Susceptible bacteria can survive antibiotic treatment in the mammalian gastrointestinal tract without evolving resistance.

Antibiotic resistance and evasion are incompletely understood and complicated by the fact that murine interval dosing models do not fully recapitulate antibiotic pharmacokinetics in humans. To better understand how gastrointestinal bacteria respond to antibiotics, we colonized germ-free mice with a pan-susceptible genetically barcoded Escherichia coli clinical isolate and administered the antibiotic cefepime via programmable subcutaneous pumps, allowing closer emulation of human parenteral antibiotic dynamics. E. coli was only recovered from intestinal tissue, where cefepime concentrations were still inhibitory. Strikingly, "some" E. coli isolates were not cefepime resistant but acquired mutations in genes involved in polysaccharide capsular synthesis increasing their invasion and survival within human intestinal cells. Deleting wbaP involved in capsular polysaccharide synthesis mimicked this phenotype, allowing increased invasion of colonocytes where cefepime concentrations were reduced. Additionally, "some" mutant strains exhibited a persister phenotype upon further cefepime exposure. This work uncovers a mechanism allowing "select" gastrointestinal bacteria to evade antibiotic treatment.

In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model.

We describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against multidrug-resistant Pseudomonas aeruginosa (meropenem MICs 8 to >256 µg/ml) in a neutropenic murine thigh infection model. WCK 5222 MICs ranged from 4 to 32 µg/ml. Substantial in vivo WCK 5222 activity was observed against all isolates, further enhancing the efficacy of zidebactam alone in 11/16 isolates (WCK 5222 mean reduction, -1.62 ± 0.58 log10 CFU/thigh), and a lack of activity was observed with cefepime monotherapy.

Physical compatibility of fosfomycin for injection with select i.v. drugs during simulated Y-site administration.

PURPOSE: The results of a study to determine the physical compatibility of ZTI-01 (fosfomycin for injection) in 0.9% sodium chloride or 5% dextrose during simulated Y-site administration with 37 i.v. antimicrobials and 58 nonantimicrobials are reported. METHODS: Fosfomycin, an epoxide antibiotic with broad-spectrum activity against multidrug-resistant bacteria, is marketed in the United States only in an oral formulation with limited bioavailability, but an i.v. formulation is in development. Fosfomycin for injection and other evaluated drugs were reconstituted according to manufacturer recommendations and further diluted with 0.9% sodium chloride or 5% dextrose to the final desired concentrations. Y-site administration was simulated in glass culture tubes. Incompatibility was defined as changes in visual characteristics or a change in turbidity of >0.5 nephelometric turbidity units over the 120-minute observation period. RESULTS: Of the 95 drugs tested, 16 were incompatible with fosfomycin in 0.9% sodium chloride, and 18 were incompatible with fosfomycin in 5% dextrose; incompatibility was observed with 10 of 37 antimicrobials, including the 3 commercially available amphotericin B products, anidulafungin, caspofungin, ceftaroline, ciprofloxacin, daptomycin, doxycycline, and isavuconazonium sulfate. CONCLUSION: Fosfomycin for injection at a concentration of 30 mg/mL was physically compatible with 73 of 95 (77%) of the i.v. drugs tested at concentrations used clinically in both 0.9% sodium chloride injection and 5% dextrose injection. Twenty-two drugs were deemed incompatible in at least 1 of the 2 diluents.

Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, in a Pseudomonas aeruginosa neutropenic murine thigh model.

Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to describe the pharmacokinetics, pharmacodynamics and 24-h efficacy of cefiderocol using dose-ranging methods in a neutropenic murine thigh infection model. Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg at 4 days and 1 day prior to inoculation, respectively) with eight Pseudomonas aeruginosa isolates [minimum inhibitory concentration (MIC) range 0.063-0.5 µg/mL] that displayed variable in vivo activity against previously tested ß-lactams with siderophore moieties. Renal excretion was controlled by administration of 5 mg/kg uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered subcutaneously in eight escalating doses [4.2-166.7 mg/kg every 8 h (q8h)]. In pharmacokinetic studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100 and 250 mg/kg) with a mean half-life of 0.86 h. In pharmacodynamic studies, the change in CFU after 24 h from the initial inoculum ranged from +3.4 to -3.1 log10 with doses of 4.2-166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape, with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT>MIC (time that the free drug concentration exceeds the MIC) for this compound, targets for stasis and 1 log10 and 2 log10 reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively. Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials.

Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo.

We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

Optimizing Antibiotic Dosing Strategies for the Treatment of Gram-negative Infections in the Era of Resistance.

Gram-negative organisms are an increasing source of concern within the healthcare setting due to their common presence as a cause of infection and emerging resistance to current therapies. However, current antimicrobial dosing recommendations may be insufficient for the treatment of gram-negative infections. Applying knowledge of an antibiotic's pharmacokinetic/pharmacodynamic profile when designing a dosing regimen leads to a greater likelihood of achieving optimal exposure, including against gram-negative pathogens with higher MICs. Additionally, administering antibiotics directly to the site of infection, such as via aerosolization for pneumonia, is another method to achieve optimized drug exposure at the site of infection. Incorporating these treatment strategies into clinical practice will assist antimicrobial stewardship programs in successfully treating gram-negative infections.