An in-vitro pharmacodynamic system was used to generate time-kill curves to demonstrate the concentration-independent pharmacodynamics of vancomycin against Staphylococcus aureus ATCC 29213. Initial vancomycin concentrations of 5, 10, 20 and 40 mg/L were studied monoexponentially while simulating a 6 h half-life. One parallel experiment was performed in duplicate using an initial peak concentration of 40 mg/L where both a distribution alpha-phase half-life of 0.66 h for 1 h and an elimination beta-phase half-life of 6 h for 11 h were simulated to determine if the transient distribution phase concentrations of vancomycin have any impact on bacterial killing beyond that provided by the elimination phase concentrations. Additionally, two monoexponential experiments with peak concentrations of 40 and 20 mg/L and a half-life of 6 h were repeated in an anaerobic chamber to determine if killing of S. aureus was affected. The time to achieve a 3 log10 kill was calculated from the linear portion of the regression line and averaged (mean +/- S.D.) 9.0 +/- 1.4 h for all aerobic monoexponential experiments and was 8.4 and 8.6 h for the aerobic biexponential experiments (P > 0.05). For the anaerobic studies, the times to reach 3 log10 kill were significantly greater averaging 18.9 +/- 1.7 h. The slopes of the bacterial kill curves were virtually identical for both monoexponential and biexponential aerobic experiments averaging -0.34 +/- 0.04, yet significantly different from the anaerobic bacterial kill curve slopes of -0.16 +/- 0.015 (P < 0.05). Time-kill curve analyses suggest that varying the concentration of vancomycin does not affect the rate or extent of bacterial killing aerobically or anaerobically against S. aureus and more efficient killing was achieved under aerobic conditions. The simulated distribution phase concentrations did not contribute to more effective killing of this strain of S. aureus.

Background Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268–81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803–14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all β-lactams and fluoroquinolones). Methods Clinical and Laboratory Standards Institute–defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (n = 10 516) and Pseudomonas aeruginosa (n = 2732) collected in 26 US hospitals in 2015–2017. Results Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (P &lt; .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible. Conclusions MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.

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In vitro pharmacodynamic studies investigating the antimicrobial properties of five fluoroquinolones, (trovafloxacin, sparfloxacin, clinafloxacin, levofloxacin, and ciprofloxacin) againstBacteroides fragilis ATCC 23745 were conducted. The times required to reduce the viable counts by 3 log units were as follows: clinafloxacin, 2.9 h; levofloxacin, 4.6 h; trovafloxacin, 6 h; and sparfloxacin, 10 h. Exposure to ciprofloxacin did not achieve a 3-log decrease in viable counts. The susceptibility ofB. fragilis was determined both prior to exposure and following 24 h of exposure to each of the five fluoroquinolones tested. The MICs of clinafloxacin, levofloxacin, trovafloxacin, sparfloxacin, ciprofloxacin, metronidazole, cefoxitin, chloramphenicol, and clindamycin were determined by the broth microdilution method. The MICs for B. fragilis preexposure were as follows: clinafloxacin, 0.25 μg/ml; trovafloxacin, 0.5 μg/ml; sparfloxacin, 2 μg/ml; levofloxacin, 2 μg/ml; and ciprofloxacin, 8 μg/ml. Similar pre- and postexposure MICs were obtained for cultures exposed to trovafloxacin, clinafloxacin, levofloxacin, and ciprofloxacin. However, following 24 h of exposure to sparfloxacin, a fluoroquinolone-resistant strain emerged. The MICs for this strain were as follows: clinafloxacin, 1 μg/ml; trovafloxacin, 4 μg/ml; sparfloxacin, 16 μg/ml; levofloxacin, 16 μg/ml; and ciprofloxacin, 32 μg/ml. No changes in the susceptibility of B. fragilispre- and postexposure to sparfloxacin were noted for metronidazole (MIC, 1 μg/ml), cefoxitin (MIC, 4 μg/ml), chloramphenicol (MIC, 4 μg/ml), and clindamycin (MIC, 0.06 μg/ml). Resistance remained stable as the organism was passaged on antibiotic-free agar for 10 consecutive days. Mutant B. fragilis strains with decreased susceptibility to clinafloxacin, trovafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were selected on brucella blood agar containing 8× the MIC of levofloxacin at a frequencies of 6.4 × 10−9, 4× the MICs of trovafloxacin and sparfloxacin at frequencies of 2.2 × 10−9 and 3.3 × 10−10, respectively, and 2× the MIC of clinafloxacin at a frequency of 5.5 × 10−11; no mutants were selected with ciprofloxacin. The susceptibilities of strains to trovafloxacin, levofloxacin, clinafloxacin, sparfloxacin, and ciprofloxacin before and after exposure to sparfloxacin were modestly affected by the presence of reserpine (20 μg/ml), an inhibitor of antibiotic efflux. The mechanism of fluoroquinolone resistance is being explored, but it is unlikely to be efflux due to a lack of cross-resistance to unrelated antimicrobial agents and to the fact that the MICs for strains before and after exposure to sparfloxacin are minimally affected by reserpine.