane protein A (ompA) gene were used in a mouse model.. In the lung tissue culture of pneumonic mice infected with standard or clinical isolate, no colony was detected when treated with the ZMB extract after 2 and 3 days (P < 0.01), respectively. In the carvacrol-treated group, bacterial clearance was seen at day 4 and day 5 (P < 0.05). Bacterial clearance was seen 5 days after treatment with thymol and imipenem and 6 days after ampicillin/sulbactam treatment. The regulation of ompA gene was significantly decreased in this order: ZMB extract, carvacrol, thymol, imipenem, and ampicillin/sulbactam.. The ZMB extract had a potent bactericidal effect against A. baumannii that could downregulate the ompA gene. ZBM extract and carvacrol could be novel therapeutic agents for antibiotic-resistant A. baumannii.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Colistin; Cymenes; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Humans; Imipenem; Lamiaceae; Lung; Lung Diseases; Mice, Inbred BALB C; Microbial Sensitivity Tests; Plant Extracts; Thymol

No animal model studies have been conducted in which the efficacy of herbal compounds has been tested against multidrug-resistant Acinetobacter baumannii infections. Very few antibiotics are available for the treatment of pulmonary infections caused by extensively drug-resistant Acinetobacter baumannii (XDRAB). To find alternative treatments, traditional Chinese herbs were screened for their antimicrobial potential.. The present study screened 30 herbs that are traditionally used in Taiwan and that are commonly prescribed for heat clearing and detoxification. The herbs with antibacterial activities were analysed by disc diffusion assays, time-kill assays and a murine lung infection model.. Of the 30 herbs tested, only Scutellaria barbata demonstrated 100% in vitro activity against XDRAB. Furthermore, we compared the antibacterial effect of the S. barbata extract with that of colistin, and the S. barbata extract showed better antibacterial effect. In the XDRAB pneumonia murine model, we compared the antimicrobial effects of the orally administered S. barbata extract (200 mg/kg, every 24 h), the intratracheally administered colistin (75,000 U/kg, every 12 h), and the control group. The bacterial load in the lungs of the treatment group that received the oral S. barbata extract showed a significant decrease in comparison to that in the lungs of the control group. In addition, histopathological examinations also revealed better resolution of perivascular, peribronchial, and alveolar inflammation in the oral S. barbata extract-treated group.. Our in vitro and in vivo data from the animal model support the use of S. barbata as an alternate drug to treat XDRAB pulmonary infections. However, detailed animal studies and clinical trials are necessary to establish the clinical utility of S. barbata in treating XDRAB pulmonary infections.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Load; Colistin; Drug Resistance, Bacterial; Female; Humans; Lung Diseases; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Plant Extracts; Scutellaria; Taiwan

In this work different nebulisers were investigated in order to assess their efficiency in combination with colistimethate sodium (CMS) inhalation products. Four nebulisers, namely I-neb(®), Aeroneb(®) Go, eFlow(®)rapid and PARI LC(®) Sprint were studied in terms of delivered dose (DD), drug delivery rate (DDR) and respirable dose (RD) of CMS. The goal was to provide scientific data to physicians for prescribing the most appropriate nebuliser for the CMS specific user. All the apparatuses nebulised ColiFin 1MIU/3 ml solution (80 mg of CMS) with delivered doses between 31% and 41% of the loaded amount. Aeroneb Go showed the longest nebulisation time (more than 20 min). When ColiFin 2 MIU/4 ml was nebulised with eFlow rapid or PARI LC Sprint, the CMS respirable dose was 45.3mg and 39.2mg, in times of 5.6 and 10.8 min, respectively. I-neb, having a medication cup capacity limited to 0.4 ml, loaded with Promixin 0.4 MIU/0.4 ml (32 mg of CMS), provided in a time of 9 min a RD of 21.5mg, a value slightly higher than those obtained by nebulising ColiFin 1 MIU/3 ml with the other nebulisers (range 15.9-17.6 mg). The results illustrate that the clinical outcome depends on the comparative analysis of nebulisation efficiency (respirable dose) and convenience (time), not disregarding the ratios between the amount loaded, delivered and deposited at lung level.

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Cystic Fibrosis; Humans; Lung Diseases; Nebulizers and Vaporizers; Solutions

Patients suffering from cystic fibrosis (CF) are commonly affected by chronic Pseudomonas aeruginosa biofilm infections. This is the main cause for the high disease severity. In this study, we demonstrate that P. aeruginosa is able to efficiently colonize murine solid tumors after intravenous injection and to form biofilms in this tissue. Biofilm formation was evident by electron microscopy. Such structures could not be observed with transposon mutants, which were defective in biofilm formation. Comparative transcriptional profiling of P. aeruginosa indicated physiological similarity of the bacteria in the murine tumor model and the CF lung. The efficacy of currently available antibiotics for treatment of P. aeruginosa-infected CF lungs, such as ciprofloxacin, colistin, and tobramycin, could be tested in the tumor model. We found that clinically recommended doses of these antibiotics were unable to eliminate wild-type P. aeruginosa PA14 while being effective against biofilm-defective mutants. However, colistin-tobramycin combination therapy significantly reduced the number of P. aeruginosa PA14 cells in tumors at lower concentrations. Hence, we present a versatile experimental system that is providing a platform to test approved and newly developed antibiofilm compounds.

Topics: Animals; Anti-Infective Agents; Biofilms; Cell Line, Tumor; Colistin; Cystic Fibrosis; Disease Models, Animal; Female; Lung Diseases; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Colistin; Disease Models, Animal; Female; Humans; Lung; Lung Diseases; Mice; Microbial Sensitivity Tests; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Thigh

The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is respiratory disease (Penketh et al., Thorax 1987; 42: 526-532). Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa (Ramsey et al., N Engl J Med 1999; 340: 23-30; Ramsey et al., Proceedings of the 12th Annual North American Cystic Fibrosis Conference, 1998, Montreal, Canada; Ramsey et al., Abstract from 23rd European Cystic Fibrosis Conference, 1999, the Hague, Netherlands). In Europe, the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread. A recently published study compared the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients . One hundred and fifteen patients were randomised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV(1) and sputum P. aeruginosa density. TNS produced a mean 6.7% improvement in lung function (P=0.006), whilst there was no significant improvement in the colistin-treated patients. The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin (P=0.008). The safety profile of both treatments was good. We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Colistin; Cystic Fibrosis; Europe; Humans; Lung Diseases; Nebulizers and Vaporizers; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiratory Function Tests; Tobramycin; Treatment Outcome

The infection of the airways of cystic fibrosis patients by Pseudomonas aeruginosa is a complex, multistaged process that is associated with a deterioration of lung function. The complexity of the formation of biofilms and their interaction with the immune system means that treatment with antibiotics has been an uncertain science. Tobramycin nebuliser solution (TNS) is a novel formulation of the antibiotic tobramycin developed specifically for inhalation. A recent large trial comparing TNS with inhaled colistin provided an opportunity to define further the effect of antibiotic treatment on microbial infection. In the TNS group, the percentage of patients with a tobramycin minimal inhibitory concentration (MIC) > or = 4 mg l(-1) increased from 38 to 49%, and the percentage of patients with a colistin MIC > or = 4 mg l(-1) remained at 55%. In the colistin group, the percentage of patients with a colistin MIC > or = 4 mg l(-1) remained at 34%, whereas the percentage of patients with a tobramycin MIC > or = 4 mg l(-1) decreased from 27 to 16%. Furthermore, clinical and bacterial response to TNS and colistin was independent of the MIC at baseline. Neither antimicrobial therapy was associated with infection by Burkholderia cepacia or other inherently resistant pathogens. We conclude that conventional measures of antimicrobial resistance may underestimate the effectiveness of tobramycin and colistin when delivered at the high concentrations achieved with the TNS formulation.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Biofilms; Colistin; Cystic Fibrosis; Europe; Humans; Lung Diseases; Microbial Sensitivity Tests; Nebulizers and Vaporizers; Pseudomonas Infections; Randomized Controlled Trials as Topic; Tobramycin

Pseudomonas aeruginosa was isolated from the sputum of 63 patients. In 34 the organism was a commensal, in 14 it was causing chronic suppuration, and in 10 had interfered with antibiotics directed against other organisms and was thus indirectly pathogenic. In five patients, all of whom died, the organism could have been acting as an acute pathogen. Attempts should be made to determine the nature of the organism's pathogenicity in a given patient and appropriate therapy withheld or administered accordingly.

Topics: Bronchitis; Carbenicillin; Colistin; Gentamicins; Humans; Lung Diseases; Postoperative Complications; Precipitin Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Tracheotomy

Topics: Ampicillin; Cloxacillin; Colistin; Cross Infection; Humans; Intensive Care Units; Klebsiella Infections; Lung Diseases; Neurosurgery; Penicillin Resistance; Urinary Tract Infections

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Colistin; Female; Humans; Infections; Lung Diseases; Male; Middle Aged; Sepsis

Topics: Bronchial Diseases; Colistin; Evaluation Studies as Topic; Humans; Lung Diseases; Suppuration

Topics: Anti-Bacterial Agents; Calcinosis; Calcium; Candida; Colistin; Diagnosis, Differential; Female; gamma-Globulins; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lung Diseases; Lung Diseases, Fungal; Phosphorus; Radiography, Thoracic; Trachea; Tuberculosis, Pulmonary

Topics: Adrenal Cortex Hormones; Bacillus; Colistin; Cross Infection; Drug Therapy; gamma-Globulins; Humans; Lung Diseases; Polymyxins; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Resuscitation; Sepsis

Topics: Aerosols; Bronchiectasis; Bronchitis; Colistin; Humans; Lung Diseases; Lung Neoplasms; Pneumococcal Infections; Proteus Infections; Staphylococcal Infections; Streptococcal Infections; Suppuration