Stability of Ampicillin plus Ceftriaxone Combined in Elastomeric Infusion Devices for Outpatient Parenteral Antimicrobial Therapy

Abstract

Currently, ampicillin plus ceftriaxone (AC) is one of the preferred treatments for Enterococcus faecalis infective endocarditis. However, there is a lack of stability data for the combination of both drugs in elastomeric devices, so the inclusion of AC in Outpatient Parenteral Antimicrobial Therapy (OPAT) programs is challenging. The objective of the study was to determine the stability of AC in elastomeric pumps when stored at 8 ± 2 °C, 25 ± 2 °C, 30 ± 2 °C and 37 ± 2 °C using LC-MS/MS. The combination was diluted in 0.9% sodium chloride and the final concentrations were ampicillin 24 g/L plus ceftriaxone 8 g/L. Physical and chemical stability were evaluated at 12, 20, 24, 36 and 48 h after preparation. Stability was met at each time point if the percentage of intact drug was ≥90% of its respective baseline concentration and color and clearness remained unchanged. The drug combination was stable for 48 h when it was kept at 8 ± 2 °C. At 25 ± 2 °C and 30 ± 2 °C, they were stable for 24 h of storage. At 37 ± 2 °C, the stability criterion was not met at any time point. These results prove that AC could be included in OPAT programs using elastomeric infusion devices for the treatment of E. faecalis infections.

Ampicillin Stability in a Portable Elastomeric Infusion Pump: A Step Forward in Outpatient Parenteral Antimicrobial Therapy

“…Therefore, our data support that of Huskey et al [ 15 ], showing that the chemical stability of AMP is not compromised at the end of the 24 h infusion period at 25 °C after a refrigerated storage period of 72 h. Data regarding stability of diluted AMP solutions at 25 °C are more variable. At 20 mg/mL, AMP remained stable for 8 h [ 14 ], whereas at 24 mg/mL stability was maintained for 24 h [ 19 ]. Another study with 30 mg/mL AMP reported >90% concentration after 72 h [ 16 ].…”

“…Previous results for the stability of concentrated AMP solutions at warm temperatures have clearly shown what is already known: excessive drug degradation of >10% during the first 24 h [ 20 , 21 ]. A recent study with 24 mg/mL AMP reported stability >90% for the initial 24 h at 30 °C, but these EIPs did not undergo a previous refrigerated storage period [ 19 ]. Likely, similar results are expected to be reported by us and others, eventually leading us to draw the same conclusion: the stability of AMP solutions at temperatures above 25 °C is not guaranteed long enough to be used in OPAT.…”

“…Assessment of AMP stability beyond 25 °C is desirable considering that EIPs are often exposed to elevated temperatures (near to 37 °C) derived from their proximity to the body during use, the influence of clothing, and the high ambient temperature of some geographical areas, which may compromise its stability, although not always required by regulatory agencies [ 17 , 18 ]. Recently, one study evaluated the stability of an infusion solution for the treatment of endocarditis that combined AMP and ceftriaxone at temperatures higher than 25 °C, reporting shelf-lives of 24 h at 30 °C and <24 h at 37 °C, respectively [ 19 ]. Less-divergent results are obtained when AMP is reconstituted at 50–60 mg/mL, but these concentrated solutions exhibit a reduced shelf-life of <24 h at 25 °C and at warmer temperatures (30–31.1 °C) [ 11 , 20 , 21 ].…”

Treatment of Enterococcus faecalis Infective Endocarditis: A Continuing Challenge

“…Using a very precise technique [ 203 ] we demonstrated the stability of this combination that we believe it would be an excellent alternative (much less toxic) to the A + G regimen, which is still used as a reference. Continuous or intermittent administration (every 4 h) of both drugs would always maintain levels above the required thresholds, without requiring any extraordinary manipulation other than periodic pump refilling [ 204 , 205 ] and have demonstrated excellent results in a few patients [ 196 ].…”

Treatment of <em>Enterococcus faecalis</em> Infective Endocarditis: A Continuing Challenge

“…However, using a very precise technique 199 , we demonstrated the stability of this combination that we believe it would be an excellent alternative (much less toxic) to the A + G regimen, which is still used as a reference. Indeed, continuous or intermittent administration (every 4 hours) of both drugs would always maintain levels above the required thresholds, without requiring any extraordinary manipulation other than periodic pump refilling 200,201 .…”