Augmented renal clearance (ARC) refers to the state of heightened renal filtration commonly observed in the critically ill. Its prevalence in this patient population is a consequence of the body’s natural response to serious disease, as well as the administration of fluids and pharmacologic therapies necessary to maintain sufficient blood pressure. ARC is objectively defined as a creatinine clearance of more than 130 mL/min/1.73 m2 and is thus a crucial condition to consider when administering antibiotics, many of which are cleared renally. Using conventional dosing regimens risks the possibility of subtherapeutic concentrations or clinical failure. Over the past decade, research has been conducted in patients with ARC who received a number of antibacterials frequently used in the critically ill, such as piperacillin-tazobactam or vancomycin. Strategies to contend with this condition have also been explored, though further investigations remain necessary.

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (20-g, 3-h infusion every 8 h [Q8H]) and ceftazidime (2-g, 2-h infusion Q8H) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/ml, and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10 CFU/thigh at 24 h compared to 0-h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; the mean bacterial reduction at 24 h was −2.67 ± 0.68 log10 CFU/thigh with ≥2-log reduction achieved in 21 isolates (87.5%) and a ≥1-log reduction achieved in the remaining 3 isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced a mean bacterial reduction of −1.38 ± 1.49 log10 CFU/thigh among 10 ceftazidime-susceptible isolates and a mean bacterial growth of 0.64 ± 0.79 log10 CFU/thigh among 14 ceftazidime-nonsusceptible isolates. Although ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-nonsusceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.

No abstract

Blood culture bottles containing antibiotic binding resins are routinely used to minimize artificial sterilization in the presence of antibiotics. However, the resin binding kinetics can differ between antibiotics and concentrations. This study assessed the impact of clinically meaningful peak, midpoint, and trough concentrations of meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam on the recovery of Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae from resin-containing BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles. P. aeruginosa-inoculated bottles alarmed positive in 4/20 (20%), 16/20 (80%), and 20/20 (100%) of those with peak, midpoint, and trough concentrations of antipseudomonal agents, respectively (P ≤ 0.001). E. coli was recovered from 8/24 (33%), 11/24 (46%), and 14/24 (58%) of bottles with peak, midpoint, and trough concentrations, respectively (P = 0.221). K. pneumoniae was recovered from 8/16 (50%) at all concentrations of the studied antibiotics (P = 1.0). BacT/Alert and Bactec bottles inoculated with antibiotics and P. aeruginosa had similar times to detection (TTD) (P = 0.352); however, antibiotic-containing BacT/Alert bottles had a shorter TTD compared with antibiotic-containing Bactec bottles for E. coli (P = 0.026) and K. pneumoniae (P ≤ 0.001). Pathogen recovery in BacT/Alert FA Plus and Bactec Aerobic/F blood culture bottles containing antibiotic binding resins was greatly reduced in the presence of antibiotics, especially at higher concentrations. These data support the practice of drawing blood cultures immediately before an antibiotic dose to maximize the chances of pathogen recovery.

Blood cultures are routinely collected in pairs of aerobic and anaerobic bottles. Artificial sterilization of Gram-negative bacteria in aerobic bottles containing clinically meaningful antibiotic concentrations has previously been observed. This study assessed recovery from anaerobic bottles with and without antibiotic binding resins. We studied the recovery of Escherichia coli and Klebsiella pneumoniae when exposed to meropenem, imipenem, cefepime, cefazolin, levofloxacin, and piperacillin-tazobactam in resin-containing BacT/Alert FN Plus and BD Bactec Plus anaerobic/F bottles as well as resin-free BacT/Alert SN and BD Bactec standard anaerobic bottles. Bottles were inoculated with bacteria and whole blood containing peak, midpoint, or trough concentrations and incubated for up to 120 hours in their respective detection systems. In E. coli resin-containing bottles, recovery was observed in 10/24 (42%), 17/24 (71%), and 18/24 (75%) (P = 0.034) of those exposed to peak, midpoint, and trough concentrations, respectively. In K. pneumoniae resin-containing bottles, recovery was observed in 8/16 (50%), 10/16 (63%), and 10/16 (63%) (P = 0.710), respectively. No growth was detected in bottles containing cefepime regardless of concentration, while recovery was observed in the presence of all concentrations of cefazolin and piperacillin-tazobactam. Recovery in bottles with meropenem and imipenem was more frequently observed in BacT/Alert FN Plus bottles compared with Bactec Plus bottles. Resin-free bottles demonstrated significantly lower recovery than bottles containing binding resin. Clinical concentrations of certain antibiotics can adversely affect detection of E. coli and K. pneumoniae in anaerobic blood culture bottles. Obtaining blood cultures immediately before a dose and utilizing resin-containing anaerobic bottles will maximize the likelihood of recovery.