Advertisement

What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles

  • Karen Bush
  • Malcolm G. P. PageEmail author
Review Paper

Abstract

There are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of β-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development. The combination of such inhibitors, which have broad activity against serine β-lactamases and may even inhibit some penicillin binding proteins, with carbapenems, cephalosporins or aztreonam, provides enhanced activity against multi-drug resistant Gram-negative bacteria. There are 6 molecules representing novel classes of antibiotics but only one of these, murepavadin, is expected to have activity against a Gram-negative pathogenic bacterium (Pseudomonas aeruginosa). Although the new analogues of existing classes, and novel combinations, have been designed to address specific resistance problems, it is by no means certain than they will not be affected by the general mechanisms of resistance, particularly decreased net flux across the Gram-negative outer membrane. The potential impact of resistance mechanisms on the new agents is assessed and the ways in which PK/PD studies are used to design dosing regimens for the new agents, especially combinations, as well as to improve dosing of existing antibiotics are discussed.

Keywords

Antibiotics Development Pipeline Resistance Pharmacodynamics 

References

  1. 1.
    Projan SJ, Shlaes DM (2004) Antibacterial drug discovery: is it all downhill from here? Clin Microbiol Infect 4:18–22CrossRefGoogle Scholar
  2. 2.
    Tomayko JF, Rex JH, Tenero DM, Goldberger M, Eisenstein BI (2014) The challenge of antimicrobial resistance: new regulatory tools to support product development. Clin Pharmacol Ther 96(2):166–168PubMedCrossRefGoogle Scholar
  3. 3.
    Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D (2013) 10 × ’20 Progress—development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis 56(12):1685–1694PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48(1):1–12PubMedCrossRefGoogle Scholar
  5. 5.
    CDC (2013) Antibiotic resistance threats in the United States, 2013. CDC, AtlantaGoogle Scholar
  6. 6.
    WHO (2015) Global action plan on antibiotic resistance. World Health Organization, GenevaGoogle Scholar
  7. 7.
    Brown ED (2013) Is the GAIN Act a turning point in new antibiotic discovery? Can J Microbiol 59(3):153–156PubMedCrossRefGoogle Scholar
  8. 8.
    Kostyanev T, Bonten MJ, O’Brien S, Steel H, Ross S, Francois B, Tacconelli E, Winterhalter M, Stavenger RA, Karlén A, Harbarth S, Hackett J, Jafri H, Vuong C, MacGowan A, Witschi A, Angyalosi G, Elborn JS, deWinter R, Goossens H (2015) The Innovative Medicines Initiative’s New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance. J Antimicrob Chemother 71(2):290–295PubMedCrossRefGoogle Scholar
  9. 9.
    Theuretzbacher U (2012) Accelerating resistance, inadequate antibacterial drug pipelines and international responses. Int J Antimicrob Agents 39(4):295–299PubMedCrossRefGoogle Scholar
  10. 10.
    Rex JH (2014) ND4BB: addressing the antimicrobial resistance crisis. Nat Rev Microbiol 12:231–232CrossRefGoogle Scholar
  11. 11.
    Butler MS, Blaskovich MA, Cooper MA (2013) Antibiotics in the clinical pipeline in 2013. J Antibiot 66:571–591PubMedCrossRefGoogle Scholar
  12. 12.
    Pucci MJ, Bush K (2013) Investigational antimicrobial agents of 2013. Clin Microbiol Rev 26(4):792–821PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Drawz SM, Papp-Wallace KM, Bonomo RA (2014) New beta-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58(4):1835–1846PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Page MGP, Bush K (2014) Discovery and development of new antibacterial agents targeting Gram-negative bacteria in the era of pandrug resistance: is the future promising? Curr Opin Pharmacol 18:91–97PubMedCrossRefGoogle Scholar
  15. 15.
    Moya B, Zamorano L, Juan C, Ge Y, Oliver A (2010) Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother 54(9):3933–3937PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Sader HS, Rhomberg PR, Farrell DJ, Jones RN (2011) Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother 55(5):2390–2394PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Livermore DM, Mushtaq S, Ge Y (2010) Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 65(9):1972–1974PubMedCrossRefGoogle Scholar
  18. 18.
    Titelman E, Karlsson IM, Ge Y, Giske CG (2011) In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn Microbiol Infect Dis 70(1):137–141PubMedCrossRefGoogle Scholar
  19. 19.
    FDA (2015) Prescribing information for Zerbaxa. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206829s001lbl.pdf. Accessed 28 June 2016
  20. 20.
    Coque TM, Baquero F, Canton R (2008) Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe. Euro Surveill 13(47):20Google Scholar
  21. 21.
    Levasseur P, Girard A-M, Miossec C, Pace J, Coleman K (2015) In vitro antibacterial activity of the ceftazidime-avibactam combination against Enterobacteriaceae, including strains with well characterized β-lactamases. Antimicrob Agents Chemother 59:1931–1934PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Ehmann DE, Jahić H, Ross PL, Gu R-F, Hu J, Durand-Réville TF, Lahiri S, Thresher J, Livchak S, Gao N, Palmer T, Walkup GK, Fisher SL (2013) Kinetics of avibactam inhibition against class A, C, and D β-lactamases. J Biol Chem 288(39):27960–27971PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL (2012) Avibactam is a covalent, reversible, non-beta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci USA 109(29):11663–11668PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    USFaD Administration (2015) FDA approves new antibacterial drug Avycaz. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435629.htm
  25. 25.
    Allergan (2016) Allergan announces FDA approval of supplemental new drug application (sNDA) for AVYCAZ® (ceftazidime and avibactam)Google Scholar
  26. 26.
    Lowes R (2016) EU regulators OK antibiotic Zavicefta for resistant bugsGoogle Scholar
  27. 27.
    Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, Rittenhouse S, Tsuji M, Yamano Y (2016) In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother 60(2):729–734PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Page MGP, Dantier C, Desarbre E (2010) In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli. Antimicrob Agents Chemother 54(6):2291–2302PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Hornsey M, Phee L, Stubbings W, Wareham DW (2013) In vitro activity of the novel monosulfactam BAL30072 alone and in combination with meropenem versus a diverse collection of important Gram-negative pathogens. Int J Antimicrob Agents 42(4):343–346PubMedCrossRefGoogle Scholar
  30. 30.
    Mushtaq S, Woodford N, Hope R, Adkin R, Livermore DM (2013) Activity of BAL30072 alone or combined with β-lactamase inhibitors or with meropenem against carbapenem-resistant Enterobacteriaceae and non-fermenters. J Antimicrob Chemother 68:1601–1608PubMedCrossRefGoogle Scholar
  31. 31.
    Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, Rhomberg PR, Jones RN, Yoshizawa H, Nakamura R, Tsuji M, Yamano Y (2016) In vitro antimicrobial activity of S-649266, a catechol-substituted siderophore cephalosporin, when tested against non-fermenting Gram-negative bacteria. J Antimicrob Chemother 71(3):670–677PubMedCrossRefGoogle Scholar
  32. 32.
    Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N, Tsuji M, Yamano Y, Yamaguchi K, Tateda K (2016) Stability of novel siderophore cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother 60(7):4384–4386PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Bush K, Tanaka SK, Ohringer S, Bonner DP (1987) Mode of action studies: pirazmonam in Escherichia coli and Pseudomonas aeruginosa. Abst. 1218. Paper presented at the Interscience conference on antimicrobial agents and chemotherapy, New York, NYGoogle Scholar
  34. 34.
    Nikaido H, Rosenberg EY (1990) Cir and Fiu proteins in the outer membrane of Escherichia coli catalyze transport of monomeric catechols: study with beta-lactam antibiotics containing catechol and analogous groups. J Bacteriol 172(3):1361–1367PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ito A, Nishikawa T, Matsumoto S, Fukuhara N, Nakamura R, Tsuji M, Yamano Y, Shimada J (2014) S-649266, a novel siderophore cephalosporin: II. Impact of active transport via iron regulated outer membrane proteins on resistance selection. Abstract F-1563. Paper presented at the 54th Interscience conference on antimicrobial agents & chemotherapy, Washington, DCGoogle Scholar
  36. 36.
    Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J (2015) Activity of imipenem with relebactam against Gram-negative pathogens from New York City. Antimicrob Agents Chemother 59(8):5029–5031PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Livermore DM, Warner M, Mushtaq S (2013) Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 68:2286–2290PubMedGoogle Scholar
  38. 38.
    Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, King P, Tsivkovski R, Sun D, Sabet M, Tarazi Z, Clifton MC, Atkins K, Raymond A, Potts KT, Abendroth J, Boyer SH, Loutit JS, Morgan EE, Durso S, Dudley MN (2015) Discovery of a cyclic boronic acid beta-lactamase inhibitor (RPX7009) with utility vs Class A serine carbapenemases. J Med Chem 58(9):3682–3692PubMedCrossRefGoogle Scholar
  39. 39.
    Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, Landman D (2015) Activity of meropenem combined with RPX7009, a novel beta-lactamase inhibitor, against Gram-negative clinical isolates in New York City. Antimicrob Agents Chemother 59(8):4856–4860PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Papp-Wallace KM, Bajaksouzian S, Abdelhamed AM, Foster AN, Winkler ML, Gatta JA, Nichols WW, Testa R, Bonomo RA, Jacobs MR (2015) Activities of ceftazidime, ceftaroline, and aztreonam alone and combined with avibactam against isogenic Escherichia coli strains expressing selected single beta-lactamases. Diagn Microbiol Infect Dis 82(1):65–69PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Li H, Estabrook M, Jacoby GA, Nichols WW, Testa RT, Bush K (2015) In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother 59(3):1789–1793PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Castanheira M, Sader HS, Farrell DJ, Mendes RE, Jones RN (2012) Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother 56(9):4779–4785PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Initiative IM (2016) COMBACTE-CARE. Combatting bacterial resistance in Europe—carbapenem resistance. http://www.imi.europa.eu/content/combacte-care. Accessed 30 June 2016
  44. 44.
    Testa R, Canton R, Giani T, Morosini MI, Nichols WW, Seifert H, Stefanik D, Rossolini GM, Nordmann P (2015) In vitro activity of ceftazidime, ceftaroline and aztreonam alone and in combination with avibactam against European Gram-negative and Gram-positive clinical isolates. Int J Antimicrob Agents 45(6):641–646PubMedCrossRefGoogle Scholar
  45. 45.
    Kazmierczak KM, Rabine S, Hackel M, McLaughlin RE, Biedenbach DJ, Bouchillon SK, Sahm DF, Bradford PA (2016) Multiyear, multinational survey of the incidence and global distribution of metallo-beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 60(2):1067–1078PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Livermore DM, Mushtaq S, Warner M, Woodford N (2015) Activity of OP0595/beta-lactam combinations against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing beta-lactamases. J Antimicrob Chemother 70(11):3032–3041PubMedCrossRefGoogle Scholar
  47. 47.
    Khande HN, Joshi PR, Palwe SR, Bhagwat SS, Patel MV (2016) WCK 5222 [cefepime (FEP)-WCK 5107 (zidebactam, ZID)]: activity against ESBL, class C, and KPC-expressing enterics and Pseudomonas (PA) expressing AmpC (PA AmpC) or OXA β-lactamases (PA OXA). Abstract SUNDAY-442. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  48. 48.
    Deshpande PK, Bhavsar SB, Joshi SN, Pawar SS, Kale RP, Mishra A, Jadhav SB, Pavase LS, Gupta SV, Yeole RD, Rane VP, Ahirrao VK, Bhagwat SS, Patel MV (2016) WCK 5107 (Zidebactam, Zid): structure activity relationship (Sar) of novel bicyclo acyl hydrazide (Bch) pharmacophore active against Gram-negatives including Pseudomonas (Pa). Abstract FRIDAY-479. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  49. 49.
    Morinaka A, Tsutsumi Y, Yamada M, Suzuki K, Watanabe T, Abe T, Furuuchi T, Inamura S, Sakamaki Y, Mitsuhashi N, Ida T, Livermore DM (2015) OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam ‘enhancer’. J Antimicrob Chemother 70(10):2779–2786PubMedCrossRefGoogle Scholar
  50. 50.
    Livermore DM, Mushtaq S, Warner M, Vickers A, Woodford N (2016) Activity of combinations of cefepime with zidebactam (WCK 5107), a novel triple-action diazabicyclooctane. SUNDAY-439. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  51. 51.
    Crandon JL, Nicolau DP (2015) In vitro activity of cefepime/AAI101 and comparators against cefepime non-susceptible Enterobacteriaceae. Pathogens 4(3):620–625PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Jacobs MR, Bajaksouzian S, Papp-Wallace KM, Bonomo RA (2016) In vitro activity of cefepime combined with tazobactam (Wck 4282) against a challenge set of Esbl and carbapenemase producing Gram negative species. MONDAY-4282. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  53. 53.
    Castanheira M, Rhomberg PR, Schaefer BA, Jones RN, Sader HS (2016) Enhanced activity of Wck 4282 (cefepime-tazobactam) against KPC-producing Enterobacteriaceae collected worldwide when tested in physiological conditions. Abstract MONDAY-427.. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  54. 54.
    Patil VJ, Tadiparthi R, Birajdar SS, Dond BD, Shaikh MU, Dekhane DV, Pawar MJ, Bhagwat SS, Patel MV (2016) WCK 4234: synthesis and structure-activity relationship (SAR) identifying a novel β-lactamase inhibitor active against Acinetobacter expressing OXA-carbapenemases (Ab-Oxa). Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  55. 55.
    Shapiro AB, Guler S, Carter N, McLeod M, Jonge BD, McLaughlin R, Huynh H, Gao N, Durand-Reville T, Miller A, Mueller J, Tommasi R (2016) ETX2514, a novel, rationally designed inhibitor of class A, C and D β-lactamases, for the treatment of Gram-negative infections. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  56. 56.
    Blais J, Lewis SR, Krause KM, Benton BM (2012) Antistaphylococcal activity of TD-1792, a multivalent glycopeptide-cephalosporin antibiotic. Antimicrob Agents Chemother 56(3):1584–1587PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Theravance (2016) Theravance Biopharma programs. http://www.theravance.com/bacterial. Accessed 1 July 2016
  58. 58.
    Werneburg M, Zerbe K, Juhas M, Bigler L, Stalder U, Kaech A, Ziegler U, Obrecht D, Eberl L, Robinson J (2012) Inhibition of lipopolysaccharide transport to the outer membrane in Pseudomonas aeruginosa by peptidomimetic antibiotics. ChemBioChem 13:1767–1775PubMedCrossRefGoogle Scholar
  59. 59.
    Mensa B, Howell GL, Scott R, DeGrado WF (2014) Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16. Antimicrob Agents Chemother 58(9):5136–5145PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Corbett D, Wise A, Birchall S, Trimby E, Smith J, Lister T, Vaara M (2016) Potentiation of antibiotic activity by a novel cationic peptide, SPR741. Abstract SATURDAY-492. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  61. 61.
    Roberts KD, Wang J, Yu H, Wang L, Lomovskaya O, Griffith D, Hecker S, Dudley M, Thompson PE, Nation RL, Velkov T, Li J (2016) Developing safer polymyxins (Pms): structure-activity (SAR) and structure-toxicity (Str) relationships of modifications to positions 6 and 7. Abstract SATURDAY-434 Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  62. 62.
    Lomovskaya O, Rubio-Aparicio D, Nelson K, Roberts KD, Thompson PE, Nation RL, Velkov T, Li J, Hecker SJ, Griffith DC, Dudley MN (2016) In vitro activity of Faddi-287, a representative of a novel series of polymyxins (Pm) with reduced nephrotoxic potential. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  63. 63.
    Basarab GS, Doig P, Galullo V, Kern G, Kimzey A, Kutschke A, Newman JP, Morningstar M, Mueller J, Otterson L, Vishwanathan K, Zhou F, Gowravaram M (2015) Discovery of novel DNA gyrase inhibiting spiropyrimidinetriones: benzisoxazole fusion with N-linked oxazolidinone substituents leading to a clinical candidate (ETX0914). J Med Chem 58(15):6264–6282PubMedCrossRefGoogle Scholar
  64. 64.
    Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, Alm RA, Barvian K, Doig P, Galullo V, Gardner H, Gowravaram M, Huband M, Kimzey A, Morningstar M, Kutschke A, Lahiri SD, Perros M, Singh R, Schuck VJ, Tommasi R, Walkup G, Newman JV (2015) Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Sci Rep 5:11827PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    So W, Crandon JL, Nicolau DP (2015) Pharmacodynamic profile of GSK2140944 against methicillin-resistant Staphylococcus aureus in a murine lung infection model. Antimicrob Agents Chemother 59(8):4956–4961PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Negash K, Andonian C, Felgate C, Chen C, Goljer I, Squillaci B, Nguyen D, Pirhalla J, Lev M, Schubert E, Tiffany C, Hossain M, Ho M (2016) The metabolism and disposition of GSK2140944 in healthy human subjects. Xenobiotica 46(8):683–702PubMedCrossRefGoogle Scholar
  67. 67.
    Ross JE, Scangarella-Oman NE, Flamm RK, Jones RN (2014) Determination of disk diffusion and MIC quality control guidelines for GSK2140944, a novel bacterial type II topoisomerase inhibitor antimicrobial agent. J Clin Microbiol 52(7):2629–2632PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Robertson GT, Ding J, Ma Z (2016) In vitro evaluation of dual-action molecule TNP-2092: studies of the mode of action in gastrointestinal pathogen Helicobacter pylori. Abstract MONDAY-458. Paper presented at the 2016 Microbe, Boston, MAGoogle Scholar
  69. 69.
    Jacobs MR, Appelbaum PA (2006) Nadifloxacin: a quinolone for topical treatment for skin infections and potential for systemic use of its active isomer, WCK771. Expert Opin Pharmacother 7:1957–1966PubMedCrossRefGoogle Scholar
  70. 70.
    Patel H, Andresen A, Vente A, Heilmann H-D, Stubbings W, Seiberling M, Lopez-Lazaro L, Pokorny R, Labischinski H (2011) Human pharmacokinetics and safety profile of finafloxacin, a new fluoroquinolone antibiotic, inhHealthy volunteers. Antimicrob Agents Chemother 55:4386–4393PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    McKeage K (2015) Finafloxacin: first global approval. Drugs 75(6):687–693PubMedCrossRefGoogle Scholar
  72. 72.
    Stubbings W, Leow P, Yong GC, Goh F, Korber-Irrgang B, Kresken M, Endermann R, Labischinski H (2011) In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. Antimicrob Agents Chemother 55(9):4394–4397PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Guo B, Wu X, Zhang Y, Shi Y, Yu J, Cao G, Zhang J (2012) Safety and clinical pharmacokinetics of nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and multiple oral doses. Clin Drug Investig 32:475–486PubMedCrossRefGoogle Scholar
  74. 74.
    Rhee CK, Chang JH, Choi EG, Kim HK, Kwon YS, Kyung SY, Lee JH, Park MJ, Yoo KH, Oh YM (2015) Zabofloxacin versus moxifloxacin in patients with COPD exacerbation: a multicenter, double-blind, double-dummy, randomized, controlled, Phase III, non-inferiority trial. Int J Chron Obstruct Pulmon Dis 10:2265–2275PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Totsuka K, Odajima M, Nakauchi M, Sesoko S, Nakashima M (2016) Phase I study to determine the safety and pharmacokinetics (PK) of single and multiple oral doses of lascufloxacin (AM-1977) in healthy subjects. Abstract SUNDAY-467. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  76. 76.
    Totsuka K, Odajima M, Nakauchi M, Sesoko S, Nakashima M (2016) Phase I study to determine the safety and pharmacokinetics (PK) of single and multiple intravenous (Iv) infusion of lascufloxacin (AM-1977) in healthy subjects. Abstract SUNDAY-470. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  77. 77.
    Bassetti M, Della-Siega P, Pecori D, Scarparo C, Righi E (2015) Delafloxacin for the treatment of respiratory and skin infections. Expert Opin Investig Drug 24:433–442CrossRefGoogle Scholar
  78. 78.
    Hafkin B, Kaplan N, Murphy B (2016) Efficacy and safety of AFN-1252, the first Staphylococcus-specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities. Antimicrob Agents Chemother 60(3):1695–1701PubMedCentralCrossRefGoogle Scholar
  79. 79.
    Park HS, Yoon YM, Jung SJ, Kim CM, Kim JM, Kwak JH (2007) Antistaphylococcal activities of CG400549, a new bacterial enoyl-acyl carrier protein reductase (FabI) inhibitor. J Antimicrob Chemother 60(3):568–574PubMedCrossRefGoogle Scholar
  80. 80.
    Hawser S, Lociuro S, Islam K (2006) Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol 71(7):941–948PubMedCrossRefGoogle Scholar
  81. 81.
    Echols RM (2011) Understanding the regulatory hurdles for antibacterial drug development in the post-Ketek world. Ann N Y Acad Sci 1:153–161CrossRefGoogle Scholar
  82. 82.
    FAD Administration (2008) Iclaprim for the treatment of complicated skin and skin structure infections. FDA briefing document for Anti-Infective Drugs Advisory Committee Meeting, 20 Nov 2008Google Scholar
  83. 83.
    Farrell DJ, Castanheira M, Sader HS, Jones RN (2010) The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). J Infect 61(6):476–483PubMedCrossRefGoogle Scholar
  84. 84.
    Van Bambeke F, Tulkens PM (2016) The role of solithromycin in the management of bacterial community-acquired pneumonia. Expert Rev Antiinfective Ther 14(3):311–324CrossRefGoogle Scholar
  85. 85.
    Sutcliffe JA (2011) Antibiotics in development targeting protein synthesis. Ann N Y Acad Sci 1:122–152CrossRefGoogle Scholar
  86. 86.
    Grossman TH (2016) Tetracycline antibiotics and resistance. Cold Spring Harb Perspect Med 6(4):a025387PubMedCrossRefGoogle Scholar
  87. 87.
    Macone AB, Caruso BK, Leahy RG, Donatelli J, Weir S, Draper MP, Tanaka SK, Levy SB (2014) In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother 58(2):1127–1135PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Traczewski MM (2016) Omadacycline (PTK0796) spectrum of activity from 2003–2015. Abstract MONDAY-567. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  89. 89.
    Almaghrabi R, Clancy CJ, Doi Y, Hao B, Chen L, Shields RK, Press EG, Iovine NM, Townsend BM, Wagener MM, Kreiswirth B, Nguyen MH (2014) Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. Antimicrob Agents Chemother 58(8):4443–4451PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH (2013) Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother 57(11):5548–5558PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N (2011) Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 66(1):48–53PubMedCrossRefGoogle Scholar
  92. 92.
    Pharmaceuticals T (2015) Tetraphase announces top-line results From IGNITE2 Phase 3 clinical trial of eravacycline in cUTI. Sept 8:2015Google Scholar
  93. 93.
    Tsai L, Zervos M, Miller L, Tenke P, Marsh A, Mohr J, Luepke K, Horn P (2016) Intravenous eravacycline with transition to oral therapy for treatment of complicated urinary tract infections (cUTI) including pyelonephritis: Results from a randomized, double-blind, multicenter, Phase 3 trial (IGNITE2). Abstract MONDAY-264. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  94. 94.
    Tetraphase Pharmaceuticals (2016) Tetraphase Pharmaceuticals provides update on eravacycline regulatory and development status. 12 May 2016Google Scholar
  95. 95.
    Paukner S, Sader HS, Ivezic-Schoenfeld Z, Jones RN (2013) Antimicrobial activity of the pleuromutilin antibiotic BC-3781 against bacterial pathogens isolated in the SENTRY antimicrobial surveillance program in 2010. Antimicrob Agents Chemother 57(9):4489–4495PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sader HS, Biedenbach DJ, Paukner S, Ivezic-Schoenfeld Z, Jones RN (2012) Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 56(3):1619–1623PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Sader HS, Paukner S, Ivezic-Schoenfeld Z, Biedenbach DJ, Schmitz FJ, Jones RN (2012) Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J Antimicrob Chemother 67(5):1170–1175PubMedCrossRefGoogle Scholar
  98. 98.
    Grossman TH, Fyfe C, Brien WO, Hackel M, Sutcliffe JA (2012) TP-271 is a potent, broad-spectrum fluorocycline with activity against community-acquired bacterial respiratory and biothreat pathogens. Abstract F-1525. Paper presented at the Interscience conference on antimicrobial agents & chemotherapy, San Francisco, CAGoogle Scholar
  99. 99.
    Tetraphase Pharmaceuticals (2016) Tetraphase Pharmaceuticals initiates Phase 1 clinical trial for TP-271. 19 Jan 2016Google Scholar
  100. 100.
    Shang R, Wang J, Guo W, Liang J (2013) Efficient antibacterial agents: a review of the synthesis, biological evaluation and mechanism of pleuromutilin derivatives. Curr Top Med Chem 13(24):3013–3025PubMedCrossRefGoogle Scholar
  101. 101.
    Satav JS, Takalkar SS, Kulkarni AM, Bhagwat SS, Patel MV (2016) WCK 4873 (Nafithromycin): in vitro and in vivo activity of novel lactone-ketolide, against clinically relevant S. pneumoniae (SPN) resistotypes and methicillin-sensitive S. aureus (MSSA). Abstract SATURDAY-456. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  102. 102.
    Chugh R, Gupta M, Iwanowski P, Bhatia A (2016) Nafithromycin Phase 1 multiple ascending dose study in healthy subjects. Abstract MONDAY-513. Paper presented at the MMcrobe 2016, Boston, MAGoogle Scholar
  103. 103.
    Chambers HF (1999) Penicillin-binding protein-mediated resistance in pneumococci and staphylococci. J Infect Dis 179(Suppl 2):S353–S359PubMedCrossRefGoogle Scholar
  104. 104.
    Neu HC, Chin NX (1985) A perspective on the present contribution of beta-lactamases to bacterial resistance with particular reference to induction of beta-lactamase and its clinical significance. Chemioterapia 4(1):63–70PubMedGoogle Scholar
  105. 105.
    Babic M, Hujer AM, Bonomo RA (2006) What’s new in antibiotic resistance? Focus on beta-lactamases. Drug Resist Updates 9(3):142–156CrossRefGoogle Scholar
  106. 106.
    Bush K (2010) Bench-to-bedside review: the role of beta-lactamases in antibiotic-resistant Gram-negative infections. Crit Care 14(3):224–231PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Henrichfreise B, Wiegand I, Pfister W, Wiedemann B (2007) Resistance mechanisms of multiresistant Pseudomonas aeruginosa strains from Germany and correlation with hypermutation. Antimicrob Agents Chemother 51(11):4062–4070PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Babouee Flury B, Ellington MJ, Hopkins KL, Turton JF, Doumith M, Loy R, Staves P, Hinic V, Frei R, Woodford N (2016) Association of novel nonsynonymous single nucleotide polymorphisms in ampD with cephalosporin resistance and phylogenetic variations in ampC, ampR, ompF, and ompC in Enterobacter cloacae isolates that are highly resistant to carbapenems. Antimicrob Agents Chemother 60(4):2383–2390PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Bush K (2013) Carbapenemases: partners in crime. J Glob Antimicrob Resist 1:7–16PubMedCrossRefGoogle Scholar
  110. 110.
    Bonomo RA, Rice LB (1999) Inhibitor resistant class A beta-lactamases. Front Biosci 4:e34–e41PubMedCrossRefGoogle Scholar
  111. 111.
    Castanheira M, Mills JC, Costello SE, Jones RN, Sader HS (2015) Ceftazidime-avibactam activity tested against Enterobacteriaceae isolates from U.S. hospitals (2011 to 2013) and characterization of β-lactamase-producing strains. Antimicrob Agents Chemother 59:3509–3517PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Winkler ML, Papp-Wallace KM, Hujer AM, Domitrovic TN, Hujer KM, Hurless KN, Tuohy M, Halld G, Bonomo RA (2015) Unexpected challenges in treating multidrug-resistant Gram-negative bacteria: resistance to ceftazidime-avibactam in archived isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 59(2):1020–1029PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Clowes A, Lam M, Hamula C, Dingle T (2016) In vitro susceptibility of a collection of carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa to ceftazidime/avibactam and ceftolozane/tazobactam. Abstract FRIDAY-480. Paper presented at the Microbe 2016, Boston, MAGoogle Scholar
  114. 114.
    Alm RA, Johnstone MR, Lahiri SD (2015) Characterization of Escherichia coli NDM isolates with decreased susceptibility to aztreonam/avibactam: role of a novel insertion in PBP3. J Antimicrob Chemother 70(5):1420–1428PubMedCrossRefGoogle Scholar
  115. 115.
    Lahiri SD, Walkup GK, Whiteaker JD, Palmer T, McCormack K, Tanudra MA, Nash TJ, Thresher J, Johnstone MR, Hajec L, Livchak S, McLaughlin RE, Alm RA (2015) Selection and molecular characterization of ceftazidime/avibactam-resistant mutants in Pseudomonas aeruginosa strains containing derepressed AmpC. J Antimicrob Chemother 70(6):1650–1658PubMedGoogle Scholar
  116. 116.
    Livermore DM, Warner M, Jamrozy D, Mushtaq S, Nichols WW, Mustafa N, Woodford N (2015) In vitro selection of ceftazidime-avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob Agents Chemother 59(9):5324–5330PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Berrazeg M, Jeannot K, Enguéné VYN, Broutin I, Loeffert S, Fournier D, Plésiat P (2015) Mutations in ß-lactamase AmpC increase resistance of Pseudomonas aeruginosa isolates to antipseudomonal cephalosporins. Antimicrob Agents Chemother 59(10):6248–6255PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Castanheira M, Mills JC, Farrell DJ, Jones RN (2014) Mutation-driven beta-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from U.S. hospitals. Antimicrob Agents Chemother 58(11):6844–6850PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Cabot G, Bruchmann S, Mulet X, Zamorano L, Moya B, Juan C, Haussler S, Oliver A (2014) Pseudomonas aeruginosa ceftolozane-tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob Agents Chemother 58(6):3091–3099PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Shields RK, Clancy CJ, Hao B, Chen L, Press EG, Iovine NM, Kreiswirth BN, Nguyen MH (2015) Effects of Klebsiella pneumoniae carbapenemase subtypes, etended-spectrum β-lactamases, and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant K. pneumoniae. Antimicrob Agents Chemother 59:5793–5797PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Humphries RM, Yang S, Hemarajata P, Ward KW, Hindler JA, Miller SA, Gregson A (2015) First report of ceftazidime-avibactam resistance in a KPC-3 expressing Klebsiella pneumoniae. Antimicrob Agents Chemother (Posted Online 20 July 2015)Google Scholar
  122. 122.
    Haidar G, Clancy CJ, Shields RK, Doi Y, Potoski BA, Nguyen MH (2016) Ceftolozane-tazobactam (C/T) is effective against most multidrug-resistant (Mdr) P. aeruginosa (pa) infections, but resistance may emerge on therapy. Abstract SUNDAY-331. Microbe 2016. American Society for Microbiology, Boston, MAGoogle Scholar
  123. 123.
    Hooper DC, Jacoby GA (2015) Mechanisms of drug resistance: quinolone resistance. Ann N Y Acad Sci 1354:12–31PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Aggen JB, Armstrong ES, Goldblum AA, Dozzo P, Linsell MS, Gliedt MJ, Hildebrandt DJ, Feeney LA, Kubo A, Matias RD, Lopez S, Gomez M, Wlasichuk KB, Diokno R, Miller GH, Moser HE (2010) Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 54(11):4636–4642PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (2016) Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16(2):161–168PubMedCrossRefGoogle Scholar
  126. 126.
    Wilkinson SG (1996) Bacterial lipopolysaccharides—themes and variations. Prog Lipid Res 35:283–343PubMedCrossRefGoogle Scholar
  127. 127.
    Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Page MGP (2012) The role of the outer membrane of Gram-negative bacteria in antibiotic resistance: Ajax’ Shield or Achilles’ heel? In: Handbook of experimental pharmacology, vol 211. Springer, BerlinGoogle Scholar
  129. 129.
    Nikaido H (1976) Outer membrane of Salmonella typhimurium. Transmembrane diffusion of some hydrophobic substances. Biochim Biophys Acta 433:118–132PubMedCrossRefGoogle Scholar
  130. 130.
    Palomar J, Puig M, Montilla R, Loren JG, Vinas M (1995) Isolation of antibiotic hypersusceptibility mutants of Acinetobacter spp. by selection for DNA release. Microbios 82:21–26PubMedGoogle Scholar
  131. 131.
    Banemann A, Deppisch H, Gross R (1998) The lipopolysaccharide of Bordetella bronchiseptica acts as a protective shield against antimicrobial peptides. Infect Immun 66:5607–5612PubMedPubMedCentralGoogle Scholar
  132. 132.
    Caroff M, Karibian D (2003) Structure of bacterial lipopolysaccharides. Carbohydr Res 338:2431–2447PubMedCrossRefGoogle Scholar
  133. 133.
    Nikaido H, Vaara M (1985) Molecular basis of bacterial outer membrane permeability. Microbiol Rev 49(1):1–32PubMedPubMedCentralGoogle Scholar
  134. 134.
    Nikaido H (1985) Role of permeability barriers in resistance to β-lactam antibiotics. In: Antibiotic inhibitors of bacterial cell wall biosynthesis. International encyclopedia of pharmacology and therapeutics, vol 127. Pergamon Press, OxfordGoogle Scholar
  135. 135.
    Vuorio R, Vaara M (1992) Comparison of the phenotypes of the lpxA and lpxD mutants of Escherichia coli. Antimicrob Agents Chemother 36:826–829PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Vaara M (1993) Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in Gram-negative enteric bacteria. Antimicrobial Agents Chemother 37(2):354–356CrossRefGoogle Scholar
  137. 137.
    Trent MS, Ribeiro AA, Lin S, Cotter RJ, Raetz CR (2001) An inner membrane enzyme in Salmonella and Escherichia coli that transfers 4-amino-4-deoxy-l-arabinose to lipid A: induction on polymyxin-resistant mutants and role of a novel lipid-linked donor. J Biol Chem 276(46):43122–43131PubMedCrossRefGoogle Scholar
  138. 138.
    Lee H, Hsu FF, Turk J, Groisman EA (2004) The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. J Bacteriol 186:4124–4133PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Yan A, Guan Z, Raetz CRH (2007) An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli. J Biol Chem 282:36077–36089PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Gibbons HS, Kalb SR, Cotter RJ, Raetz CRH (2005) Role of Mg2 + and pH in the modification of Salmonella lipid A after endocytosis by macrophage tumour cells. Molec Microbiol 55:425–440CrossRefGoogle Scholar
  141. 141.
    Parr TR Jr, Moore RA, Moore LV, Hancock REW (1987) Role of porins in intrinsic antibiotic resistance of Pseudomonas cepacia. Antimicrob Agents Chemother 31:121–123PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Ochs MM, McCusker MP, Bains M, Hancock RE (1999) Negative regulation of the Pseudomonas aeruginosa outer membrane porin OprD selective for imipenem and basic amino acids. Antimicrob Agents Chemother 43(5):1085–1090PubMedPubMedCentralGoogle Scholar
  143. 143.
    Ruiz N, Montero T, Hernandez-Borrell J, Vinas M (2003) The role of Serratia marcescens porins in antibiotic resistance. Microb Drug Resist 9:257–264PubMedCrossRefGoogle Scholar
  144. 144.
    Olesky M, Zhao S, Rosenberg RL, Nicholas RA (2006) Porin-mediated antibiotic resistance in Neisseria gonorrhoeae: ion, solute, and antibiotic permeation through PIB proteins with penB mutations. J Bacteriol 188:2300–2308PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Vila J, Marti S, Sanchez-Céspedes J (2007) Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii. J Antimicrob Chemother 59:1210–1215PubMedCrossRefGoogle Scholar
  146. 146.
    Dreier J (2007) Active drug efflux in bacteria enzyme-mediated resistance to antibiotics: mechanisms, dissemination, and prospects for inhibition. ASM Press, Washington, DCGoogle Scholar
  147. 147.
    Pai H, Kim J-W, Kim J, Lee JH, Choe KW, Gotoh N (2001) Carbapenem resistance mechanisms in Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 45:480–484PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Bajaj H, Scorciapino MA, Moynié L, Page MG, Naismith JH, Ceccarelli M, Winterhalter M (2016) Molecular basis of filtering carbapenems by porins from β-lactam-resistant clinical strains of Escherichia coli. J Biol Chem 291:2837–2847PubMedCrossRefGoogle Scholar
  149. 149.
    Turnidge JD (1998) The pharmacodynamics of beta-lactams. Clin Infect Dis 27(1):10–22PubMedCrossRefGoogle Scholar
  150. 150.
    Drusano GL (2004) Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2:289–300PubMedCrossRefGoogle Scholar
  151. 151.
    Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12PubMedCrossRefGoogle Scholar
  152. 152.
    Mouton JW, Punt N, Vinks AA (2007) Concentration-effect relationship of ceftazidime explains why the time above the MIC is 40 percent for a static effect in vivo. Antimicrob Agents Chemother 51:3449–3451PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Mouton JW, Brown DF, Apfalter P, Cantón R, Giske CG, Ivanova M, MacGowan AP, Rodloff A, Soussy CJ, Steinbakk M, Kahlmeter G (2012) The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 18:E37–E45PubMedCrossRefGoogle Scholar
  154. 154.
    Muller AE, Punt N, Mouton JW (2013) Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia. J Antimicrob Chemother 68:900–906PubMedCrossRefGoogle Scholar
  155. 155.
    Muller AE, Punt N, Mouton JW (2014) Exposure to ceftobiprole is associated with microbiological eradication and clinical cure in patients with nosocomial pneumonia. Antimicrob Agents Chemother 58:2512–2519PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    De Waele JJ, Lipman J, Akova M, Bassetti M, Dimopoulos G, Kaukonen M, Koulenti D, Martin M, Montravers P, Rello J, Rhodes A, Udy AA, Starr T, Wallis SC, Roberts JA (2014) Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients. Int Care Med 40:1340–1351CrossRefGoogle Scholar
  157. 157.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL (2014) Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14:498–509PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Strayer AH, Gilbert DH, Pivarnik P, Medeiros AA, Zinner SH, Dudley MN (1994) Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection. Antimicrob Agents Chemother 38(10):2351–2356PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Bush K (2015) A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents 46(5):483–493PubMedCrossRefGoogle Scholar
  160. 160.
    Craig WA, Andes DR (2013) In vivo activities of ceftolozane, a new cephalosporin, with and without tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae, including strains with extended-spectrum beta-lactamases, in the thighs of neutropenic mice. Antimicrob Agents Chemother 57(4):1577–1582PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    VanScoy B, Mendes RE, Nicasio AM, Castanheira M, Bulik CC, Okusanya OO, Bhavnani SM, Forrest A, Jones RN, Friedrich LV, Steenbergen JN, Ambrose PG (2013) Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. Antimicrob Agents Chemother 57(6):2809–2814PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Bhagunde P, Chang K-T, Hirsch EB, Ledesma KR, Nikolaou M, Tam VH (2012) A novel modeling framework to guide design of optimal dosing strategies for beta-lactamase inhibitors. Antimicrob Agents Chemother 56:2237–2240PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Mavridou E, Melchers RJB, vanMil ACHAM, Mangin E, Motyl MR, Mouton JW (2015) Pharmacodynamics of imipenem in combination with β-lactamase inhibitor MK7655 in a murine thigh model. Antimicrob Agents Chemother 59:790–795PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Singh R, Kim A, Tanudra MA, Harris JJ, McLaughlin RE, Patey S, O’Donnell JP, Bradford PA, Eakin AE (2015) Pharmacokinetics/pharmacodynamics of a beta-lactam and beta-lactamase inhibitor combination: a novel approach for aztreonam/avibactam. J Antimicrob Chemother 70(9):2618–2626PubMedCrossRefGoogle Scholar
  165. 165.
    Sy SKB, Beaudoin M-E, Zhuang L, Löblein KI, Lux C, Kissel M, Tremmel R, Frank C, Strasser S, Heuberger JAAC, Mulder MB, Schuck VJ, Derendorf H (2016) In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms. J Antimicrob Chemother 71:1866–1880PubMedCrossRefGoogle Scholar
  166. 166.
    Sykes RB, Koster WH, Bonner DP (1988) The new monobactams: chemistry and biology. J Clin Pharmacol 28(2):113–119PubMedCrossRefGoogle Scholar
  167. 167.
    Zurenko GE, Truesdell SE, Yagi BH, Mourey RJ, Laborde AL (1990) In vitro antibacterial activity and interactions with beta-lactamases and penicillin-binding proteins of the new monocarbam antibiotic U-78608. Antimicrob Agents Chemother 34(5):884–888PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Han S, Zaniewski RP, Marr ES, Lacey BM, Tomaras AP, Evdokimov A, Miller JR, Shanmugasundaram V (2010) Structural basis for effectiveness of siderophore-conjugated monocarbams against clinically relevant strains of Pseudomonas aeruginosa. Proc Natl Acad Sci USA 107(51):22002–22007PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Murphy-Benenato KE, Bhagunde PR, Chen A, Davis HE, Durand-Reville TF, Ehmann DE, Galullo V, Harris JJ, Hatoum-Mokdad H, Jahic H, Kim A, Manjunatha MR, Manyak EL, Mueller J, Patey S, Quiroga O, Rooney M, Sha L, Shapiro AB, Sylvester M, Tan B, Tsai AS, Uria-Nickelsen M, Wu Y, Zambrowski M, Zhao SX (2015) Discovery of efficacious Pseudomonas aeruginosa-targeted siderophore-conjugated monocarbams by application of a semi-mechanistic pharmacokinetic/pharmacodynamic model. J Med Chem 58(5):2195–2205PubMedCrossRefGoogle Scholar
  170. 170.
    Tomaras AP, Crandon JL, McPherson CJ, Nicolau DP (2015) Potentiation of antibacterial activity of the MB-1 siderophore-monobactam conjugate using an efflux pump inhibitor. Antimicrob Agents Chemother (accepted manuscript posted online 20 January 2015)Google Scholar
  171. 171.
    McPherson CJ, Aschenbrenner LM, Lacey BM, Fahnoe KC, Lemmon MM, Finegan SM, Tadakamalla B, O’Donnell JP, Mueller JP, Tomaras AP (2012) Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophore-conjugated monocarbam. Antimicrob Agents Chemother 56(12):6334–6342PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kim A, Kutschke A, Ehmann DE, Patey SA, Crandon JL, Gorseth E, Miller AA, McLaughlin RE, Blinn CM, Chen A, Nayar AS, Dangel B, Tsai AS, Rooney MT, Murphy-Benenato KE, Eakin AE, Nicolau DP (2015) Pharmacodynamic profiling of a siderophore-conjugated monocarbam in Pseudomonas aeruginosa: assessing the risk for resistance and attenuated efficacy. Antimicrob Agents Chemother 59(12):7743–7752PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    van Delden C, Page MG, Kohler T (2013) Involvement of Fe uptake systems and AmpC β-lactamase in susceptibility to the siderophore monosulfactam BAL30072 in Pseudomonas aeruginosa. Antimicrob Agents Chemother 57(5):2095–2102PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Tomaras AP, Crandon JL, McPherson CJ, Banevicius MA, Finegan SM, Irvine RL, Brown MF, O’Donnell JP, Nicolau DP (2013) Adaptation-based resistance to siderophore-conjugated antibacterial agents by Pseudomonas aeruginosa. Antimicrob Agents Chemother 57(9):4197–4207PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Page M, Müller C, Hofer B, Desarbre E, Dreier J, Vidal F (2010) The role of iron transport in the activity of the siderophore sulfactam BAL30072 against Pseudomonas aeruginosa—P 1241 Abstracts of 20th ECCMID Clin Microbiol Infect 16. Suppl 2:S1–S720Google Scholar
  176. 176.
    Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, Pandey R, Doi Y, Kreiswirth BN, Nguyen MH, Clancy CJ (2016) Emergence of ceftazidime-avibactam resistance due to plasmid-borne bla KPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother (published online 28 Dec 2016)Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Indiana UniversityBloomingtonUSA
  2. 2.Jacobs UniversityBremenGermany

Personalised recommendations