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JAC Advance Access published online on December 12, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm457
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Potential synergy activity of the novel ceragenin, CSA-13, against clinical isolates of Pseudomonas aeruginosa, including multidrug-resistant P. aeruginosa

Judy N. Chin1, Ronald N. Jones2, Helio S. Sader2, Paul B. Savage3 and Michael J. Rybak1,*

1 Anti-infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA 2 JMI Laboratories, North Liberty, IA, USA 3 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA

* Corresponding author. Tel: +1-313-577-4376; Fax: +1-313-577-8915; E-mail: m.rybak{at}wayne.edu

Received 15 August 2007; returned 23 September 2007; revised 23 October 2007; accepted 30 October 2007


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Objectives: Previous data from our research had shown that the novel ceragenin, CSA-13, demonstrated concentration-dependent bactericidal activity against glycopeptide-resistant Staphylococcus aureus. However, it is unknown whether CSA-13 demonstrates a similar property against Pseudomonas aeruginosa. We evaluated CSA-13 antipseudomonal activity compared with cefepime, meropenem, piperacillin/tazobactam, tobramycin and ciprofloxacin by susceptibility testing as well as in combination with cefepime, tobramycin and ciprofloxacin.

Methods: Fifty clinical isolates of P. aeruginosa were analysed by reference broth microdilution methods. Four strains with various susceptibilities were evaluated by time-killing curve (TKC) analysis at 0.5x, 1x, 2x and 4x MIC using an initial inoculum of 106 cfu/mL. For synergy testing, TKC analysis of CSA-13 alone and in combination with cefepime, tobramycin and ciprofloxacin at 0.5x MIC was performed.

Results: CSA-13 MIC50 and MBC50 were 16 and 16 mg/L, respectively. TKC analysis demonstrated concentration-dependent activity, with CSA-13 at 4x MIC achieving earliest kill at 1 h (99.9%, detection limit). Combination TKC analysis demonstrated synergy or additive effect with cefepime and ciprofloxacin, in some cases achieving early synergy. The addition of tobramycin to CSA-13 resulted in no difference in kill for two strains.

Conclusions: CSA-13 showed concentration-dependent activity against clinical isolates of P. aeruginosa, including multidrug-resistant P. aeruginosa. The addition of cefepime or ciprofloxacin to CSA-13 enhanced bacterial kill, achieving early synergy.

Key Words: Gram-negative , cationic steroid antimicrobial , resistance


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The emergence of multidrug resistance in Pseudomonas aeruginosa and other Gram-negative pathogens is concerning and underscores the need for more therapeutic options and alternative agents. Reported rates of multidrug-resistant (MDR) P. aeruginosa have varied from 0.6% to as high as 49% depending on geographic location, study interval and type of surveillance study with their respective definitions.1–6 Infections with MDR P. aeruginosa are associated with considerable morbidity and mortality. Some studies have reported increased length of hospital stay and a mortality rate as high as 31.1% with MDR P. aeruginosa infections.7–9

This advent of MDR, especially among Gram-negative pathogens, has coincided with a renewed interest in the development of novel antimicrobial agents. The drive to produce newer agents targeting novel sites that may circumvent resistance is critical to long-term control of bacterial infection. One frequently studied target is the bacterial membrane. This is an appealing target given that most structural elements are conserved and resistance to membrane-targeting antibiotics would require major changes in the membrane structure, which may influence the permeability barrier.10 Many agents that target the bacterial membrane are cationic, facially amphiphilic molecules including endogenous antimicrobial peptides. Unlike typical amphiphilic compounds, facially amphiphilic molecules display separate hydrophilic and hydrophobic faces. Examples of facially amphiphilic antimicrobial peptides include the magainins and the human antimicrobial peptide LL37. Most antimicrobial peptides display broad-spectrum antibacterial activity and target the bacterial membrane. However, many antimicrobial peptides are difficult to synthesize and purify due to their complexity and size.11 In addition, antimicrobial peptides can be substrates for proteases, which limit their in vivo half-lives.

Recently, facially amphiphilic compounds designed to mimic the activities of antimicrobial peptides have been generated from a steroid scaffold. This non-peptide-based approach has yielded a class of compounds termed ceragenins with antibacterial activity comparable to that of antimicrobial peptides.12–14 Given that the amphiphilic properties of ceragenins and antimicrobial peptides are similar, it has been postulated that these agents share a mechanism of action including depolarization of bacterial membranes.15 As a consequence of the bacterial membrane activity of ceragenins, they effectively permeabilize the outer membranes of Gram-negative bacteria, and thus make these organisms susceptible to hydrophobic antimicrobials.16,17

Many of the ceragenins reported in the literature and at recent scientific meetings display broad-spectrum antibacterial activity. Some of these agents such as CSA-13 are bactericidal at low concentrations with similar MIC and MBC values. Previous data from our research have shown that the novel ceragenin, CSA-13, is more potent than CSA-8 and demonstrates concentration-dependent activity against glycopeptide-resistant Staphylococcus aureus.18 MIC testing against common Gram-negative aerobic and facultative bacilli, strict anaerobes such as Propionibacterium acnes and Clostridium perfringens as well as MDR S. aureus has demonstrated that CSA-13 possesses a broad spectrum of activity.19,20

To better understand the antibacterial activity of CSA-13 against Gram-negative bacteria, we evaluated CSA-13 against clinical isolates of P. aeruginosa, including MDR-P. aeruginosa. We also examined CSA-13 for concentration-dependent activity and potential synergy in combination with various antimicrobials.


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Bacterial strains

Fifty clinical isolates of P. aeruginosa, including MDR P. aeruginosa from the clinical collections of JMI Laboratories (North Liberty, IA, USA) and the Anti-Infective Research Laboratory, Detroit, MI, USA, were obtained for susceptibility testing. All isolates were obtained from various sources (blood, respiratory, wound and urine cultures). The clinical isolates from the Anti-Infective Research Laboratory were obtained in 1999–2000. Clinical isolates from JMI Laboratories were obtained between the years 2001–06. Four strains with differing susceptibilities were then randomly selected for time–kill analysis to test for concentration-dependent activity and for synergy (Table 1).


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  		Table 1. Reference susceptibility results (MICs in mg/L) of four clinical isolates of P. aeruginosa used in time–kill curve analysis [strains 316, 711 and 727 were obtained from the clinical collection of JMI Laboratories and strain R1130 was obtained from the Anti-Infective Research Laboratory (Wayne State University)]

 
Antimicrobial agents

CSA-13 was synthesized and provided by one of the authors (P. B. S.). CSA-13 was synthesized from a cholic acid scaffolding technique as previously described.12–14 Piperacillin (Wyeth Pharmaceuticals, Inc., Pearl River, NY, USA), meropenem (AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA) and cefepime (Elan Pharmaceuticals, Inc., San Diego, CA, USA) were commercially purchased. Ciprofloxacin, tobramycin and tazobactam (analytical grade) were obtained from Sigma-Aldrich Co. (St Louis, MO, USA).

Medium

Mueller–Hinton broth (MHB; Difco Laboratories, Detroit, MI, USA) supplemented with magnesium (12.5 mg/L total concentration) and calcium (25 mg/L total concentration) (SMHB) was used for all microdilution susceptibility testing and time–kill analysis. Mueller–Hinton agar (MHA; Difco Laboratories, San Jose, CA, USA) was used for growth and to quantify colony counts.

Susceptibility testing

MICs as well as MBCs were determined by utilizing standardized broth microdilution techniques with a starting inoculum of 5 x 105 cfu/mL according to CLSI guidelines and incubated for 24 h at 35°C.21 MICs were determined in duplicate, with concentrations ranging up to 256 mg/L for meropenem, cefepime, ciprofloxacin, piperacillin/tazobactam and CSA-13; and up to 32 mg/L for tobramycin.

Time–kill curve analysis

All time–kill experiments were performed in triplicate with an initial inoculum of 106 cfu/mL. To evaluate concentration-dependent activity, four clinical strains were exposed to CSA-13 at 0.5x, 1x, 2x and 4x the MIC. To evaluate for synergy, the same strains were exposed to CSA-13 alone and in combination with tobramycin, cefepime and ciprofloxacin at 0.5x the MIC. Aliquots (0.1 mL) were removed from cultures at 0, 1, 4, 8 and 24 h and serially diluted in cold 0.9% sodium chloride. Synergy, additive effect, antagonism and indifference were defined as >2 log kill, <2 but >1 log kill, >1 log growth and ±1 log kill, respectively. Bacterial counts were determined by spiral plating appropriate dilutions using an automatic spiral plater (WASP; DW Scientific, West Yorkshire, UK) and by counting colonies using the protocol colony counter (Synoptics Limited, Frederick, MD, USA). The lower limit of detection for colony count was 2 log10 cfu/mL. Time–kill curves were constructed by plotting mean colony counts (log10 cfu/mL) versus time. To eliminate antimicrobial carryover, all samples were either diluted sufficiently prior to plating or subjected to vacuum filtration with 0.9% sodium chloride if close to the MIC post-dilution.


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Susceptibility

Susceptibility testing of the clinical isolates (n = 50) demonstrated that the MIC50 (range) and MBC50 (range) for CSA-13 were (mg/L) 16 (1–32) and 16 (2–32) (Table 2). Twenty-two clinical isolates, some MDR, had MIC50 (range) values of meropenem, cefepime, ciprofloxacin, tobramycin and piperacillin/tazobactam (mg/L) of 128 (4 to >256), 256 (4 to >256), 16 (≤0.03–64), 64 (4 to >256) and ≥32 (0.125 to >32), respectively. Of those 22 strains, 17 were meropenem-resistant (MIC50 256 mg/L, range 16 to ≥256 mg/L). In addition, the MIC50 for CSA-13 for that subset population was 8 mg/L, comparably lower than the other antimicrobial agents. Overall, the MIC50/MBC50 ratio of CSA-13 for all 50 strains was 1, suggesting that the bactericidal activity is close to the inhibitory concentration.


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  		Table 2.. Susceptibility results of CSA-13 and comparator antimicrobial agents (MIC and MBC values with ranges, mg/L) against 50 clinical isolates of P. aeruginosa

 
Concentration-dependent bactericidal killing

Time–kill analysis of all four strains demonstrated concentration-dependent activity. Time to 99.9% kill (detection limit) occurred by 1 h for three strains and by 4 h for one strain when the concentration tested was 4x the MIC (Figure 1). At 1x and 2x the MIC, time to achieve 99.9% kill was by 24 and 8 h, respectively. Reduction in bacterial growth was not detected with the subinhibitory concentration of 0.5x the MIC for two strains. Instead, regrowth occurred by 4 h in those strains.


Figure 1
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  		Figure 1. Time–kill curve of CSA-13 activity against (a) 727, (b) 316, (c) 711 and (d) R1130 at 0.5x (filled circles), 1x (filled triangles, inverted), 2x (filled squares) and 4x (filled triangles) the MIC over a 24 h period. Limit of detection is 2 log10 cfu/mL. GC (filled diamonds) denotes growth control.

 
Combination testing

The addition of cefepime and ciprofloxacin to CSA-13 demonstrated enhanced activity with the novel ceragenin. Time–kill analysis demonstrated additive effect at 24 h in two strains (711 and R1130), synergy in strain 727 and indifference in strain 316 when cefepime was combined with CSA-13. However, early synergy was detected at 4–8 h with this combination (average log10 cfu/mL reduction of –2.32 ± 0.18, Figure 2a). The addition of ciprofloxacin to CSA-13 demonstrated synergy at 24 h (–3.31 ± 1.21, Figure 2b) in three strains (316, 711 and R1130), achieving early synergy at 4–8 h (–2.78 ± 0.69) and even earlier additive effect at 1–4 h (–1.72 ± 0.34, Figure 2c). Time–kill analysis showed no improvement in kill at 24 h (0.51 ± 0.56) for two of the four strains (R1130 and 316) when tested with CSA-13 in combination with tobramycin (Figure 2d). However, antagonism was detected at 24 h (+1.41 ± 0.31) in one strain (727), whereas in another strain (711), synergy was detected at 24 h (–2.06 ± 0.52).


Figure 2
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  		Figure 2. Time–kill results showing: (a) early synergy with cefepime (CPM) at 8 h (open circles, CSA-13 + CPM); (b) synergy with ciprofloxacin (CIP) at 24 h (open circles, CSA-13 + CIP); (c) early additive effect at 1 h with CIP (open circles, CSA-13 + CIP); and (d) indifference with tobramycin (TOB) combined with CSA-13 (open circles, CSA-13 + TOB). Limit of detection is 2 log10 cfu/mL. GC (filled diamonds) denotes growth control.

 

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Ceragenins are unique, small molecular weight compounds that have potent bactericidal activity against both Gram-negative and -positive bacteria. Previous data have suggested potent activity of CSA-13 against Gram-positive pathogens such as methicillin-resistant S. aureus and glycopeptide-intermediate and -resistant S. aureus. However, ceragenin data on Gram-negative organisms are limited. Although a collection of Gram-negative pathogens including Acinetobacter spp., Escherichia coli and Klebsiella pneumoniae were evaluated elsewhere, the number of organisms tested for susceptibility for each species was 10. Here, we report an MIC50 of 16 mg/L for 50 P. aeruginosa strains, and an MIC50 of 8 mg/L for a subset of carbapenem-resistant isolates. This is similar to previous data as reported by Savage who observed an MIC50 of 8 mg/L in two separate small studies.19,20 Indeed, the CSA-13 antimicrobial activity is lower in this population of Gram-negative pathogens compared with results previously reported on Gram-positive organisms. This could be attributed to a high content of phosphatidylethanolamine and may inhibit CSA-13 from inducing leakage of aqueous contents from phosphatidylethanolamine-rich liposomes.22

Our study also showed that CSA-13 has an MIC50/MBC50 ratio of 1, suggesting that the bactericidal activity is close to the inhibitory concentration. Indeed, varying CSA-13 concentrations at, below and above the MIC demonstrated concentration-dependent antimicrobial activity, similar to previous published data on glycopeptide-resistant S. aureus. These findings suggest that CSA-13 exhibits concentration-dependent activity against both Gram-positive and -negative organisms. In addition, CSA-13 can be used to enhance other antimicrobial agents against P. aeruginosa. Combination time–kill studies against four clinical strains, three of which were meropenem intermediate to resistant, demonstrated synergy or additive effect with the addition of cefepime or ciprofloxacin, achieving early synergy or additive effect at 4–8 and 1–4 h, respectively. However, we were only able to demonstrate synergy with the combination of tobramycin and CSA-13 in one strain (711). Evaluating synergy in a time–kill assay would be technically difficult in this case given that the tobramycin MICs for three of the strains were ≤1 mg/L, with the exception of strain 711 which has an MIC of 4. The addition of CSA-13 may have enhanced the bacterial activity of tobramycin against this relatively resistant strain and thus perhaps explains the observed synergy. In addition, tobramycin has been used as a synergistic agent against Pseudomonas in vitro and enhanced activity is usually best observed in β-lactam combinations.23,24 It is possible that two synergistic agents may counteract each other. However, more studies with a greater range of clinical isolates would be necessary to establish that theory.

Previous preliminary data have studied the potential synergy of a similar ceragenin, CSA-8 (with less activity than CSA-13) in combination with rifampicin against tobramycin-resistant P. aeruginosa.25 The authors concluded that CSA-8 and CSA-13 can permeabilize the outer membrane of Gram-negative organisms thus resulting in sensitization to antimicrobials. This mechanism may explain the synergy that we observed with cefepime and ciprofloxacin in combination with CSA-13.

Our findings support CSA-13 as a potential agent against Gram-negative organisms. CSA-13 demonstrates synergy with cefepime and ciprofloxacin against P. aeruginosa. Further studies with other compounds in combination with CSA-13 as well as on other Gram-negative pathogens such as Acinetobacter spp., E. coli and K. pneumoniae should also be explored.


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No specific funding was received for this study.


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M. J. R. serves on an advisory board for Ceragenix Pharmaceuticals. P. B. S. serves as a consultant for Ceragenix Pharmaceuticals. Ceragenins have been licensed by Brigham Young University to Ceragenix Pharmaceuticals. J. N. C., R. N. J. and H. S. S.: none to declare.


   Acknowledgements
 
A portion of this work was presented at the Forty-seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2007 (Abstract F1-1655).


   References
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1 . Crespo MP, Woodford N, Sinclair A, et al. Outbreak of carbapenem-resistant Pseudomonas aeruginosa producing VIM-8, a novel metallo-β-lactamase, in a tertiary care center in Cali, Colombia. J Clin Microbiol (2004) 42:5094–101.[Abstract/Free Full Text]

2 . Kirby JT, Fritsche TR, Jones RN. Influence of patient age on the frequency of occurrence and antimicrobial resistance patterns of isolates from hematology/oncology patients: report from the Chemotherapy Alliance for Neutropenics and the Control of Emerging Resistance Program (North America). Diagn Microbiol Infect Dis. (2006) 56:75–82.

3 . Meyer E, Schwab F, Gastmeier P, et al. Surveillance of antimicrobial use and antimicrobial resistance in German intensive care units (SARI): a summary of the data from 2001 through 2004. Infection (2006) 34:303–9.[CrossRef][Web of Science][Medline]

4 . Nouér SA, Nucci M, de-Oliveira MP, et al. Risk factors for acquisition of multidrug-resistant Pseudomonas aeruginosa producing SPM metallo-β-lactamase. Antimicrob Agents Chemother (2005) 49:3663–7.[Abstract/Free Full Text]

5 . Sader HS, Castanheira M, Mendes RE, et al. Dissemination and diversity of metallo-β-lactamases in Latin America: report from the SENTRY Antimicrobial Surveillance Program. Int J Antimicrob Agents (2005) 25:57–61.[CrossRef][Web of Science][Medline]

6 . Yamaguchi K, Mathai D, Biedenbach DJ, et al. Evaluation of the in vitro activity of six broad-spectrum β-lactam antimicrobial agents tested against over 2000 clinical isolates from 22 medical centers in Japan. Diagn Microbiol Infect Dis (1999) 34:123–34.[CrossRef][Web of Science][Medline]

7 . Aloush V, Navon-Venezia S, Seigman-Igra Y, et al. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob Agents Chemother (2006) 50:43–8.[Abstract/Free Full Text]

8 . Giamarellos-Bourboulis EJ, Papadimitriou E, Galanakis N, et al. Multidrug resistance to antimicrobials as a predominant factor influencing patient survival. Int J Antimicrob Agents (2006) 27:476–81.[CrossRef][Web of Science][Medline]

9 . Lautenbach E, Weiner MG, Nachamkin I, et al. Imipenem resistance among Pseudomonas aeruginosa isolates: risk factors for infection and impact of resistance on clinical and economic outcomes. Infect Control Hosp Epidemiol (2006) 27:893–900.[CrossRef][Web of Science][Medline]

10 . Savage PB, Li C, Taotafa U, et al. Antibacterial properties of cationic steroid antibiotics: a minireview. FEMS Microbiol Lett (2002) 217:1–7.[CrossRef][Web of Science][Medline]

11 . Van 't Hof W, Veerman EC, Helmerhorst EJ, et al. Antimicrobial peptides: properties and applicability. Biol Chem (2001) 382:597–619.[CrossRef][Web of Science][Medline]

12 . Guan Q, Schmidt EJ, Boswell SR, et al. Preparation and characterization of cholic acid-derived antimicrobial agents with controlled stabilities. Org Lett (2000) 2:2837–40.[CrossRef][Web of Science][Medline]

13 . Li C, Budge LP, Driscoll CD, et al. Incremental conversion of outer-membrane permeabilizers into potent antibiotics for Gram-negative bacteria. J Am Chem Soc (1999) 121:931–40.[CrossRef][Web of Science]

14 . Li C, Peters AS, Meredith EL, et al. Design and synthesis of potent sensitizers of Gram-negative bacteria based on a cholic acid scaffolding. J Am Chem Soc (1998) 120:2961–2.[CrossRef][Web of Science]

15 . Ding B, Guan Q, Walsh JP, et al. Correlation of the antibacterial activities of cationic peptide antibiotics and cationic steroid antibiotics. J Med Chem (2002) 45:663–9.[CrossRef][Web of Science][Medline]

16 . Kikuchi K, Bernard EM, Sadownik A, et al. Antimicrobial activities of squalamine mimics. Antimicrob Agents Chemother (1997) 41:1433–8.[Abstract]

17 . Li C, Lewis MR, Gilbert AB, et al. Antimicrobial activities of amine- and guanidine-functionalized cholic acid derivatives. Antimicrob Agents Chemother (1999) 43:1347–51.[Abstract/Free Full Text]

18 . Chin JN, Rybak MJ, Cheung CM, et al. Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus. Antimicrob Agents Chemother (2007) 51:1268–73.[Abstract/Free Full Text]

19 . Savage PB, Chambers HF, Genberg C, et al. Activity of a novel cationic steroid antimicrobial (CSA-13) targeting aerobic and facultative Gram-negative bacilli, Gram-positive anaerobes and select agent surrogate strains. Abstracts of the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005. Washington, DC, USA: American Society for Microbiology. Abstract F-1231.

20 . Savage PB, Chambers HF, Genberg C, et al. Activity of a novel cationic steroid antimicrobial (CSA-13) against Staphylococcus aureus and bacterial species associated with infections in cystic fibrosis patients. Abstracts of the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, USA, 2005. Washington, DC, USA: American Society for Microbiology. Abstract F-1232.

21 . Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Sixteenth Informational Supplement CLSI document M7-A7 (2006) Wayne, PA, USA: CLSI.

22 . Epand RF, Savage PB, Epand RM. Bacterial lipid composition and the antimicrobial efficacy of cationic steroid compounds (ceragenins). Biochim Biophys Acta (2007) 1768:2500–9.[Medline]

23 . Owens RC Jr, Banevicius MA, Nicolau DP, et al. In vitro synergistic activities of tobramycin and selected β-lactams against 75 gram-negative clinical isolates. Antimicrob Agents Chemother (1997) 41:2586–8.[Abstract]

24 . Tam VH, Schilling AN, Lewis RE, et al. Novel approach to characterization of combined pharmacodynamic effects of antimicrobial agents. Antimicrob Agents Chemother (2004) 48:4315–21.[Abstract/Free Full Text]

25 . Savage PB, Orsak T, Burns JL. A cationic steroid antibiotic active against highly tobramycin-resistant Pseudomonas aeruginosa. Abstracts of the 2005 Annual Conference on Antimicrobial Resistance, Bethesda, MD, 2005. Bethesda, MD, USA: National Foundation for Infectious Diseases. Abstract P12.


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