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We describe the activity of a novel cephalosporin, CXA-101 (FR26 4205), against a panel of highly resistant Pseudomonas aeruginosa isolates collected from U.S. hospitals. CXA-101 demonstrated increased potency against this population of resistant isolates, with activity that is 4- to 10-fold higher than that of comparator agents in each phenotypic category. The addition of tazobactam did not improve its activity. CXA-101 appears to be a promising addition to the category of antipseudomonal β-lactams.
Pseudomonas aeruginosa is a nosocomial pathogen commonly implicated in patients with severe underlying medical conditions (1, 9). It demonstrates considerable intrinsic resistance through mechanisms such as efflux pumps, decreased outer membrane permeability, and chromosomal AmpC β-lactamases and can also acquire additional mechanisms. These various and extensive mechanisms often lead to cross-resistance with other antimicrobial classes (12). Recent data have shown a consistent rise in the number of isolates considered multidrug resistant (MDR) (resistant to three or more classes of antipseudomonal antimicrobial agents), rendering many currently available antipseudomonal antimicrobials inactive (3, 7).
Ceftazidime, which has been considered by many as the cephalosporin demonstrating the greatest antipseudomonal activity, unfortunately shows very limited activity against the ever growing numbers of P. aeruginosa strains showing partial or full derepression of AmpC β-lactamase (8, 13). CXA-101 is a novel parenteral cephalosporin that shares a spectrum of activity similar to that of ceftazidime. It has increased stability against AmpC β-lactamase-producing isolates and is less affected, and in some instances unaffected, by porin deficiency or efflux mechanisms through enhanced binding to penicillin-binding protein 3 (13). In this study, the potency of CXA-101, alone and in combination with a fixed concentration of tazobactam, was tested against a panel of highly resistant clinical P. aeruginosa isolates.
Nonduplicate, nonurine, drug-resistant P. aeruginosa isolates collected from 40 hospitals distributed throughout the United States over the period of October 2005 to March 2008 were examined. MICs were determined using the reference Clinical and Laboratory Standards Institute broth microdilution method (2). CXA-101 was tested alone and in combination with a fixed 4-μg/ml concentration of tazobactam. MICs for the antimicrobials imipenem, meropenem, piperacillin-tazobactam, cefepime, ceftazidime, ciprofloxacin, levofloxacin, and tobramycin were also determined by broth microdilution. P. aeruginosa ATCC 27853 was used as the quality control, and the ranges for CXA-101 and for CXA-101 plus 4 μg/ml tazobactam were 0.25 to 1 μg/ml and 0.25 to 1 μg/ml, respectively.
A total of 408 P. aeruginosa isolates were selected from a population of 1,044 isolates collected from the 40 hospitals (4). The isolates were selected to represent the following resistance phenotypes: imipenem resistance (MIC ≥ 16 μg/ml), ceftazidime resistance (MIC ≥ 32 μg/ml), MDR (resistance to three classes of antimicrobials), piperacillin-tazobactam (MIC ≥ 32 μg/ml), and tobramycin resistance (MIC ≥ 16 μg/ml). Table Table11 shows the characteristics of the patients from whom the selected isolates were obtained. The majority of isolates were collected from patients of >51 years of age, 47% of isolates were collected from patients in the intensive care unit, and the respiratory tract was the most common collection site.
The MICs for CXA-101 with and without tazobactam were very similar, leading to the conclusion that the addition of tazobactam does not improve the potency of CXA-101 against this battery of isolates (Table (Table2).2). CXA-101 already displays excellent activity against AmpC β-lactamase-overproducing P. aeruginosa, and therefore, the addition of tazobactam does little to enhance the potency (8, 11, 12). Table Table22 displays the enhanced potency of CXA-101 relative to those of the comparator agents as assessed by the MIC range, modal MIC, and MIC50 and MIC90 values. The MIC distribution for each agent tested is provided in Table Table3.3. When examining the group of isolates with the MDR phenotype, the majority (63%) had an MIC to CXA-101 of ≤4 μg/ml. For isolates that were imipenem resistant, the MIC90 was 8 μg/ml for CXA-101, fourfold more active than imipenem, and CXA-101 inhibited 84% of these isolates at a concentration of ≤4 μg/ml. In isolates considered resistant to ceftazidime, the MIC90 values for CXA-101 and ceftazidime were 16 μg/ml and 256 μg/ml, respectively, showing a 16-fold increase in activity with CXA-101. A large majority of isolates had a CXA-101 MIC of ≤4 μg/ml (74%), while the corresponding ceftazidime MIC was ≥32 μg/ml. Isolates with a piperacillin-tazobactam MIC of ≥32 μg/ml demonstrated a CXA-101 MIC90 of 8 μg/ml, while the MIC90 for piperacillin-tazobactam was 256 μg/ml. For this phenotype, CXA-101 was 32-fold more active than piperacillin-tazobactam. Isolates with a tobramycin MIC of ≥16 μg/ml (tobramycin resistant) showed a CXA-101 MIC90 of 64 μg/ml, fourfold more active than tobramycin. Over 70% of isolates with this resistance phenotype had an MIC to CXA-101 of ≤4 μg/ml.
In this study, the antibacterial potency of CXA-101 was evaluated against a highly resistant panel of clinically derived P. aeruginosa isolates. Results indicate that CXA-101 possesses superior activity with MIC50 and MIC90 values that are noticeably lower than those of ceftazidime, imipenem, piperacillin-tazobactam, and tobramycin. When focused specifically on ceftazidime, CXA-101 was 16-fold more active. Although specific resistance mechanisms were not elucidated in our ceftazidime-resistant isolates, AmpC β-lactamases are known to be responsible for reduced susceptibility to this agent (10). Thus, the enhanced activity of CXA-101 for these isolates may be due to its stability against AmpC β-lactamases (11).
Among the isolates evaluated in this study, multidrug resistance was seen in 23%, a value comparable to the proportion seen in a survey done between 1999 and 2002 (5). Previous studies have indicated that combinations of efflux, membrane impermeability, and AmpC β-lactamases or carbapenemases render P. aeruginosa an MDR pathogen (8). When looking at our MDR isolates, CXA-101 showed more activity than did imipenem, a commonly advocated agent in the setting of MDR P. aeruginosa. Although specific resistance mechanisms were not elucidated in our organism population, this increased activity may be due to CXA-101's decreased susceptibility to MDR mechanisms, such as porin channel changes and efflux pumps.
In the context of the isolates tested over the range of phenotypic profiles, CXA-101 demonstrates enhanced activity, with the majority of isolates having an MIC to CXA-101 of ≤4 μg/ml. This enhanced activity enforces the lack of cross-resistance of CXA-101 with other antimicrobial agents (11). However, despite this enhanced activity, some isolates did show resistance to CXA-101 with <10% of isolates with MICs above 32 μg/ml. Resistance to CXA-101 has been shown to be due to the presence of extended-spectrum β-lactamases, such as PER, VEB, and OXA (6, 8). Since we did not determine the genotypic profiles of our organisms, it is entirely possible that these extended-spectrum β-lactamases are present in our test population.
Overall, our data show that CXA-101 retains excellent potency against a population of highly resistant P. aeruginosa isolates. Moreover, this agent displays improved activity compared to commonly used antipseudomonal agents, but most importantly, CXA-101 demonstrates enhanced activity compared to ceftazidime, previously considered the most active cephalosporin against P. aeruginosa. This novel cephalosporin could provide a much needed addition to the practitioner's dwindling armamentarium against P. aeruginosa.
This work was supported by a grant from Calixa Therapeutics Inc.
Additionally, we disclose that D.P.N. is a member of the scientific advisory board of the study sponsor.
Published ahead of print on 16 November 2009.