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Home , Cefalexin, Dalbavancin, Lipoglycopeptide, Oritavancin, Telavancin

REVIEWS

New antimicrobial agents for -resistant

Marin H Kollef

In bacterial and fungal , optimal outcomes are ABSTRACT obtained through the timely provision of adequate antimi- crobial coverage in an initial anti-infective treatment regi- In bacterial and fungal infections, optimal outcomes are men.Crit However, Care Resusc selecting ISSN: 1441-2772 appropriate 7 Decem- antimicrobial obtained through the timely provision of adequate regimensber 2009 to treat11 4 282-286 infections in the intensive care unit can be antimicrobial coverage in an initial anti-infective treatment ©Crit Care Resusc 2009 challengingwww.jficm.anzca.edu. because of au/aaccm/journal/publi-the expansion of resist- regimen. However, selecting appropriate antimicrobial ance.cations.htm Multidrug anti-infective regimens are typically needed regimens to treat infections in the intensive care unit is to adequatelyReviews cover the common important pathogens in challenging because of the expansion of antibiotic ICUs. The term “ESKAPE” has been coined for the group resistance. Multidrug anti-infective regimens are typically that causes most hospital-acquired infections able to needed to adequately cover common important pathogens “escape” our antibiotic arsenal in the United States: Entero- in ICUs. faecium, Staphylococcus aureus, Klebsiella pneumo- Here, we describe novel antibacterial agents in the late niae, Acinetobacter baumannii, aeruginosa, stages of clinical development that show potential for and Enterobacter spp. Their existence mandates the discov- treating methicillin-resistant Staphylococcus aureus (MRSA) ery of new antimicrobial agents. Here, we describe novel infections. antibacterial agents in the late stages of clinical develop- These include the fifth-generation , ment that show potential for treating methicillin-resistant ceftaroline and ; the glycopeptides, S. aureus (MRSA) infections. , , and ; and iclaprim.

Crit Care Resusc 2009; 11: 282–286 Ceftaroline is a fifth-generation pro- drug with activity against a broad range of gram-positive and Early-phase clinical trials established a dosing regimen for gram-negative bacteria. The active agent, ceftaroline, is ceftaroline of 600 mg intravenously (IV) every 12 hours (as a active against MRSA and has a minimum inhibitory concen- 1-hour infusion) as the preferred regimen for future study. μ tration for 90% of organisms (MIC90) of 1–2 g/mL because Less than 20% of the drug is protein bound in serum, and it of its enhanced binding to -binding protein 2a has a volume of distribution similar to the extracellular fluid (PBP2a), as compared with other β-lactam .1 The volume at around 16–17 L. Ceftaroline is primarily elimi- drug is also active against penicillin- and cephalosporin- nated by renal , and multiple-dose pharmaco- resistant pneumoniae and β-haemolytic strep- kinetic studies have shown the half-life is around 2.5–3 tococci, and has variable activity against faeca- hours. It does exhibit an extended half-life or area under the lis but little or no activity against -resistant plasma concentration time curve under conditions of mild- Enterococcus faecium. Against relevant gram-negative path- to-moderate renal impairment, and would be expected to ogens, it has broad-spectrum activity similar to that of require dose adjustment in these populations. No data are . However, its MICs are generally higher than currently available on ceftaroline clearance in dialysis. Its those of against most non-fermenting gram-nega- potential for use in is supported by the finding tive bacteria and Enterobacteriaceae, and it is expected to be that lung tissue penetration in rabbits at the end of inactive against Pseudomonas spp. and Acinetobacter spp. ceftaroline infusion was 42% of serum concentrations.2 Ceftaroline appears to be a weak inducer of AmpC β- A phase II has compared ceftaroline (preferred lactamases, and, like other clinically available cephalosporins regimen for 7–14 days) with vancomycin (1 g IV every 12 (besides cefepime), is labile to AmpC and expected to be hours, with or without (1 g IV every 8 hours) for clinically ineffective against AmpC isolates. Like other the treatment of complicated skin and skin structure infec- advanced-generation cephalosporins, ceftaroline is not relia- tion (cSSSI).3 Clinical cure rates were similar for the ceftaro- bly active against strains of Enterobacteriaceae that produce line (96.7%) and standard therapy (88.9%) groups. Phase III extended spectrum β-lactamases (ESBLs). clinical trials for this indication are now complete, but data

282 Critical Care and Resuscitation • Volume 11 Number 4 • December 2009 REVIEWS had not been published at the time of writing. Perhaps diabetic foot and mixed bacterial cSSSI infections and more interesting for ICU practitioners, phase III trials are compared ceftobiprole (500 mg IV every 8 hours) with currently ongoing to compare 5–7 days of ceftaroline vancomycin (1 g IV every 12 hours) plus (1 g IV therapy with ceftriaxone (1 g IV daily) for treatment of every 8 hours) for 7–14 days. Clinical cure rates were also community-acquired pneumonia. similar for the ceftobiprole (90.5%) and standard therapy (90.2%) groups. Ceftobiprole (500 mg IV every 8 hours) was also compared with a combination of ceftazidime and Ceftobiprole for treatment of nosocomial pneumonia.7 Ceftobiprole medocaril is another fifth-generation cepha- Although the study showed ceftobiprole was non-inferior losporin pro-drug, with a broad spectrum of activity similar versus the combination regimen, it was unexpectedly asso- to that of ceftaroline. Like ceftaroline, ceftobiprole was ciated with lower cure rates in patients with ventilator- designed to maximise binding to PBP2a and yield potent associated pneumonia, particularly those younger than 45 μ 4 anti-MRSA activity, with an MIC90 of 2 g/mL. Ceftobiprole years and those with high creatinine clearance. is active against cephalosporin-resistant S. pneumoniae and -susceptible E. faecalis, but not E. faecium. Cefto- biprole has broader gram-negative activity than ceftaroline; Dalbavancin it appears to have a gram-negative spectrum of activity Dalbavancin is a currently under investiga- intermediate between that of ceftriaxone and cefepime, tion. It has a bacteriocidal similar to largely because of its greater stability to AmpC β-lactam- that of other glycopeptides in that it complexes with the D- ases than ceftriaxone and ceftaroline. Ceftobiprole also has alanyl-D- (D-Ala-D-Ala) terminal of and activity against P. aeruginosa, and MICs against this patho- inhibits transglycosylation and transpeptidation.8 Like teico- gen are generally similar to those of cefepime and ceftazi- planin, dalbavancin possesses a lipophilic side chain that dime. Activity against Acinetobacter spp. appears to be leads to both high protein-binding and an extended half- highly variable. As with other advanced-generation cepha- life, which allows once-weekly dosing. losporins, ceftobiprole is not reliably active against ESBL- Dalbavancin is more potent than vancomycin against producing bacteria. staphylococci, and is highly active against both methicillin-

The volume of distribution is similar to the extracellular susceptible S. aureus (MSSA) and MRSA, with MIC90 values fluid volume, at about 18 L, although this may be doubled of < 0.13 mg/L and 0.25 mg/L, respectively. Dalbavancin is in patients with ventilator-associated pneumonia. There are also active against vancomycin-intermediate S. aureus μ currently no data on the epithelial lining fluid penetration of (VISA), although MIC90 ranges are higher, at 1–2 g/mL. It ceftobiprole, but a pharmacokinetic study is ongoing to inhibits streptococci, including penicillin-resistant S. pneu- evaluate concentrations of ceftobiprole in bronchoalveolar moniae, and enterococci with the VanB or VanC phenotype, lavage fluid after IV infusion. The drug is 16% bound to but is not active against enterococci with the VanA pheno- plasma proteins, is primarily eliminated in the urine, and has type. a half-life of around 3–4 hours. Because of its extensive Dalbavancin is administered intravenously, and the most renal clearance, dose adjustments have been proposed for commonly used dose in clinical trials has been 1000 mg on patients with mild-to-moderate renal impairment. Ceftobi- Day 1, followed by 500 mg weekly thereafter. This dose prole appears to be removed effectively by some haemodi- achieves a maximum serum concentration of 312 μg/mL, alysis modalities. with mean serum concentrations > 35 μg/mL maintained for Results of early phase clinical trials and Monte Carlo a 7-day dosing period. The drug has a volume of distribu- simulations suggested two dosing regimens for ceftobip- tion of 0.11 L/kg and a half-life of 147–258 hours, support- role: 500 mg IV as a 1-hour infusion every 12 hours for ing once-weekly dosing. Only 40% is eliminated by the treatment of gram-positive infections, and 500 mg IV as a kidneys, with no apparent need for dose adjustments in the 2-hour infusion every 8 hours for empirical treatment of setting of either moderate renal or hepatic impairment. It mixed gram-positive and gram-negative infections. Two does not appear to interact with any of the P450 cyto- phase III clinical trials of ceftobiprole for cSSSI have been chromes and is not known to possess any clinically relevant completed.5,6 The first trial enrolled patients with suspected drug interactions. gram-positive and utilised a ceftobiprole regimen Clinical data for dalbavancin include phase II and III trials of 500 mg every 12 hours, compared with IV vancomycin in both uncomplicated and complicated SSSIs, and catheter- (1 g) every 12 hours for 7–14 days. Clinical cure rates were related bloodstream infections. Dalbavancin (1000 mg IV on similar for the ceftobiprole (93.3%) and vancomycin Day 1 followed by 500 mg IV on Day 8) was compared with (93.5%) groups. The second trial included patients with linezolid (600 mg twice daily for 14 days) in a randomised,

Critical Care and Resuscitation • Volume 11 Number 4 • December 2009 283 REVIEWS double-blind phase III trial for treatment of cSSSI.9 The met criteria for non-inferiority versus vancomycin plus overall success rates at the test-of-cure visit were similar for . Patients receiving either dose of oritavancin and linezolid, at 88.4% and 86.8%, respec- showed a shorter mean duration of therapy (5.3 or 5.7 tively (P not given). Dalbavancin was compared with β- days, respectively) than those in the vancomycin group lactams, clindamycin, vancomycin, and linezolid in other (11.9 days). A second cSSSI trial of a fixed oritavancin dose SSSI trials, and was shown to be at least non-inferior in of 200 mg IV daily versus vancomycin plus cefalexin found each.10 Another phase II study evaluated dalbavancin versus clinical cure rates of 78.6% for oritavancin and 76.2% for vancomycin for treatment of bloodstream infections, using vancomycin plus cefalexin (95% CI for difference, −3.4% to the weekly dalbavancin dosing regimen described above 7.8%). Again, the average duration of therapy was shorter versus vancomycin, 1 g twice daily for 7 days.11 Dalbavancin for oritavancin than for vancomycin plus cefalexin (5.3 v had a statistically higher overall success rate than vancomy- 10.9 days, P < 0.001). An additional study (SIMPLIFI), cin (87% versus 50%, P < 0.05). designed to assess novel oritavancin dosing regimens in the Dalbavancin provides coverage for both glycopeptide- treatment of cSSSI, compared oritavancin as a single large susceptible and resistant MRSA, but coverage of vancomy- dose, as a dose on Day 1 with an optional dose on Day 5, or cin-resistant enterococci (VRE) is limited. The drug has the as a dose of 200 mg once daily for 3–7 days.12 The study has convenience of once-weekly dosing, which should allow been completed, but results were not available at the time simplified regimens both in hospital and at home. of writing. Oritavancin has also showed equivalence to vancomycin or an active β-lactam for treatment of S. aureus septicaemia Oritavancin when administered at 5–10 mg/kg daily.13 Data evaluating Oritavancin, another investigational glycopeptide, contains oritavancin for treatment of meningitis and cardiac infec- novel structural modifications that allow it to dimerise and tions exist only in animal models. In these, oritavancin anchor itself in the bacterial membrane. These modifica- successfully treated meningitis caused by S. pneumoniae tions also confer an enhanced spectrum of activity over and endocarditis caused by MRSA and VRE. traditional glycopeptide antibiotics. Oritavancin has similar Oritavancin has been well tolerated in clinical trials, with in-vitro activity to vancomycin against staphylococci and is the most predominant adverse effects being headache, equipotent against both MSSA and MRSA. It also has , , sleep disorders, and injection-site reac- activity against VISA and vancomycin-resistant S. aureus tions. Elevated aminotransferase concentrations seen in (VRSA), but MICs are increased to 1 mg/L and 0.5 mg/L, early trials of oritavancin were not seen in either of the respectively. Oritavancin is active against enterococci, phase III clinical trials in patients with cSSSI. including VRE; however, MICs are significantly higher Oritavancin is highly active against both S. aureus and against VRE than against vancomycin-susceptible strains. Enterococcus spp., covering the most resistant strains of The drug is also active against both penicillin-susceptible both. However, clinical data are very limited, and it is and penicillin-resistant S. pneumoniae. unclear whether future studies are planned for more critical Oritavancin has been typically administered at a dose of infections. The potential for oritavancin to bind to pulmo- 1.5–3 mg/kg IV once daily, as well as at a flat dose of nary surfactant may significantly limit its utility for treating 200 mg daily. Despite being 90% bound to plasma proteins, pulmonary infections. The very high intracellular concentra- it is rapidly distributed to the tissues. However, its propen- tion profile will also need to be carefully assessed. At the sity for binding to pulmonary surfactant needs to be time of writing, oritavancin had not yet secured approval assessed, on the basis of an effect noted in a murine from the US Food and Drug Administration (FDA) because pneumonia model. About 60% of the administered dose of of lack of adequate and safety data. oritavancin is retained in the liver, but there is no evidence that it undergoes hepatic . In-vitro studies of cultured macrophages show intracellular levels up to 400 Telavancin times those seen in the serum, but the clinical significance Telavancin is an investigational glycopeptide derivative of of this is unknown. The drug is predominantly eliminated by vancomycin. Like oritavancin, telavancin has the ability to the kidneys, but renal clearance is very slow because of high anchor itself in the bacterial membrane, disrupting poly- protein binding and extensive tissue distribution, with only merisation and cross-linking of peptidoglycan. Telavancin 5% unchanged drug recovered at 7 days after a dose. also interferes with the normal function of the bacterial Clinical data for oritavancin are limited. Two phase III membrane, decreasing its ability to act as a barrier. This dual trials evaluating oritavancin for cSSSI have been completed. mechanism helps explain telavancin’s high potency and In the first study, oritavancin (1.5 mg/kg or 3 mg/kg daily) rapid bactericidal activity.14

284 Critical Care and Resuscitation • Volume 11 Number 4 • December 2009 REVIEWS

Telavancin is bactericidal against staphylococci, including teria, exerting bactericidal effects.16 Iclaprim is active against

MRSA, VISA, and VRSA, with MIC90 values of 0.25–1 mg/L, MSSA, community- and nosocomial-MRSA, VISA, VRSA, 0.5–2 mg/L, and 2–4 mg/L, respectively. Telavancin, like groups A and B streptococci, and pneumococci, and is oritavancin, is potent against both penicillin-susceptible and variably active against enterococci. Iclaprim appears to have penicillin-resistant strains of S. pneumoniae. It is also active gram-negative activity similar to that of trimethoprim, against vancomycin-susceptible strains of E. faecium and E. including activity against E. coli, K. pneumoniae, Entero- faecalis, but MICs are increased for vancomycin-resistant bacter spp., Citrobacter freundii, and Proteus vulgaris. strains of both species. Iclaprim also appears to have activity against the atypical The usual dose of telavancin is 7.5–10 mg/kg/day. The respiratory pathogens Legionella and Chlamydia pneumo- drug is highly protein-bound and has a volume of distribu- niae, but is not active against P. aeruginosa or anaerobes. tion of 0.1 L/kg. It has a half-life of 7–9 hours, is predomi- Although iclaprim appeared to be rendered bacteriostatic nantly eliminated by the kidneys, and will likely require dose against a wild-type isolate of S. aureus in the presence of adjustments in patients with renal impairment. increasing concentrations of thymidine in vitro, the effect of Of the investigational glycopeptides and lipoglycopep- thymidine release from bacteria and infected host tissues on tides, telavancin has the richest set of clinical data support- its activity in vivo is unknown. ing its use. A set of two identical phase III trials, ATLAS I and Iclaprim achieves a maximum serum concentration of ATLAS II, compared telavancin (10 mg/kg per day) with 0.85 μg/mL after a dose of 0.8 mg/kg by intravenous infu- vancomycin (1 g every 12 hours) for treating cSSSI.15 They sion over 30 minutes and appears to have linear pharma- found telavancin to be non-inferior to vancomycin, with a cokinetics. It is 93% plasma-protein bound, has a volume of combined clinical cure rate in patients with MRSA infection distribution of 1.15 L/kg, and achieves concentrations in of 90.6% (telavancin) versus 86.4% (vancomycin, P = 0.06). epithelial lining fluid that exceed plasma concentrations by Telavancin has also been studied in hospital-acquired pneu- a factor of 2.7–12.17 The drug is primarily metabolised to monia. ATTAIN 1 and ATTAIN 2 were both randomised, phase I metabolites, and subsequently to glucuronide double-blind trials with a combined population of 1503 metabolites. Its half-life is 2.5–4.1 hours. Clearance is patients, of whom 464 had documented MRSA infection. reduced in moderate hepatic insufficiency to the extent that Patients were randomly allocated to receive telavancin dosage adjustments appear warranted, but is unaffected by (10 mg/kg IV once daily) or vancomycin (1 g IV every 12 renal insufficiency. hours). Telavancin was shown to be non-inferior to vanco- A drug application for iclaprim as treatment of cSSSI was mycin. In addition, preliminary results showed that clinical submitted to the US FDA in 2008,16 on the basis of cure rates were 82% for telavancin and 74% for vancomy- combined results from two similar randomised, multicentre, cin in patients infected with MRSA (P, not significant). Also double-blind phase III trials versus linezolid (ASSIST-1 and of interest was the finding that a subset of patients with ASSIST-2).18 In revised analyses by FDA reviewers, iclaprim ventilator-associated pneumonia had a cure rate of 80% for (0.8 mg/kg every 12 hours) failed to achieve non-inferiority telavancin and 68% for vancomycin (P not given). versus linezolid for treatment of cSSSI, and was potentially Telavancin has been well tolerated in clinical trials, with inferior to linezolid in ASSIST-1. These findings cast doubt the most common adverse effects being taste disturbances, on the feasibility of treating cSSSI with iclaprim. However, at headache and dizziness. Other potentially serious adverse the time of writing, a clinical trial comparing iclaprim with effects include raised serum creatinine concentration, vancomycin for treatment of hospital-acquired, ventilator- microalbuminuria, and decreased platelet count, each of associated or health care-associated pneumonia was which occurred at rates similar to those for comparator recruiting.19 agents. Of potential concern is an apparent risk of low birth Overall, iclaprim appears to be fairly well tolerated, but it weight and limb defects in pregnant animals receiving has been associated with gastrointestinal disturbances, telavancin. The FDA has recommended that this drug including elevations in hepatic aminotransferase levels, should be used in pregnant women only when the benefits anaemia, pyrexia, headache, and pruritis. Iclaprim also outweigh the risk. prolongs the QTc interval, but was not associated with any known cases of torsades de pointes or other ventricular arrhythmias in phase III studies. The drug may inhibit Iclaprim CYP3A4 and P-glycoprotein, but the clinical significance of Iclaprim (formerly AR-100 or Ro 48-2622) is an investiga- any potential resultant drug interactions is uncertain. tional IV diaminopyrimidine antibacterial agent that, like The possible role of iclaprim in treating infections in the trimethoprim, selectively inhibits the dihydrofolate reduct- ICU is unclear. Recent FDA advisory committee deliberations ase enzyme of both gram-positive and gram-negative bac- suggest that it may not have a role for cSSSI. However, at

Critical Care and Resuscitation • Volume 11 Number 4 • December 2009 285 REVIEWS the time of writing, it was being studied for hospital- crobial Agents and Chemotherapy. Washington, DC; 2008: abstract acquired, ventilator-associated or health care-associated K-486. pneumonia; pending results, it may prove useful as a 8 Zhanel GG, Trapp S, Gin AS, et al. Dalbavancin and telavancin: novel for the treatment of gram-positive infec- component of a multidrug regimen for these infections tions. Expert Rev Anti Infect Ther 2008; 6: 67-81. because of its activity against MRSA. However, its inability 9 Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double- to cover P. aeruginosa will likely limit its utility as empirical blind comparison of once-weekly dalbavancin versus twice-daily monotherapy for many infections in the ICU. linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis 2005; 41: 1407-15. 10 Seltzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin Author details versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis 2003; 37: 1298-303. Marin H Kollef, Professor of Medicine 11 Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly Washington University School of Medicine, St Louis, MI, USA. dalbavancin therapy for catheter-related bloodstream infection Correspondence: [email protected] caused by gram-positive pathogens. Clin Infect Dis 2005; 40: 374- 80. 12 A study for patients with complicated skin and skin structure References infections (SIMPLIFI). http://clinicaltrials.gov/ct2/show/ NCT00514527?term=oritavancin&rank=1, (accessed Feb 2009). 1 Ge Y, Biek D, Talbot GH, Sahm DF. In vitro profiling of ceftaroline 13 Loutit JS, et al. Phase 2 trial comparing four regimens of oritavancin against a collection of recent bacterial clinical isolates from across vs. comparator in the treatment of patients with S aureus bacterae- the United States. Antimicrob Agents Chemother 2008; 52: 3398- mia. Abstract P541. Clin Microbiol Infect 2004; 10: 122. 407. 2 Jacqueline C, et al. Penetration of ceftaroline (PPI-0903), a new 14 Leonard SN, Rybak MJ. Telavancin: an antimicrobial with a multi- cephalosporin, into lung tissues: measurement of plasma and lung functional mechanism of action for the treatment of serious gram- tissue concentrations after a short IV infusion in the rabbit. In: positive infections. Pharmacotherapy 2008; 28: 458-68. Abstracts of the 46th Annual Interscience Conference on Antimi- 15 Dunbar LM, Tang DM, Manausa RM. A review of telavancin in the crobial Agents and Chemotherapy. San Francisco; 2006: abstract A- treatment of complicated skin and skin structure infections (cSSSI). 1938. Ther Clin Risk Manag 2008; 4: 235-44. 3 Talbot GH, Thye D, Das A, Ge Y. Phase 2 study of ceftaroline versus 16 Food and Drug Administration. FDA briefing document for Anti- standard therapy in the treatment of complicated skin and skin infective Drugs Advisory Committee Meeting, November 20, 2008 structure infections. Antimicrob Agents Chemother 2007; 51: (Iclaprim for the treatment of complicated skin and skin structure 3612-6. infection). http://fda.gov/ohrms/dockets/ac/08/briefing/2008- 4 Fritsche TR, Sader HS, Jones RN. Antimicrobial activity of ceftobip- 4394b3-01-FDA.pdf (accessed Dec 2008). role, a novel anti-methicillin-resistant Staphylococcus aureus cepha- 17 Andrews J, Honeybourne D, Ashby J, et al. Concentrations in losporin, tested against contemporary pathogens: results from the plasma, epithelial lining fluid, alveolar macrophages and bronchial SENTRY antimicrobial surveillance program (2005–2006). Diagn mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim Microbiol Infect Dis 2008; 61: 86-95. (AR-100) in healthy men. J Antimicrob Chemother 2007; 60: 677- 5 Noel GJ, Strauss RS, Amsler K, et al. Results of a double-blind, 80. randomized trial of ceftobiprole treatment of complicated skin and 18 Hadvary P, et al. Clinical efficacy of iclaprim in complicated skin and skin structure infections caused by gram-positive bacteria. Antimi- skin structure infection (cSSSI): results of combined ASSIST phase III crob Agents Chemother 2008; 52: 37-44. studies. In: Abstracts of the 48th Annual Interscience Conference 6 Noel GJ, Bush K, Bagchi P, et al. A randomized, double-blind trial on Antimicrobial Agents and Chemotherapy. Washington, DC; comparing ceftobiprole medocaril with vancomycin plus ceftazi- 2008: abstract L-1512. dime for the treatment of patients with complicated skin and skin 19 Clinical Efficacy of Intravenous Iclaprim versus Vancomycin in the structure infections. Clin Infect Dis 2008; 46: 647-55. Treatment of Hospital-Acquired, Ventilator-Associated, or Health- 7 Noel GJ, et al. Ceftobiprole versus ceftazidime combined with Care-Associated Pneumonia. http://www.clinicaltrials.gov/ct2/ linezolid for treatment of patients with nosocomial pneumonia. In: show/NCT00543608?term=iclaprim&rank=1 (accessed Jan Abstracts of the 48th Annual Interscience Conference on Antimi- 2009). ❏

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