netilmicin and Cystic-Fibrosis

High-dose anti-Pseudomonas chemotherapy is mandatory in the treatment of acute pulmonary exacerbations in patients with advanced cystic fibrosis and Pseudomonas aeruginosa isolated from their sputum. However, neither the regimen itself nor its objective evaluation have been optimized yet. In a prospective controlled evaluation 42 such exacerbations were treated for two weeks with netilmicin combined by randomisation with either azlocillin or ticarcillin. Other aspects of therapy were constant. The two therapy groups were comparable in all aspects. Both regimens produced similar improvements in clinical, radiological, laboratory, bacteriological and pulmonary function measurements. Concentrations of sputum bacteria were significantly reduced; transient eradication was documented in 29% and correlated with antibiotic susceptibility of the initially isolated Pseudomonas strains. The highly dosed antibiotics were well tolerated and emergence of resistance was rarely observed. It is concluded that both antibiotic combinations are beneficial and safe in cystic fibrosis. Monitoring of such intensive hospital treatment must include multiple parameters.

Topics: Adolescent; Adult; Azlocillin; Child; Child, Preschool; Clinical Trials as Topic; Cystic Fibrosis; Drug Combinations; Female; Humans; Lung Diseases; Male; Netilmicin; Penicillins; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Ticarcillin

Seventeen cystic fibrosis patients aged 3.1 years to 19.8 years had 30 courses of intensive treatment for relapse of their pseudomonas chest infection. The combination of netilmicin and ticarcillin was compared with tobramycin and ticarcillin in an open study. A significant subjective and objective improvement occurred in all patients. Pseudomonas was cleared temporarily from the sputum in 11 out of the 30 courses of treatment (37%). There was no significant difference between the netilmicin and tobramycin groups, nor evidence of sustained renal or ototoxicity. Intensive therapy of pseudomonas chest infection in cystic fibrosis patients is described in detail.

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Cystic Fibrosis; Drug Combinations; Female; Gentamicins; Humans; Lung Volume Measurements; Male; Netilmicin; Penicillins; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Ticarcillin; Tobramycin

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.

Topics: Adult; Animals; Anti-Bacterial Agents; Cystic Fibrosis; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Endocarditis, Bacterial; Female; Gentamicins; Glomerular Filtration Rate; Guinea Pigs; Humans; Male; Netilmicin; Pneumonia; Pseudomonas Infections; Rabbits; Rats; Rats, Inbred Strains; Tobramycin

This study was aimed to develop poly(dl-lactide-co-glycolide) (PLGA) nanoparticle of highly water soluble antibiotic drug, netilmicin sulfate (NS) with improved entrapment efficiency (EE) and antibacterial activity. Dextran sulfate was introduced as helper polymer to form electrostatic complex with NS. Nanoparticles were prepared by double emulsification method and optimized using 2(5-1) fractional factorial design. EE was mainly influenced by dextran sulfate: NS charge ratio and PLGA concentration, whereas particle size (PS) was affected by all factors examined. The optimized NS-loaded-NPs had EE and PS of 93.23 ± 2.7% and 140.83 ± 2.4 nm respectively. NS-loaded-NPs effectively inhibited bacterial growth compared to free NS. Sustained release protected its inactivation and reduced the decline in its killing activity over time even in presence of bronchial cells. A MIC value of 18 μg/mL was observed for NPs on P. aeruginosa. Therefore, NPs with sustained bactericidal efficiency against P. aeruginosa may provide therapeutic benefit in chronic pulmonary infection, like cystic fibrosis.

Topics: Anti-Bacterial Agents; Cell Line; Cystic Fibrosis; Humans; Lactic Acid; Nanoparticles; Netilmicin; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pseudomonas aeruginosa

We describe the case of a 22 yr old male patient with cystic fibrosis, who, after long-term antibiotic treatment of pulmonary infection, developed a haemorrhagic diathesis with severe bleeding from the mucus membrane of the mouth, and haematuria. Rapid recovery was observed after infusion of vitamin K. During 8 months of follow-up, no evidence of recurrence of the clotting disturbances and anaemia were noted. The combination of impaired absorption of vitamin K due to underlying disease with the antibiotic-induced suppression of vitamin K synthesis by intestinal bacteria could be a possible explanation for this disorder.

Topics: Adult; Cefuroxime; Cephalosporins; Cystic Fibrosis; Follow-Up Studies; Gentamicins; Hemorrhagic Disorders; Humans; Male; Netilmicin; Pneumonia; Time Factors; Vitamin K

Topics: Adult; Cystic Fibrosis; Humans; Middle Aged; Netilmicin

The pharmacokinetics of netilmicin was studied in 14 patients with cystic fibrosis, aged 4-21 years (mean 16 years) during treatment of pulmonary exacerbations of pseudomonas infection. The patients received 24 courses of netilmicin (10 mg/kg/day) in combination with azlocillin (600 mg/kg/day), cefsulodin (200 mg/kg/day) or ceftazidime (150 mg/kg/day) for 9-14 days. Seven patients received two or three courses of different combinations. Serum and sputum concentrations of netilmicin were determined on day 2 and 6. Mean (+/- S.E.M.) trough serum values were 1.4 +/- 0.2 mg/l (same on day 2 and 6), peak values at 10 min 13.6 +/- 1.0 and 13.7 +/- 0.9 mg/l, and serum concentration at 1 h 7.5 +/- 0.6 and 7.5 +/- 0.5 mg/l, on days 2 and 6 respectively. The half-life was about 1 h. The pharmacokinetics did not differ on day 2 and 6. Sputum concentrations increased up to 2-3 h after administration, mean (+/- S.E.M.) peak values being 2.6 +/- 0.6 and 1.5 +/- 0.4 mg/l at day 2 and 6, respectively. The study shows that the pharmacokinetics of netilmicin was not influenced by different combinations with beta-lactams. All patients improved clinically, but pseudomonas growth was only reduced in nine courses. In one case transient resistance to netilmicin developed during the treatment. The clinical efficacy and tolerance were good and similar to those seen with combinations with other aminoglycosides.

Topics: Adolescent; Adult; Azlocillin; Cephalosporins; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Lung Diseases; Male; Netilmicin; Pseudomonas aeruginosa; Sputum

Large amounts of free granulocyte elastase (GE), an enzyme capable of mediating airway damage, have been found in bronchial secretions of patients with cystic fibrosis who are infected with Pseudomonas aeruginosa. This finding indicates an imbalance between GE and its antiproteases, alpha 1-proteinase inhibitor (alpha 1-PI) and bronchial mucosal inhibitor (BMI), in the airways of these individuals. The effect of intravenous antimicrobial treatment against P. aeruginosa on activity and concentration of GE, BMI, and alpha 1-PI was evaluated in 30 treatment courses of 20 patients with cystic fibrosis. Although sputum volume and level of immunoreactive GE decreased and concentrations of alpha 1-PI and BMI increased significantly (P less than .05), a high level of free GE persisted. No active alpha 1-PI and BMI were detectable after treatment. High levels of GE correlated with a poor pulmonary condition (rs = .98, P less than .001). In vitro, elastolytic activity of bronchial secretions from patients with cystic fibrosis was significantly inhibited by eglin C and an oxidation-resistant variant of alpha 1-PI, both compounds currently produced by recombinant DNA technology.

Topics: alpha 1-Antitrypsin; Anti-Bacterial Agents; Azlocillin; Blood Proteins; Bronchi; Cystic Fibrosis; Granulocytes; Humans; Netilmicin; Pancreatic Elastase; Protease Inhibitors; Proteins; Pseudomonas Infections; Serpins; Sputum; Ticarcillin

The pharmacokinetics of netilmicin were determined in 10 patients with cystic fibrosis. Mean (+/- standard error of the mean) values for total body clearance and volume of distribution were 2.62 (+/- 0.18) ml/min per kg of body weight and 0.38 (+/- 0.01) liter/kg, respectively, and were considerably larger than the same parameters reported for patients without cystic fibrosis.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Drug Administration Schedule; Female; Half-Life; Humans; Kinetics; Male; Metabolic Clearance Rate; Netilmicin; Respiratory Tract Diseases

Minimum bacteriostatic (MIC) and bactericidal (MBC) levels were done on 37 clinical isolates of mucoid Pseudomonas aeruginosa from cystic fibrosis patients against azthreonam, netilmicin and piperacillin. Results show that piperacillin had the greatest bacteriostatic activity; however there was more likely to be a significant disparity between MIC and MBC with this drug. Netilmicin was less active than piperacillin, but there was less difference between MICs and MBCs. Azthreonam was the least active compound tested.

Topics: Anti-Bacterial Agents; Aztreonam; Cystic Fibrosis; Humans; Microbial Sensitivity Tests; Netilmicin; Piperacillin; Pseudomonas aeruginosa

The pharmacokinetics of intravenous netilmicin was studied in cystic fibrosis (CF) and non-CF patients who were closely matched according to age. The serum concentrations showed a moderately higher variance within the CF group. The serum half-life in CF patients was 1.37 h compared with 2.29 h in the non-CF subjects (P less than 0.05). The apparent distribution coefficients were 0.306 and 0.356 liters/kg in the CF and non-CF groups, respectively. The mean body clearance was 6.6 liters/h per 1.73 m2 in the CF group compared with 5.3 liters/h per m2 in the non-CF controls, but the difference was not significant. The mean renal clearance in CF patients was 4.7 liters/h per 1.73 m2. From a pharmacokinetic point of view, the dosage of netilmicin required may be the same in CF as in non-CF patients.

Topics: Child; Cystic Fibrosis; Female; Gentamicins; Humans; Kinetics; Male; Netilmicin