Antibiotic Efficacy during Spaceflight: Impact of Simulated Microgravity on Killing of S. pneumoniae by Ciprofloxacin
Johannes Kast (1), Edgar L. Schuck (1), Amelia N. Deitchman (1), Lakshmi Putcha (2, *) and Hartmut Derendorf (1)
(1) University of Florida, Department of Pharmaceutics, USA, (2) NASA Johnson Space Center, USA, *Author is deceased.
Objectives: To explore the effects of the microgravity environment observed during spaceflight on the killing of S. pneumoniae by ciprofloxacin by developing a PK/PD model to compare the efficacy of dosing regimens in simulated microgravity and Earth’s gravity.
Methods: Free interstitial tissue concentration-time profiles of ciprofloxacin in simulated microgravity (0G) and Earth’s gravity (1G) were simulated for different dosing regimens in R v.3.3.2. The model was obtained from the literature [1]. Pharmacokinetic profiles were simulated for 36 hours after oral administration of ciprofloxacin with a dose of 250, 500 and 750 mg every 12 hours (BID). To describe the killing of S. pneumoniae by ciprofloxacin, in vitro time kill curve experiments were performed at 0.25 to 16XMIC in simulated microgravity and Earth’s gravity. The bacterial killing was modelled using a one bacterial population model where the ciprofloxacin effect was described as a sigmoidal Emax model in NONMEM v.7.3. Finally, bacterial response for each dosing regimen was predicted using the developed pharmacodynamic model.
Results: Free interstitial tissue ciprofloxacin concentrations were lower in 0G as compared to 1G for all simulated dosing regimens. Ciprofloxacin concentrations after 36 hours were 35.13, 70.27, 105.40 ng/ml in 0G and 40.23, 80.45, 120.68 ng/ml in 1G for 250, 500 and 750 mg ciprofloxacin BID, respectively. The in vitro time kill curves of ciprofloxacin against S. pneumoniae were successfully described with the developed model (for 0G: EC50 0.60 mg/l ciprofloxacin, Hill factor 1.34, maximal kill rate constant 3.81 h-1, for 1G: EC50 0.67 mg/l ciprofloxacin, Hill factor 1.18, maximal kill rate constant 4.26 h-1). Bacterial concentrations after 36h were higher in 0G as compared to 1G. Bacterial loads in log(CFU/ml) after 36h were 8.72, 8.67, 8.42 in 0G and 8.70, 8.63, 8.10 in 1G for 250, 500, 750 mg ciprofloxacin BID, respectively.
Conclusion: Based on the simulated kill-curve profiles of different ciprofloxacin dosing regimens against S. pneumoniae, none of the simulated dosing regimens are adequate to treat infections of S. pneumoniae with ciprofloxacin on Earth or in microgravity since adequate killing of bacteria is not achieved in either scenario after 36h. More research, especially inflight studies, is needed to further investigate the impact of the spaceflight environment on the pharmacokinetics and pharmacodynamics of antibiotics to ensure adequate pharmacotherapy during space missions.
References:
[1] Schuck EL et al. J Clin Pharmacol. Jul 2005;45(7):822-31.