Carbapenem-Containing Combination Antibiotic Therapy against Carbapenem-Resistant Uropathogenic Enterobacteriaceae

Abstract

The increasing global prevalence of carbapenem-resistant Enterobacteriaceae (CRE) combined with the decline in effective therapies is a public health care crisis. After respiratory tract infections, urinary tract infections and associated urosepsis are the second most affected by CRE pathogens. By using checkerboard analysis, we tested eight different antibiotics in combination with carbapenems in CAMHB (cation-adjusted Müller-Hinton broth) and artificial urine against seven CRE strains and three susceptible strains. To further determine whether these combinations are also effective in a dynamic model, we have performed growth curves analyses in a dynamic bladder model with three uropathogenic CRE strains. In this model, we simulated the urinary pharmacokinetic after application of 1,000 mg intravenous (i.v.) ertapenem alone or in combination with 500 mg i.v. levofloxacin, 1,000 mg oral rifampin, or 3,000 mg oral fosfomycin. Bacterial growth was measured for 48 h, simulating voiding of the bladder every 3 h. According to the median fractional inhibitory concentration indices (ΣFICIs), the values we found were additive to synergistic results across all tested CRE strains for combinations of carbapenems with colistin sulfate, levofloxacin, fosfomycin, rifampin, and tigecycline in CAMHB and artificial urine. In the dynamic bladder model, all three CRE strains tested showed regrowth after treatment with ertapenem up to 48 h. Regrowth could be prevented by combination with levofloxacin, fosfomycin, or rifampin. Carbapenem-containing combination therapy with fosfomycin or rifampin could be an option for better treatment of urinary tract infections (UTIs) caused by CRE strains. This should be further investigated in clinical studies.

Keywords: CRE; antimicrobial combinations; carbapenems; urinary tract infection.

FIG 1

Antibiotic concentrations measured in the bladder compartment of the dynamic model over time following a single dose. Single-dose application of ertapenem (1,000 mg), levofloxacin (500 mg), rifampin (600 mg), and fosfomycin (3,000 mg) were simulated mathematically and were measured at different time points in the bladder compartment of the dynamic model.

FIG 2

Bacterial growth in the dynamic model following single dose of antibiotics alone or in combination. Urine pharmacokinetic of ertapenem (1,000 mg), levofloxacin (500 mg), fosfomycin (3,000 mg), and rifampin (600 mg) alone or in combination were simulated according to the respective plasma elimination constant and urinary recovery rate at an assumed average urine production rate of 1.5 liters/24 h with a simulated bladder voiding every 3 h. Bacteria were inoculated with 1 × 10⁶ CFU/ml in the bladder compartment, and bacterial growth was measured over 48 h by sample dilution and plating.