Treatment of Gram Negative Infections (Have We Already Lost?) Larry Danziger, PharmD Professor of Pharmacy Professor of Pharmacy in Medicine University of Illinois at Chicago . Objectives • • • • Epidemiology Current Treatment Options Maximizing our Arsenal Future Treatment Options William Stewart, M.D. United States Surgeon General 1965 - 1969 “The time has come to close the book on infectious diseases and declare the war against pestilence won.” Bacteria have evolved despite the presence of naturally occurring toxic substances. The development of resistance is a natural phenomenon. Nov 22, 1947 Introduction of Antibiotic Resistance Resistance is Nothing New Community-acquired Resistance Escherichia coli (ESBL producers) Haemophilus influenzae Methicillin-resistant Staphylococcus aureus Mycobacterium tuberculosis Penicillin -resistant pneumococci Salmonella Hospital-acquired Resistance Enterobacter species Klebsiella species Methicillin-resistant Staphylococcus aureus Pseudomonas species Acinetobacter baumannii VISA / VRSA The Problem • 1.7 million patients acquire a noscomial infection each year • Resistant infections are associated with clinical failures or relapse in 25 - 75% of patients • Roughly 70% of bacteria causing hospital-acquired infections are resistant to ≥ 1 antibiotics1 1. IDSA. Available at: http://www.idsociety.org/badbugsnodrugs.html. Accessed April 8, 2012 The Problem • Cost of antibiotic resistance estimated to be over $40 billion annually • Documented increase in Morbidity and Mortality • The toll on human life as a result of resistant bacterial infections ranges between 80,000 – 100,000* patients each year David Shlase- ASM, 1993;59 Dickema DJ, JAMA, 2008;299:1190 Today’s Problematic Bacteria • Klebsiella pneumoniae • Enterobacter species • Acinetobacter Baumannii • Pseudomonas aeruginosa ESBL / KPC / NDM-1 AmpC production XDR, PDR bacteria No standard definitions for MDR, XDR (extreme drugresistant), or PDR (pan drug resistant) organisms Susceptibility Trends MYSTIC Program (1999–2008) K. pneumoniae Isolates (2,694 strains) Rhomberg PR, et al. Diagn Microbiol Infect Dis. 2009;65:414-426. Enterobacteriaceae Isolates (13,001 strains) LOYOLA UNIVERSITY MEDICAL CENTER ANTIBIOGRAM Acinetobacter baumannii Enterobacter cloacae E. cloacae-ESBL (7.4%) Klebsiella pneumoniae K pneumonia- ESBL TMP/SMX Nitrofurantoin (Urine) Ciprofloxacin Tobramycin Gentamicin Meropenem Aztreonam Cefepime Ceftazidime Ceftriaxone Cefazolin Piperacillin/Tazobactam Piperacillin Piperacillin Ampicillin/Sulbactam Ampicillin/ Ampicillin GRAM NEGATIVE RODS Total No. Tested JANUARY 1 – DECEMBER 31, 2011 70 0 66 - - 0 53 71 57 0 66 64 69 52 0 66 242 0 0 - 90 0 83 83 99 - 100 97 95 92 24 91 12 0 0 - 17 0 0 0 0 0 100 92 92 83 40 75 1107 0 77 - 90 93 93 93 - 93 96 91 88 48 84 51 0 0 - 39 8 8 0 0 0 0 0 90 39 14 18 44 8 896 0 0 82 - 0 - 88 87 72 84 80 87 78 0 0 (3.4%) Pseudomonas aeruginosa How did we get here? Inappropriate Antibiotic Use !! Veterinary Antimicrobial Use Data obtained from IMS Jan 2006 thru December 2007 Unnecessary Antibiotic Prescriptions 50% 30% 50% 80% 100% Total Prescriptions per Year (millions) CDC 2007 Relationship between Fluoroquinolone use (□) and resistance rates in Pseudomonas aeruginosa (•) and Gram-negative bacilli (○) in the USA during the 1990s Neuhauser MM, Weinstein RA, Rydman R, Danziger LH, Karam G, Quinn JP. JAMA 2003; 289: 885–888. Association Between Antimicrobial Consumption And Isolation Rates Goel N et al. J. Antimicrob. Chemother. 2011;66:1625-1630 What are Our Treatment Options for Multidrug Resistance in Gram-Negative Bacilli ?? Klebsiella pneumoniae KPC – Producing Percent resistant to the following* – Carbapenems – Pip/tazobactam – Ciprofloxacin – Tobramycin – Cefepime – Doxycycline *96 Isolated; 10 NY Hospitals Bratu S. JAC 2005;56:128-132 100% 100% 98% 94% 60% 44% Nonfermeters Gram-Negative Percent Resistant Acinetobacter spp.** – – – – – – Meropenem Pip/tazobactam Ciprofloxacin Tobramycin Cefepime Doxycycline 32% 76% 74% 94% 82% 44% Sader H Diagn Micro Inf Dis 2005;52:181 P. aeruginosa* – – – – – – Meropenem Pip/tazobactam Ciprofloxacin Tigecycline Cefepime Tetracycline 13% 20% 28% 77% 13% 86% *1121 Isolates - Worldwide **326 Isolates - Worldwide Resistance rates of Acinetobacter spp. in the USA (1999–2006) Laxminarayan R , Klugman K P BMJ Open 2011;1:e000135 The Problem 14 Classes of antibiotics were introduced between 1935 and 1968; since then only 5 have been developed Only three of the approved antibiotics in the last 10 years have a new mode of action Poor Outcomes Organism Resistant to: Mortality LOS Enterobacter 1 3rd-generation cephalosporins 5.02 (1.10–22.9) 1.47 (1.25–1.72) P aeruginosa 2 imipenem 1.94 (1.22–3.10) 15.5 vs 9 days* (P = .02) Acinetobacter 3 MDR 2.6 (0.3–26.1) 2.5 (1.2–5.2) 1. Cosgrove SE, et al. Arch Intern Med. 2002;162:185-190. 2. Lautenbach E, et al. Infect Control Hosp Epidemiol. 2006;27:893-900. 3. Sunenshine RH, et al. Emerg Infect Dis. 2007;13:97-103. Current Treatment Options Carbapenems Colistin Tigecycline Sulbactam Doxcycline / Minocycline Rifampin Carbapenems • Imipenem / Meropenem / Doripenem (but not Ertapenem) are active vs P aeruginosa and Acinetobacter1-4 • Recent meta-analysis suggests that Doripenem may be more effective for P aeruginosa infections than comparators5 • Used for ESBL producers and all are susceptible to Acinetobacter carbapenemases2,3 • Acinetobacter activity of Dori ≥ Imipenim > Mero, but differences are small • Used in combination therapy for MDR bacteria Kattan JN, et al. Clin Microbiol Infect. 2008;14:1102-1111. 2. Mushtaq S, et al. AAC. 2004;48:3086-3092. 3. Pillar CM, et al. AAC. 2008;52:4388-4399. 4. Mushtaq S, et al. AAC. 2004;48:1313-1319. 5. Jenkins SG, et al. Curr Med Res Opin. 2009;25:3029-3036. The Polymyxins Discovered in the 1940s Polymyxin B and polymyxin E (colistin) differ by one amino acid Concentration dependent, bactericidal Forms: Colistin sulfate Colistimethate sodium (CMS) MOA: Binds to bacterial cell membrane lipopolysaccharide moieties Increased membrane permeability (cell lysis) Gilad J. Drugs 2008; 68:165-89 Karageorgopoulos DE. Lancet Infect Dis 2008; 8:751-62. The Polymyxins • Active against mosy Gram-negative pathogens1-3 – >90% of Acinetobacter, P aeruginosa, E coli, Klebsiella, and Citrobacter – >80% of Enterobacter are susceptible • Resistance increasing, particularly in P aeruginosa, Acinetobacter, and KPC producers4-6 • Colistin susceptibility generally predicts polymyxin B1 • Susceptability issues / Formulation issues 1. Landman D, et al. Clin Microbiol Rev. 2008;21:449-465. 2. Gales AC, et al. Clin Microbiol Infect. 2006;12:315-321. 3. Walkty A, et al. Antimicrob Agents Chemother. 2009;53:4924-4926. 4. Landman D, et al. J Antimicrob Chemother. 2005;55:954-957. 5. Nordmann P, et al. Lancet Infect Dis. 2009;9:228-236. 6. Nation RL, et al. Curr Opin Infect Dis. 2009;22:535-543. Polymxins • Place in therapy – Bacteremia – VAP • Aerosolized administration – Meningitis • Intraventricular or intrathecal route plus systemic – Now mainstay treatment for MDR / XDR / PDR isolates Tigecycline • Broad spectrum – Aerobes and anaerobes – Lacks activity: P. aeruginosa • Place in therapy – VAP • Clinical resolution reported • Non-bacteremia – Activity against MDR isolates – Low serum concentrations Sulbactam • Place in therapy – VAP • Aerosolized administration experimental – Bacteremia – Meningitis • Limited data, non-conclusive – MDR/XDR/PDR isolates – Not available in US 1. Betrosian AP et al. J of Infect 2008;56:432-436 Doxcycline/Minocycline • Place in therapy – Minocycline has essentially the same spectrum of activity against microorganisms as doxycycline – Stenotrophomonas (Xanthomonas) maltophilia – MDR Acinetobacter baumannii – Place in therapy VAP? Bacteremia? Do We Have Any Novel Treatment Strategies? “Timing is everything” William Shakespeare Julius Caesar, Act 4, scene 3 Appropriate Initial Therapy • Research indicates inappropriate initial therapy is an independent risk factor for mortality1 • Kumar et al, retrospectively evaluated 5,715 patients with septic shock2 • Survival after appropriate initial therapy was 52.0%, compared to 10.3% after inappropriate initial therapy (OR 9.45, P < .0001) 1. Kollef M. Clini Infect Dis. 2008;47(Suppl):3-13 2. Kumar A, et al. Chest 2009;136:1237-1248 Hospital mortality and inappropriate initial antimicrobial therapy (IIAT) according to classification of infection source. Micek S T et al. Antimicrob. Agents Chemother. 2010;54:1742-1748 Early Initiation of Appropriate Antibiotic Therapy for Septic Shock Deresinski S. Clin Infect Dis. 2007;45:S177-S183 CID 2007:44 (15 January) 159 Dose Opitmization Maintaining antibiotic concentrations above the minimum inhibitory concentration (MIC) is necessary to achieve in vivo potency and is dependent on the pharmacokinetics of the drug. AUC, area under the concentration-time curve; Cmax, maximum plasma concentration; T > MIC, time spent above the MIC. Nicolau Critical Care 2008 12(Suppl 4):S2 Carbapenems Optimized Dosing • Bactericidal activity seen when T>MIC exceeds 40%–50% • Bacteriostatic at T>MIC of 20%–30% • Can increase T>MIC by use of “prolonged” infusions • Issue: reconstituted carbapenems have limited stability at room temperature T>MIC = percentage of dosing interval that drug concentrations remain above the MIC. Kuti JL, et al. J Clin Pharmacol. 2003;43:1116-1123. Optimized Dosing 1.0 mcg/ml Cirillo I et al. J Clin Pharm. 2009;7:798 Benefits of Combination Therapy Synergy Among Antimicrobials Targets Multiple Mechanisms Overcomes Limitations of Monotherapy Pediatrics 1958;21;1000 Susceptibility for Combination Therapy Monotherapy* Versus Susceptibility for combination therapy, % (P) Susceptibility for monotherapy Gentamicin Ciprofloxacin Tobramycin Amikacin Imipenem 88.8 % 93.4 (.007) 92.1 (.056) 94.2 (.001) 95.8 (<.001) Ceftazidime 69.2% 84.4 (<.001) 81.3 (<.001) 84.6 (<.001) 92.6 (<.001) Piperacillintazobactam 68.8% 85.6 (<.001) 81.4 (<.001) 85.4 (<.001) 91.6 (<.001) Therapy *In vitro data. Percentage of All Gram‐Negative Pathogens Isolated from Blood Cultures Susceptible to Combination Antimicrobial Therapy vs Monotherapy Christoff et al. Infect Control Hosp Epidemiol 2010;31:256 Clinical Failures Monotherapy vs Combination Therapy In the treatment of sepsis the addition of an aminoglycoside to beta lactams should be discouraged. Fatality remains unchanged, while the risk for adverse events is increased. Favors Monotherapy Paul M. BMJ:2004;20:668 Favors Combination Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients Furno P. Lancet Infect Dis. 2002;2:231 Combination Therapy Colistin, carbapenems, rifampin, azithromycin, fluoroquinolones, sulbactam, tigecycline, aminoglycosides, doxycycline/minocycline No combination exhibits synergy consistently Combination therapy remains controversial Petrosillo. Clin Microbiol Infect 2008;14:816-27. Kroeger LA. AAC 2007; 51:3431-3. Combination Theray: Is More, More? Conclusion: Combination antibiotic therapy improves survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients. Kumar et al, Crit Care Med 2010; 38(8):1651-64. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.. Studies Comparing Combination Antibiotic Therapy with Monotherapy for Reducing Mortality of Life-threatening Infections Associated with Sepsis Note the gradual shift of the odds ratio from right to left as monotherapy mortality increases. The size of the squares is proportional to reciprocal of the variance of the studies. Kumar et al, Crit Care Med 2010; 38(8):1651-64. Treatment Outcome of Bacteremia Due to KPC-Producing K. pneumoniae Definitive treatment n (%) Mortality n (%) Combination therapy 15 (44) 2 (13.3) 5 (33) 1 (7) 1 (7) 1 (20) 0 0 3 (20) 2 (12) 0 0 1 (7) 1 (100) 1 (7) 1 (7) 19 (46) 7 (36.8) 5 (26.3) 4 (21) 1 5.2) 1 (5.2) 1 (5.2) 34 (83) 0 0 11 (57.8) 4 (57.1) 4 (80) 2 (50) 0 0 1 (100) 13 (38.2) Colistin-polymyxin B combined with: Carbapenem Tigecycline Fluoroquinolone Tigecycline combined with: Carbapenem Aminoglycoside Carbapenemfluoroquinolone Aztreonam-fluoroquinolone Cefepime-gentamicin Monotherapy Colistin-polymyxin B Tigecycline Carbapenem Gentamicin Ampicillin-sulbactam Piperacillin-tazobactam Total Zubair A. Antimicrob. Agents Chemother. 2012;56:2108-2113 Promising Combinations • • • • • • • Polymxin B + Polymxin B + Polymxin B + Polymxin B + Polymxin B + Carbapemens Tigecycline + carbapenems rifampin carbapenems + rifampin Doxycycline ceftriaxone + rifampin aminoglycoside Tigecycline Combination Therapy • Most studies have found indifference with tigecycline combinations1 • Occasionally synergy reported1 – Particularly with aminoglycosides, rifampin, TMP/SMX, pip-tazo and amp-sulbactam • Inconsistent synergy reported with the carbapenems • Antagonism has been rare with combinations • Although indifference with the polymyxins has been seen most often, synergy and antagonism have also been described1-3 1. Entenza JM, et al. Int J Antimicrob Agents. 2009;34:8e1-8.e9. 2. Shields RK, et al. 49th ICAAC. San Francisco; Sept. 12-15, 2009. 3. Kwak E, et al. 49th ICAAC. San Francisco; Sept. 12-15, 2009. Polymyxins Combination Therapy • Synergy noted with rifampin, the carbapenems, and azithromycin1,2 – Synergy may be seen even with resistance – Triple synergy has been observed with polymyxin B + rifampin + doripenem or imipenem3,4 • Antagonism also reported with these agents • Antagonism noted with colistin + rifampin or colistin + tigecycline in 6% of pandrugresistant Acinetobacter isolates tested5 1. Landman D, et al. Clin Microbiol Rev. 2008;21:449-465. 2. Petrosillo N, et al. Clin Microbiol Infect. 2008;14:816-827. 3. Yoon J, et al. Antimicrob Agents Chemother. 2004;48:753-757. 4. Urban C, et al. 49th ICAAC. San Francisco; Sept. 12-15, 2009. 5. Shields RK, et al. 49th ICAAC. San Francisco; Sept. 12-15, 2009. Polymyxins Combination Therapy • Caution; rifampin or tigecyclinecontaining regimens associated with worse clinical outcomes1 • Also reports of emergence of resistance to colistin when compared to colistin + a carbapenem1 • Reinforces the importance of testing for synergy in each patient 1. Kwak E, et al. 49th ICAAC. San Francisco; Sept. 12-15, 2009. Sulbactam Combination Therapy: Case Reports Age/ Sex Underlying Conditions Infection Antimicrobial Therapy Microbiologic and Clinical Outcomes at 2 Weeks after Bacteremia Onset 67/F Hematologic malignancy Pneumonia Meropenem 1 g q6h + sulbactam 1 g q6h x 14 d Bacteria eradicated, patient survived 39/M Hypoxic encephalopathy Pneumonia Imipenem 500 mg q6h + sulbactam 1 g q6h x 10 d Bacteria eradicated, patient survived 40/F Necrotizing fasciitis, acute renal failure Catheterrelated infection Imipenem 250 mg q12h + sulbactam 2 g daily x 14 d Bacteria eradicated, patient survived 41/F Postpartum hemorrhage Catheterrelated infection Imipenem 500 mg q6h + sulbactam 1 g q6h x 12 d Bacteria eradicated, patient survived 1 Lee NY et al. Pharmacotherapy 2007; 27:1506-11 Rifampin Combination Therapy for Gram-negative Infections Authors/Year Country Type of study/no. patients Korvick et al.,1992; USA Multicenter, prospective randomised trial; 121 patients of which 58 treated with RIFcontaining regimen Rodriguez Guardado et al., 2007 Spain Retrospective, 8 patients of which 1 treated with RIFcontaining regimen Pathogen/type of antibiotic resistance Site of infection/ward (when specified) Antimicrobial association Outcome P. aeruginosa Bacteremia RIF 600 mg t.i.d. for at least 3 days, then 600 mg b.i.d. for 7 days p.o. + β-lactam + aminoglycoside (58 patients) vs. βlactam + aminoglycoside (63 patients) 14 patients died, 44 patients cured vs. 11 patients died, 52 patients cured A. baumannii MDR 5 joint infections of knee prosthesis 1 patient treated with: RIF 600 mg/24 h i.v. + COL 160 mg t.i.d. i.v. 1 died, 4 cured A. baumannii IM-R 4 VAP/ICU 3 intraabdominal abscess/ICU 1 empyema/ICU 1 catheter bacteremia/ICU 1 arthroplasty hip infection/ non-ICU RIF 600 mg/12 h i.v. + IM 2 g b.i.d. i.v. 2 cured, 2 died 2 cured, 1 died 1 cured 1 cured 1 cured Saballs et al.,2006 Spain Prospective clinical study, 14 months, 10 patients Bassetti et al.,2008 Italy Prospective uncontrolled caseseries 29 patients A. baumannii pan resistant 19 VAP of which 2 with BSI/ICU 10 BSI/ICU RIF 10 mg/kg/12 h i.v. + COL 2 MU t.i.d. i.v. 6 deaths attributable to A. baumannii, and 5 to other causes 18 cured Young et al.,2008 Corea Retrospective 10 patients A.baumannii MDR 10 VAP/ICU RIF 600 mg/24 i.v. + COL* 150 mg/b.i.d. i.v. 3 failed# 7 cured Drapeau CMJ. Int J Antimicrob Agents. 2010;35:39 Aerosolized Antibiotics • In several case series, aerosolized antibiotics have been effective as adjunctive therapy for VAP due to MDR gram negative organisms1-4 – Predominantly P aeruginosa and Acinetobacter • Doses used have not been consistent, but examples include1-5: – – – – Tobramycin 300 mg q12h Amikacin 400–1,000 mg q12h Colistimethate 80–360 mg q12h Polymyxin B 500,000 units q12h 1. Kwa AL, et al. Clin Infect Dis. 2005;41:754-757. 2. Pereira GH, et al. Diagn Microbiol Infect Dis. 2007;58:235-240. 3. Michalopoulos A, et al. Resp Med. 2008;102:407-412. 4. Czosnowski QA, et al. Pharmacotherapy. 2009;29:1054-1060. 5. Luyt C-E, et al. Curr Opin Infect Dis. 2009;22:154-158. Aerosolized Antibiotics • May be advantageous for antibiotics with low pulmonary concentrations such as the aminoglycosides and polymyxin1,2 • Although systemic adverse events are minimized, but bronchospasm may occur1 – IV formulations often contain irritating preservatives – Pre-administration of a β2-agonist has been used3 – Inhaled colistimethate implicated in death of a patient4 • Attributed to excess conversion to the more toxic colistin in the premixed solution, • Leading to recommendation that the drug should be reconstituted immediately prior to administration 1. Luyt C-E, et al. Curr Opin Infect Dis. 2009;22:154-158. 2. Landman D, et al. Clin Microbiol Rev. 2008;21:449-465. 3. Pereira GH, et al. Diagn Microbiol Infect Dis. 2007;58:235-240. 4. McCoy KS, et al. N Engl J Med. 2007;357:2310-2311. Aerosolized Antibiotics 1st Author/Year n Antibiotic Outcomes Klastersky/1972 7/8 Gentamicin 80 mg via ETT q 8h x 6-12d vs gentamicin 80 mg IM q 8h ETT cure rate superior to IM (100% vs 25%, p<0.01) Klastersky/1974 85 Gentamicin 80 mg tid vs placebo Less respiratory infection Greenfield/1973 58 Polymyxin 2.5 mg/kg/d No effect Klastersky/1979 18/20 Sisomycin 25 mg via ETT q 8h x 7d vs placebo ETT cure rate superior to placebo (77% vs 45%, p<0.05) Aerosolized Colistin Falagas et alResp Med 2008;102:407–12. Aerosolized Antibiotics • Despite the lack of evidence from well designed studies, treatment guidelines state that aerosolized antibiotics may be considered for adjunctive therapy • Consider for patients with MDR gramnegative VAP who have not responded to systemic therapy (level III recommendation)1 . 1. ATS, IDSA. Am J Respir Crit Care Med. 2005;171:388-416 CNS Infections Due to MDR Gram-Negative Organisms • Intrathecal (IT) or intraventricular administration • In addition to longstanding experience with the aminoglycosides, these routes of administration have been used successfully for the polymyxins1-3 – Recommended adult daily doses4 Gentamicin/tobramycin: 4–8 mg Amikacin 30 mg Colistimethate 10 mg Polymyxin B 50,000 units • IV rifampin has been combined with IT colistin to treat meningitis due to carbapenem-resistant A baumannii 5 • IV ampicillin-sulbactam has been used for Acinetobacter meningitis, with varying outcomes6,7 1. Falagas ME, et al. Int J Antimicrob Agents. 2007;29:9-25. 2. Rodríguez Guardado A, et al. J Antimicrob Chemother. 2008;61:908-913. 3. Landman D, et al. Clin Microbiol Rev. 2008;21:449-465. 4. Tunkel AR, et al. Clin Infect Dis. 2004;39:1267-1284. 5. Motaouakkil S, et al. J Infect. 2006;53:274-278. 6. Peleg AY, et al. Clin Microbiol Rev. 2008;21:538-582. 7. Kim B-N, et al. Lancet Infect Dis. 2009;9:245-255. CNS Infections MDR Gram-Negative Organisms • Meningitis guidelines recommend meropenem as the drug of choice for ESBL producers or other β-lactamase hyperproducers (eg, Enterobacter) and as an alternative for P aeruginosa1 • Although clear data are lacking, prolonged infusion of meropenem (ie, 3–4 hours) may be advantageous2 – Particularly for organisms with elevated MICs – Successfully used to treat cases of P aeruginosa and S marcescens infection, although MICs in both cases were <0.2 µg/mL3 • Tigecycline has low CSF levels, but has been used successfully for a case of Acinetobacter meningitis2 1. Tunkel AR, et al. Clin Infect Dis. 2004;39:1267-1284. 2. Kim B-N, et al. Lancet Infect Dis. 2009;9:245-255. 3. Capitano B, et al. Pharmacotherapy. 2004;24:803-807. Investigational Antimicrobials • CB-182,804 • CXA-201 • NXL 104 • POL7001 & POL7080 • MK7655 • GSK 299493 CB-182,804 • Novel Polymyxin Analogue • Cubist began a Phase I in 1st quarter of 2009 • Rapid cidality in vitro against MDR bacteria including: – – – – P. Aeruginosa E. coli K. pneumoniae A. baumannii • Synergistic effect with rifampin slightly greater with CB-182,804 than with polymyxin B against K. pneumoniae and Enterobacter spp. CXA-201 • CXA-201 (ceftolozane/tazobactam), acitve against serious Gram-negative bacteria • Includes those caused by multi-drug resistant Pseudomonas aeruginosa • Phase III trials in 2011-2012 will compare the safety and efficacy of CXA-201 in patients with cUTI. • Phase 3 trial of CXA-201 in patients with complicated cIAI was initiated in December 2011 Cubist NXL - 104 • A non- ß-lactamase inhibitor of ß-lactamase (not NDM-1) • Discovered 2004 • Astra-Zeneca completed Phase II trials with ceftazidime-NXL-104 • Forest is developing NXL-104 in combination with ceftaroline • Needs to be used in combination with other agents to cover Pseudomonas sp. in proven or suspected mixed infections • Investigational Antimicrobials • POL7001 & POL7080 • Protein epitope mimetics of the antimicrobial peptide protegrin I • Mechanism of action is distinct from other membrane-disrupting activity • POL7001 and POL7080 are highly specific for P. aeruginosa • In an antimicrobial activity assay, both compounds were inactive against other Gram-negative and Gram-positive bacteria MK-7655 • Merck's ß-lactamase inhibitor • Similar in structure and activity to AstraZeneca/Forest NXL-104 • Inhibits class A and C enzymes including ESBLs and KPC types • Active versus Pseudomonas spp. as not a substrate for efflux pumps • To be paired with imipenem • Resistance already reported 1 KPC P. aeruginosa has MIC of 32 µg/ml to imipenem GSK 2251052 (AN-3365) • A novel boron containing compound for Gram-negative infections licensed from Anacor Pharmaceuticals Inc., • GSK voluntarily suspended enrollment in all Phase I and II trials in February 2012 • Due to a microbiological failure in patients enrolled in the Phase IIb in complicated urinary tract infections Conclusions • Multidrug resistance in hospitalassociated gram-negative organisms continues to be a problem • Infections due to MDR organisms are associated with adverse clinical and economic outcomes • Appropriate initial and immediate antibiotic therapy is associated with decreased mortality • Few new treatment options in latestage development Conclusions • Use of Carbapenems and Tigecycline • Polymyxins are often the only drugs active against carbapenem-resistant organisms • Clinical experience and data for optimal dosing remains limited • Combination therapy may be warranted but poorly studied • Use of Alternative administration strategies Vigilance Ceftaroline fosamil: Forest Labs Approved; October 29, 2010 APOCALYPSE And the Rodlet of Klebs went in unto the tent of the Nonfermenter; even to know her. And great Plasmids arose from the bowels of the people. And Kana came up from the East, and smote the Rodlet of Klebs. But against the Plasmid, he prevailed not. And Kana begat Genta; and Tobra, and Amik; even unto Siso and Netil. Adapted from: Stephen A. Berger. M.D; 1978 APOCALYPSE But the people were still sorely afflicted. And then Mycins arose from the Earth; and Chloro and the Cyclines. But the people feared the Mycins and turned away from the Cyclines. And they did hold assemblies without stint; and even sermons such as this at which circles of hot Roman Tomato Bread is devoured. But the people will remember Qohelet , and moan: "This is nothing new under the sun." Adapted from: Stephen A. Berger. M.D; 1978