Comparative stability studies of antipseudomonal beta-lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units)

Abstract

The stability of antipseudomonal beta-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37 degrees C (mezlocillin [128 g/liter] was stable at 25 degrees C but not at 37 degrees C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25 degrees C but only for 8, 7.25, and 13 h at 37 degrees C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30 degrees C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37 degrees C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25 degrees C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.

FIG. 1.

Stability of the β-lactams in water at 37°C over time at the maximum concentration tested. (A) Symbols: ▵, 10% aztreonam; □, 12.8% piperacillin; ▪, 12.8% piperacillin plus tazobactam (since the slope for 12.8% azocillin was almost identical to that for piperacillin-tazobactam, it was omitted for the sake of clarity); ▾ 12.8% mezlocillin. (B) Symbols: ▪, 12% ceftazidime; □, 5% cefepime; ▴, 3.2% cefpirome. (C) Symbols: □, 0.8% imipenem plus cilastatin; ▵, 6.4% meropenem; ▿, 6.4% faropenem. All values are the means of three independent determinations ± the standard deviation (SD; symbols without bars indicate values for which the SD is smaller than the symbol size).

FIG. 2.

Influence of temperature on the degradation of selected β-lactams (24 h of incubation) at the maximum concentration tested as follows: 12.8% piperacillin (○), 5% cefepime (▵), 6.4% meropenem (▪), and 0.8% imipenem plus cilastatin (□). All values are the means of three independent determinations ± the SD (symbols without bars indicate values for which the SD is smaller than the symbol size).

FIG. 3.

Release of pyridine from ceftazidime upon incubation at 4°C (□), 25°C (▨), and 37°C (▪) at two different initial concentrations (left panel, 8.3% [wt/vol]; right panel, 12% [wt/vol]). Freshly prepared samples contained <0.1 mg of pyridine/ml. The dotted line indicates the upper limit allowed for pyridine content in ceftazidime solutions according to the U.S. Pharmacopeia (39).