Effects of dosing frequency on the clinical efficacy of ampicillin/sulbactam in Japanese elderly patients with pneumonia: A single-center retrospective observational study

Abstract

This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C-reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively (p = .0459). QID tended to be more effective in patients with gram-negative rods detected (p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 μg/ml, respectively (p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.

Keywords: ampicillin/sulbactam; elderly patients; pharmacokinetics-pharmacodynamics; pneumonia; retrospective study.

FIGURE 1

Flow of patient selection applied for this retrospective study. ABPC/SBT: ampicillin/sulbactum, CLcr: creatinine clearance

FIGURE 2

Simulated plasma concentration–time profiles of ABPC (BID vs. QID). A population pharmacokinetic model ⁵ was employed to simulate the plasma ampicillin concentrations after initiating 1.5 g ABPC/SBT intravenous treatment every 6 h, or 3 g every 12 h (30‐min intravenous infusion). Straight line represents BID mean (n = 61), and dotted line represents QID mean (n = 45)

FIGURE 3

Probability of target attainment (PTA) for ABPC/SBT. Achieving 40% f･T>MIC for 24 h as simulated unbound plasma ABPC concentration following multiple 30 min intravenous infusions of 1.5 g or 3 g ABPC/SBT at day 4. Protein bound ratio 28%. * p = .0332, **p = .0016, *** p = 0.0011 as determined by Chi Square test. Closed circles represent BID (n = 61) and open circles are QID (n = 45). Both symbols overlap at an MIC range <2 μg/ml