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.