Penetration of netilmicin in the lower respiratory tract after once-daily dosing.

A major criticism of the use of aminoglycosides for the treatment of pneumonia is the poor penetration in infected airways. Once-daily dosing of aminoglycosides results in higher peak plasma concentrations without increasing toxic reactions and with optimization of pharmacodynamic properties. To predict intrapulmonary antimicrobial activity after once-daily dosing of aminoglycosides, it is necessary to determine the respective bronchial and alveolar disposition. We prospectively conducted a pharmacokinetic study of netilmicin following the first intravenous administration of a once-daily dosing schedule in 20 ventilated patients with pneumonia. A bronchoscopic sampling of bronchial secretions and a subsegmental bronchoalveolar lavage (BAL) were performed 60, 90, 120, and 180 min (five patients at each time point) on the first treatment day after intravenous administration over 30 min of 450 mg of netilmicin. The netilmicin concentrations in the alveolar lining fluid (ALF) were calculated using urea as an endogenous marker of dilution. In bronchial secretions, a peak concentration of 2.00 (SEM: 0.26) mg/L or 6 percent of the 30-min plasma concentration was reached at 120 min. In ALF, much higher levels were found. At 120 min, a peak ALF concentration of 14.7 (SEM: 2.22) mg/L or 41 percent of the 30-min plasma concentration was reached. Spearman's rank correlation testing failed to show a correlation between bronchial and ALF concentrations. Higher plasma concentrations of netilmicin after once-daily dosing give rise to ALF concentrations exceeding the minimum inhibitory concentration of susceptible respiratory pathogens involved in nosocomial pneumonia, while bronchial concentrations remain low. Aminoglycoside concentrations in bronchial secretions cannot be used to predict alveolar concentrations. Low diffusibility can no longer be considered as a disadvantage of aminoglycosides for treating pneumonias.

Philadelphia-positive T-acute lymphoblastic leukemia.

A case of typical T-acute lymphoblastic leukemia (T-ALL) is reported in which, at diagnosis, 100% of bone marrow metaphases showed a Philadelphia (Ph) translocation, t(9;22). These cells completely disappeared following chemotherapy. The significance of the Ph chromosome in T and B leukemic cells is discussed.

Pharmacokinetic evaluation of tobramycin in the alveolar lining fluid of the rat after endotracheal administration.

Using bronchoalveolar lavage (BAL) we evaluated the concentration-time profile of tobramycin in the alveolar lining fluid (ALF) of rats after direct endotracheal instillation (1.5 mg/kg) and aerosolization (10 mg/ml for 15 min). Very high and long-persisting concentrations of tobramycin were reached in ALF after both modes of administration. After aerosolization a peak concentration in ALF of 339 +/- 41 micrograms/ml was reached with a slow but progressive decline to 45 +/- 8 micrograms/ml at 6 h. After direct endotracheal instillation significantly higher (p less than 0.01) concentrations in ALF (peak concentration, 2,100 +/- 16 micrograms/ml) were reached and formed a stable plateau until 4 h after administration, progressively declining thereafter (400 +/- 30 micrograms/ml at 6 h). Systemic vascular absorption from the alveoli was minimal, but it was higher after direct endotracheal instillation (peak serum concentration, 1.55 +/- 0.21 micrograms/ml). We conclude that in view of the favorable pharmacokinetic profile and the minimal systemic absorption, endobronchial administration of aminoglycosides may be a valuable alternative to systemic administration, which eventually can reduce systemic toxicity and the need for therapeutic drug monitoring.

Penetration of ampicillin and sulbactam in the lower airways during respiratory infections.

We studied the penetration of ampicillin-sulbactam in the alveolar lining fluid (ALF) of eight patients after intravenous administration of 2,000 mg of ampicillin and 1,000 mg of sulbactam three times daily over 30 min. Bronchoalveolar lavage was performed on day 3, 30 min after the end of the morning drug administration. The mean penetration ratios (i.e., the ratios of the concentrations in ALF versus those in serum) were 53% (standard error, 12%) and 61% (standard error 31%) for ampicillin and sulbactam, respectively. The concentration ratio of ampicillin versus sulbactam in serum was not significantly different from that in ALF. From a pharmacokinetic point of view, ampicillin-sulbactam is a good choice for treatment of infectious exacerbation of chronic obstructive pulmonary disease and community-acquired bacterial pneumonia, since the concentrations of both drugs in ALF exceed the MICs for the respiratory pathogens responsible.

Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine.

BACKGROUND: The modest improvement in median survival of advanced non-small-cell lung cancer (NSCLC) by cisplatin-based chemotherapy has led to the current opinion that clinical benefit for the patient is at least as important an end-point as objective response rate (ORR) or survival. Clinical benefit response was the primary end-point of this prospective randomised trial in symptomatic, advanced stage IIIB/IV NSCLC, comparing single agent gemcitabine (GEM) to cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m2, days 1, 8 and 15) or cisplatin (100 mg/M2, day 1) plus Vindesine (3 mg/m2, days 1 and 15) (PV), both every four weeks. Clinical benefit was measured by a simple metric based on changes in a visual analogue symptom score list, the Karnofsky performance status and the weight. RESULTS: One hundred sixty-nine patients were randomised (84 GEM, 85 PV). Prognostic factors and baseline symptoms were well balanced between the two arms. Most of the the objective responders and about half of the patients with disease stabilisation experienced clinical benefit. Compared to PV, a significantly larger number of GEM-treated patients experienced a clinical benefit (48.1 vs. 28.9%, P = 0.03) that lasted significantly longer (median duration 16 vs. 10 weeks, P = 0.01). No important differences in ORR, time-to-progression or median survival were observed. Grade 3 + 4 toxicity was significantly higher in the PV-group for leukopenia (P = 0.0003), neutropenia (P < 0.0001), nausea/vomiting (P = 0.0006), alopecia (P < 0.0001), and neurotoxicity (P = 0.04). Some severe pulmonary toxicity to GEM was noted. CONCLUSION: Comparison of GEM with cisplatin-based therapy in symptomatic, advanced NSCLC demonstrates that GEM produces significantly a stronger and longer-lasting clinical benefit, probably due to its equal effectiveness in terms of ORR, time-to-progression or survival, combined with significantly less severe therapy-related toxicity.