In Vitro Activity of Ceftaroline Alone and in Combination against Clinical Isolates of Resistant Gram-Negative Pathogens, Including β-Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa

Abstract

Ceftaroline is a novel broad-spectrum cephalosporin that exhibits bactericidal activity against many grampositive and -negative pathogens. However, the activity of ceftaroline cannot be solely relied upon for eradication of multidrug-resistant gram-negative isolates, such as Pseudomonas aeruginosa and extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae, which represent a current clinical concern. As drug combinations might be beneficial by potential synergy, we evaluated the in vitro activity of ceftaroline combined with meropenem, aztreonam, cefepime, tazobactam, amikacin, levofloxacin, and tigecycline. Susceptibility testing was performed for 20 clinical P. aeruginosa isolates, 10 ESBL-producing Escherichia coli isolates, 10 ESBL-producing Klebsiella pneumoniae isolates, and 10 AmpC-derepressed Enterobacter cloacae isolates. Timekill experiments were performed for 10 isolates using antimicrobials at one-fourth the MIC. Ceftaroline exhibited a MIC range of 0.125 to 1,024 g/ml and was reduced 2-to 512-fold by combination with tazobactam (4 g/ml) for ESBL-producing strains. In time-kill experiments, ceftaroline plus amikacin was synergistic against 90% of the isolates (and indifferent for one P. aeruginosa isolate). Ceftaroline plus tazobactam was indifferent for E. cloacae and P. aeruginosa strains but synergistic against 100% of E. coli and K. pneumoniae isolates. Combinations of ceftaroline plus meropenem or aztreonam were also synergistic for all E. coli and E. cloacae isolates, respectively, but indifferent against 90% of the other isolates. Finally, combinations of ceftaroline plus either tigecycline, levofloxacin, or cefepime were indifferent for 100% of the isolates. No antagonism was observed with any combination. Ceftaroline plus amikacin appeared as the most likely synergistic combination. This represents a promising therapeutic option, and further studies are warranted to elucidate the clinical value of ceftaroline combinations against resistant gram-negative pathogens.

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Enhancement of activity was defined as an increase in kill of Ն2-log 10 CFU/ml by the combination of antimicrobials versus the most active single agent of that combination. Improvement was defined as a 1-to 2-log 10 CFU/ml increase in kill compared to the most active single agent, while combinations that result in a Ն1-log 10 CFU/ml bacterial growth compared to the least active single agent were considered antagonistic (32,33).…”

“…Samples from each model were collected at 0, 4,8,24,32,48,56, and 72 h and diluted in 0.9% saline. Colony counts were determined by spiral plating appropriate dilutions using an automatic spiral plater (WASP; DW Scientific, West Yorkshire, England) to enumerate CFU/ml and avoid antibiotic carryover.…”

In Vitro Synergism of Ciprofloxacin and Cefotaxime against Nalidixic Acid-Resistant Salmonella enterica Serotypes Paratyphi A and Paratyphi B

“…Time-kill curves were constructed by plotting the mean colony counts on a logarithmic scale versus the time with a lower limit detection of 2 log 10 CFU/ml. According to the 2009 guidelines of Antimicrobial Agents and Chemotherapy, synergy was defined as a Ն2-log 10 -unit decrease (100-fold drop) in the numbers of CFU per ml achieved with the combination and with the most efficient agent used alone at 24 h. Indifference and antagonism were defined as Ϯ1-to Ͻ2-log 10 -unit killing at 24 h compared to the activity of the most efficient agent alone and Ͼ1 log 10 unit of growth at 24 h compared with the activity of the least active agent, respectively (31). The bactericidal activities of the drugs alone and the drug combinations were defined as a reduction of Ն3 log 10 CFU/ml (99.9%) compared to the starting inoculum and to the most active antimicrobial agent at 24 h, respectively (15).…”

“…To account for the potential breakdown of antibiotics in broth, bacterial cells grown in each tube were spun down and resuspended in fresh drug-containing broth at 24 and 48 h. Additionally, at 36, 48, and 72 h of incubation, culture aliquots of 100 l were taken from each tube and the drug carryover was minimized by dilution in MHB, as described above. Bacterial counts were determined by plating 100 l of the appropriate dilutions on duplicate Mueller-Hinton agar (MHA) plates and overnight incubation under ambient conditions at 37°C to enumerate the numbers of CFU/ml (16,31). Time-kill curves were constructed by plotting the mean colony counts on a logarithmic scale versus the time with a lower limit detection of 2 log 10 CFU/ml.…”

New Treatment Options against Gram-negative Organisms

“…Similar to cefotaxime in single-step experiments, in multistep procedures it selected ESBL variants of TEM [36]. Another study showed that ceftaroline was synergistic with the β-lactamase inhibitor, tazobactam, (up to 500-fold) against MDR Gram-negative pathogens such as ESBL-producing E. coli and K. pneumoniae [37]. Despite being active against resistant Gram-positive bacteria, ceftaroline was less active than currently used antimicrobial agents against Gram-negatives.…”