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Synergistic Antibiotic Combinations

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Antibacterials

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 25))

Abstract

Synergy between antibiotics is a strictly defined microbiological phenomenon, requiring two bioactive agents to exhibit enhanced bacterial killing when the two are combined. Because of increasing antibiotic resistance, and few new drugs to treat multidrug-resistant bacteria, combination therapy is often used in the clinical setting. Frequently, these combinations have demonstrated synergistic activity both in vitro and in animal models before being used therapeutically. Antibiotic combinations are more likely to be used in patients with drug-resistant staphylococcal or enterococcal infections, as well as in patients whose diseases are caused by carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, or Acinetobacter spp. Although well-defined combinations have been approved by regulatory authorities as single agents, such as trimethoprim–sulfamethoxazole or β-lactamase inhibitor combinations, many combinations are used empirically with no clinical data to support their use. Because combination therapy will continue to be used in the absence of supportive clinical data, it will be important in the future to investigate mechanistic principles that may lead to predictive models for successful patient outcomes.

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References

  1. Blake FG (1940) Chemotherapy with the sulfonamide derivatives: general principles. Bull N Y Acad Med 16:197–207

    PubMed  PubMed Central  CAS  Google Scholar 

  2. Chain E, Florey HW, Gardner AD et al (1940) Penicillin as a chemotherapeutic agent. Lancet 236:226–228

    Article  Google Scholar 

  3. Waksman SA, Woodruff HB (1942) Selective antibiotic action of various substances of microbial origin. J Bacteriol 44:373–384

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Kirby WMN (1944) Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science 99:452–453

    Article  CAS  PubMed  Google Scholar 

  5. Barber M, Whitehead JE (1949) Bacteriophage types in penicillin-resistant staphylococcal infection. Br Med J 2:565–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Medeiros AA (1997) Evolution and dissemination of β-lactamases accelerated by generations of β-lactam antibiotics. Clin Infect Dis 24:S19–S45

    Article  CAS  PubMed  Google Scholar 

  7. CDC (2017) Get smart: know when antibiotics work. https://www.cdc.gov/getsmart/community/about/index.html. Accessed 5 Feb 2017

  8. Dall C (2016) UN leaders pledge to fight antimicrobial resistance. http://www.cidrap.umn.edu/news-perspective/2016/09/un-leaders-pledge-fight-antimicrobial-resistance. Accessed 2 Feb 2017

  9. CDC (2013) Antibiotic resistance threats in the United States, 2013. CDC, Atlanta

    Google Scholar 

  10. WHO (2017) WHO publishes list of bacteria for which new antibiotics are urgently needed. Press Release by WHO, Geneva

    Google Scholar 

  11. Mutlu GM, Wunderink RG (2006) Severe pseudomonal infections. Curr Opin Crit Care 12:458–463. doi:10.1097/01.ccx.0000244127.92612.b4

    Article  PubMed  Google Scholar 

  12. Arthur LE, Kizor RS, Selim AG et al (2016) Antibiotics for ventilator-associated pneumonia. Cochrane Database Syst Rev 10:CD004267. doi:10.1002/14651858.CD004267.pub4

    Article  PubMed  Google Scholar 

  13. Perez F, El Chakhtoura NG, Papp-Wallace KM et al (2016) Treatment options for infections caused by carbapenem-resistant Enterobacteriaceae: can we apply “precision medicine” to antimicrobial chemotherapy? Expert Opin Pharmacother 17:761–781. doi:10.1517/14656566.2016.1145658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kurz SG, Furin JJ, Bark CM (2016) Drug-resistant tuberculosis: challenges and progress. Infect Dis Clin N Am 30:509–522. doi:10.1016/j.idc.2016.02.010

    Article  Google Scholar 

  15. Drago L, De Vecchi E, Nicola L et al (2005) In vitro selection of resistance in Pseudomonas aeruginosa and Acinetobacter spp. by levofloxacin and ciprofloxacin alone and in combination with beta-lactams and amikacin. J Antimicrob Chemother 56:353–359. doi:10.1093/jac/dki204

    Article  PubMed  CAS  Google Scholar 

  16. Chait R, Craney A, Kishony R (2007) Antibiotic interactions that select against resistance. Nature 446:668–671. doi:10.1038/nature05685

    Article  PubMed  CAS  Google Scholar 

  17. Ly NS, Bulitta JB, Rao GG et al (2015) Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance. J Antimicrob Chemother 70:1434–1442. doi:10.1093/jac/dku567

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Vestergaard M, Paulander W, Marvig RL et al (2016) Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa. Int J Antimicrob Agents 47:48–55. doi:10.1016/j.ijantimicag.2015.09.014

    Article  PubMed  CAS  Google Scholar 

  19. Janardhanan J, Meisel JE, Ding D et al (2016) In vitro and in vivo synergy of the oxadiazole class of antibacterials with β-lactams. Antimicrob Agents Chemother 60:5581–5588. doi:10.1128/AAC.00787-16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Odds FC (2003) Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 52:1. doi:10.1093/jac/dkg301

    Article  PubMed  Google Scholar 

  21. Greco WR, Bravo G, Parsons JC (1995) The search for synergy: a critical review from a response surface perspective. Pharmacol Rev 47:331–385

    PubMed  CAS  Google Scholar 

  22. Johnson MD, MacDougall C, Ostrosky-Zeichner L et al (2004) Combination antifungal therapy. Antimicrob Agents Chemother 48:693–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sy CL, Huang TS, Chen CS et al (2016) Synergy of β-lactams with vancomycin against methicillin-resistant Staphylococcus aureus: correlation of disk diffusion and checkerboard methods. J Clin Microbiol 54:565–568. doi:10.1128/JCM.01779-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. American Society for Microbiology (2017) Instructions to authors. Antimicrob Agents Chemother 1–25. aac.asm.org. Accessed 1 June 2017

    Google Scholar 

  25. Bushby SR, Hitchings GH (1968) Trimethoprim, a sulphonamide potentiator. Br J Pharmacol Chemother 33:72–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gleckman R, Alvarez S, Joubert DW (1979) Drug therapy reviews: trimethoprim-sulfamethoxazole. Am J Hosp Pharm 36:893–906

    PubMed  CAS  Google Scholar 

  27. Brumfitt W, Hamilton-Miller JM (1994) Limitations of and indications for the use of co-trimoxazole. J Chemother 6:3–11

    Article  CAS  PubMed  Google Scholar 

  28. Brumfitt W, Hamilton-Miller JM (1995) Combinations of sulphonamides with diaminopyrimidines: how, when and why? J Chemother 7:136–139

    Article  CAS  PubMed  Google Scholar 

  29. Wylie BA, Amyes SG, Young HK et al (1988) Identification of a novel plasmid-encoded dihydrofolate reductase mediating high-level resistance to trimethoprim. J Antimicrob Chemother 22:429–435

    Article  CAS  PubMed  Google Scholar 

  30. Lin L, Nonejuie P, Munguia J et al (2015) Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant Gram-negative bacterial pathogens. EBioMedicine 2:690–698. doi:10.1016/j.ebiom.2015.05.021

    Article  PubMed  PubMed Central  Google Scholar 

  31. Abdul Rahim N, Cheah SE, Johnson MD et al (2015) Synergistic killing of NDM-producing MDR Klebsiella pneumoniae by two ‘old’ antibiotics-polymyxin B and chloramphenicol. J Antimicrob Chemother 70:2589–2597. doi:10.1093/jac/dkv135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Leite GC, Oliveira MS, Perdigao-Neto LV et al (2016) Antimicrobial combinations against pan-resistant Acinetobacter baumannii isolates with different resistance mechanisms. PLoS One 11:e0151270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sakoulas G, Rose W, Berti A et al (2017) Classical β-lactamase inhibitors potentiate the activity of daptomycin against methicillin-resistant Staphylococcus aureus and colistin against Acinetobacter baumannii. Antimicrob Agents Chemother 61:e01745–e01716

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Ni W, Han Y, Liu J et al (2016) Tigecycline treatment for carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis. Medicine 95(11):e3126. doi:10.1097/MD.0000000000003126

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Taccone FS, Rodriguez-Villalobos H, De Backer D et al (2006) Successful treatment of septic shock due to pan-resistant Acinetobacter baumannii using combined antimicrobial therapy including tigecycline. Eur J Clin Microbiol Infect Dis 25:257–260. doi:10.1007/s10096-006-0123-1

    Article  PubMed  CAS  Google Scholar 

  36. Principe L, D'Arezzo S, Capone A et al (2009) In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii. Ann Clin Microbiol Antimicrob 8:18. doi:10.1186/1476-0711-8-18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Humphries RM, Kelesidis T, Bard JD et al (2010) Successful treatment of pan-resistant Klebsiella pneumoniae pneumonia and bacteraemia with a combination of high-dose tigecycline and colistin. J Med Microbiol 59:1383–1386. doi:10.1099/jmm.0.023010-0

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sakoulas G, Moise PA, Casapao AM et al (2014) Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther 36:1317–1333

    Article  CAS  PubMed  Google Scholar 

  39. Berti AD, Theisen E, Sauer JD et al (2015) Penicillin binding protein 1 is important in the compensatory response of Staphylococcus aureus to daptomycin-induced membrane damage and is a potential target for β-lactam-daptomycin synergy. Antimicrob Agents Chemother 60:451–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Snydman DR, McDermott LA, Jacobus NV (2005) Evaluation of in vitro interaction of daptomycin with gentamicin or beta-lactam antibiotics against Staphylococcus aureus and enterococci by FIC index and timed-kill curves. J Chemother 17:614–621. doi:10.1179/joc.2005.17.6.614

    Article  PubMed  CAS  Google Scholar 

  41. Smith JR, Barber KE, Raut A et al (2015) β-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. J Antimicrob Chemother 70:1738–1743. doi:10.1093/jac/dkv007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Aktas G, Derbentli S (2017) In vitro activity of daptomycin combined with dalbavancin and linezolid, and dalbavancin with linezolid against MRSA strains. J Antimicrob Chemother 72:441–443. doi:10.1093/jac/dkw416

    Article  PubMed  CAS  Google Scholar 

  43. Davis JS, Van Hal S, Tong SY (2015) Combination antibiotic treatment of serious methicillin-resistant Staphylococcus aureus infections. Semin Respir Crit Care Med 36:3–16. doi:10.1055/s-0034-1396906

    Article  PubMed  CAS  Google Scholar 

  44. Jiang JH, Peleg AY (2015) Daptomycin-nonsusceptible Staphylococcus aureus: the role of combination therapy with daptomycin and gentamicin. Genes 6:1256–1267. doi:10.3390/genes6041256

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Lemonovich TL, Haynes K, Lautenbach E et al (2011) Combination therapy with an aminoglycoside for Staphylococcus aureus endocarditis and/or persistent bacteremia is associated with a decreased rate of recurrent bacteremia: a cohort study. Infection 39:549–554. doi:10.1007/s15010-011-0189-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Silvestri C, Cirioni O, Arzeni D et al (2012) In vitro activity and in vivo efficacy of tigecycline alone and in combination with daptomycin and rifampin against Gram-positive cocci isolated from surgical wound infection. Eur J Clin Microbiol Infect Dis 31:1759–1764. doi:10.1007/s10096-011-1498-1

    Article  PubMed  CAS  Google Scholar 

  47. Head BM, Alfa M, Sitar DS et al (2017) In vitro evaluation of the effect of linezolid and levofloxacin on Bacillus anthracis toxin production, spore formation and cell growth. J Antimicrob Chemother 72:417–420. doi:10.1093/jac/dkw427

    Article  PubMed  CAS  Google Scholar 

  48. Davis JS, Sud A, O'Sullivan MV et al (2016) Combination of vancomycin and β-lactam therapy for methicillin-resistant Staphylococcus aureus bacteremia: a pilot multicenter randomized controlled trial. Clin Infect Dis 62:173–180. doi:10.1093/cid/civ808

    Article  PubMed  CAS  Google Scholar 

  49. Gonzales PR, Pesesky MW, Bouley R et al (2015) Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA. Nat Chem Biol 11:855–861. doi:10.1038/nchembio.1911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Barber KE, Rybak MJ, Sakoulas G (2015) Vancomycin plus ceftaroline shows potent in vitro synergy and was successfully utilized to clear persistent daptomycin-non-susceptible MRSA bacteraemia. J Antimicrob Chemother 70:311–313

    Article  CAS  PubMed  Google Scholar 

  51. Gritsenko D, Fedorenko M, Ruhe JJ et al (2017) Combination therapy with vancomycin and ceftaroline for refractory methicillin-resistant Staphylococcus aureus bacteremia: a case series. Clin Ther 39:212–218

    Article  CAS  PubMed  Google Scholar 

  52. Bernardo K, Pakulat N, Fleer S et al (2004) Subinhibitory concentrations of linezolid reduce Staphylococcus aureus virulence factor expression. Antimicrob Agents Chemother 48:546–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stevens DL, Ma Y, Salmi DB et al (2007) Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis 195:202–211. doi:10.1086/510396

    Article  PubMed  CAS  Google Scholar 

  54. Claeys KC, Smith JR, Casapao AM et al (2015) Impact of the combination of daptomycin and trimethoprim-sulfamethoxazole on clinical outcomes in methicillin-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother 59:1969–1976. doi:10.1128/AAC.04141-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Leonard SN, Kaatz GW, Rucker LR et al (2008) Synergy between gemifloxacin and trimethoprim/sulfamethoxazole against community-associated methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 62:1305–1310. doi:10.1093/jac/dkn379

    Article  PubMed  CAS  Google Scholar 

  56. Kang YR, Chung DR, Kim J et al (2016) In vitro synergistic effects of various combinations of vancomycin and non-β-lactams against Staphylococcus aureus with reduced susceptibility to vancomycin. Diagn Microbiol Infect Dis 86:293–299. doi:10.1016/j.diagmicrobio.2016.08.009

    Article  PubMed  CAS  Google Scholar 

  57. Linden P (1999) Quinupristin-dalfopristin. Curr Infect Dis Rep 1:480–487

    Article  CAS  PubMed  Google Scholar 

  58. Isnard C, Malbruny B, Leclercq R et al (2013) Genetic basis for in vitro and in vivo resistance to lincosamides, streptogramins A, and pleuromutilins (LSAP phenotype) in Enterococcus faecium. Antimicrob Agents Chemother 57:4463–4469. doi:10.1128/AAC.01030-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Bush K, Bradford PA (2016) β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harb Perspect Med 6:a025247. doi:10.1101/cshperspect.a025247

    Article  PubMed  PubMed Central  Google Scholar 

  60. Drawz SM, Papp-Wallace KM, Bonomo RA (2014) New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother 58:1835–1846. doi:10.1128/AAC.00826-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Bush K (2015) A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens. Int J Antimicrob Agents 46:483–493. doi:10.1016/j.ijantimicag.2015.08.011

    Article  PubMed  CAS  Google Scholar 

  62. Drawz SM, Bonomo RA (2010) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23:160–201. doi:10.1128/CMR.00037-09

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Mulvey MR, Bryce E, Boyd D et al (2004) Ambler class A extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella spp. in Canadian hospitals. Antimicrob Agents Chemother 48:1204–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mushtaq S, Ge Y, Livermore DM (2004) Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases. Antimicrob Agents Chemother 48:1313–1319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yigit H, Queenan AM, Rasheed JK et al (2003) Carbapenem-resistant strain of Klebsiella oxytoca harboring carbapenem-hydrolyzing beta-lactamase KPC-2. Antimicrob Agents Chemother 47:3881–3889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bush K, Jacoby GA, Medeiros AA (1995) A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob Agents Chemother 39:1211–1233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bush K (2013) Carbapenemases: partners in crime. J Glob Antimicrob Resist 1:7–16. doi:10.1016/j.jgar.2013.01.005

    Article  PubMed  Google Scholar 

  68. Chandorkar G, Huntington JA, Gotfried MH et al (2012) Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother 67:2463–2469. doi:10.1093/jac/dks246

    Article  PubMed  CAS  Google Scholar 

  69. Miller B, Hershberger E, Benziger D et al (2012) Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses. Antimicrob Agents Chemother 56:3086–3091. doi:10.1128/AAC.06349-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Estabrook M, Bussell B, Clugston SL et al (2014) In vitro activity of ceftolozane-tazobactam as determined by broth dilution and agar diffusion assays against recent U.S. Escherichia coli isolates from 2010 to 2011 carrying CTX-M-type extended-spectrum β-lactamases. J Clin Microbiol 52:4049–4052. doi:10.1128/JCM.02357-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Buehrle DJ, Shields RK, Chen L et al (2016) Evaluation of the in vitro activity of ceftazidime-avibactam and ceftolozane-tazobactam against meropenem-resistant Pseudomonas aeruginosa isolates. Antimicrob Agents Chemother 60:3227–3231. doi:10.1128/AAC.02969-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Neu HC, Fu KP (1978) Clavulanic acid, a novel inhibitor of β-lactamases. Antimicrob Agents Chemother 14:650–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Penwell WF, Shapiro AB, Giacobbe RA et al (2015) Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii. Antimicrob Agents Chemother 59:1680–1689. doi:10.1128/AAC.04808-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Asli A, Brouillette E, Krause KM et al (2016) Distinctive binding of avibactam to penicillin-binding proteins of Gram-negative and Gram-positive bacteria. Antimicrob Agents Chemother 60:752–756. doi:10.1128/AAC.02102-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Lagace-Wiens PR, Tailor F, Simner P et al (2011) Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum β-lactamases and class C β-lactamases. Antimicrob Agents Chemother 55:2434–2437. doi:10.1128/AAC.01722-10

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Ehmann DE, Jahic H, Ross PL et al (2012) Avibactam is a covalent, reversible, non-β-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 109:11663–11668. doi:10.1074/jbc.M113.485979

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Ehmann DE, Jahić H, Ross PL et al (2013) Kinetics of avibactam inhibition against class A, C, and D β-lactamases. J Biol Chem 288:27960–27971. doi:10.1074/jbc.M113.485979

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Stachyra T, Levasseur P, Pechereau MC et al (2009) In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 64:326–329. doi:10.1093/jac/dkp197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Livermore DM, Mushtaq S, Warner M et al (2008) NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum β-lactamases and carbapenemases. J Antimicrob Chemother 62:1053–1056. doi:10.1093/jac/dkn320

    Article  PubMed  CAS  Google Scholar 

  80. Li H, Estabrook M, Jacoby GA et al (2015) In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother 59:1789–1793. doi:10.1128/AAC.04191-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Marshall S, Hujer AM, Rojas LJ et al (2017) Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother 61:e02243-16. doi:10.1128/AAC.02243-16

    Article  PubMed  PubMed Central  Google Scholar 

  82. Hirsch EB, Ledesma KR, Chang K-T et al (2012) In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob Agents Chemother 56:3753–3757. doi:10.1128/AAC.05927-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Morinaka A, Tsutsumi Y, Yamada M et al (2015) OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam ‘enhancer’. J Antimicrob Chemother 70:2779–2786. doi:10.1093/jac/dkv166

    Article  PubMed  CAS  Google Scholar 

  84. Livermore DM, Mushtaq S, Warner M et al (2017) In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria. J Antimicrob Chemother 72:1373–1385. doi:10.1093/jac/dkw593

    Article  PubMed  CAS  Google Scholar 

  85. Durand-Reville T (2017) Discovery of ETX2514, a novel, rationally designed inhibitor of class A, C and D beta-lactamases, for the treatment of Gram-negative infections. In: Abstr 253rd ACS general meeting, San Francisco, CA, Apr 2017

    Google Scholar 

  86. Shields RK, Chen L, Cheng S et al (2017) Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother 61:e02097–16. doi:10.1128/AAC.02097-16

    Article  PubMed  PubMed Central  Google Scholar 

  87. 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 70:1420–1428. doi:10.1093/jac/dku568

    Article  PubMed  CAS  Google Scholar 

  88. Zhang Y, Kashikar A, Brown CA et al (2017) An unusual E. coli PBP3 insertion sequence identified from a collection of carbapenem-resistant Enterobacteriaceae (CRE) tested in vitro with ceftazidime-, ceftaroline- or aztreonam-avibactam combinations. Antimicrob Agents Chemother 61 (accepted manuscript posted online 30 May 2017). doi:10.1128/AAC.00389-17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Nabarro LE, Veeraraghavan B (2015) Combination therapy for carbapenem-resistant Enterobacteriaceae: increasing evidence, unanswered questions, potential solutions. Eur J Clin Microbiol Infect Dis 34:2307–2311. doi:10.1007/s10096-015-2486-7

    Article  PubMed  CAS  Google Scholar 

  90. Poirel L, Kieffer N, Nordmann P (2016) In vitro evaluation of dual carbapenem combinations against carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 71:156–161. doi:10.1093/jac/dkv294

    Article  PubMed  CAS  Google Scholar 

  91. Tumbarello M, Trecarichi EM, De Rosa FG et al (2015) Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 70:2133–2143. doi:10.1093/jac/dkv086

    Article  PubMed  CAS  Google Scholar 

  92. Stein C, Makarewicz O, Bohnert JA et al (2015) Three dimensional checkerboard synergy analysis of colistin, meropenem, tigecycline against multidrug-resistant clinical Klebsiella pneumonia isolates. PLoS One 10:e0126479. doi:10.1371/journal.pone.0126479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Čivljak R, Giannella M, Di Bella S et al (2014) Could chloramphenicol be used against ESKAPE pathogens? A review of in vitro data in the literature from the 21st century. Expert Rev Anti Infect Ther 12:249–264. doi:10.1586/14787210.2014.878647

    Article  PubMed  CAS  Google Scholar 

  94. O'Driscoll T, Crank CW (2015) Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infect Drug Resist 8:217–230. doi:10.2147/IDR.S54125

    Article  PubMed  PubMed Central  Google Scholar 

  95. Otero LH, Rojas-Altuve A, Llarrull LI et al (2013) How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A 110:16808–16813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Henson KER, Yim J, Smith JR et al (2017) β-Lactamase inhibitors enhance the synergy between β-lactam antibiotics and daptomycin against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 61:e01564–e01516

    Article  CAS  PubMed  Google Scholar 

  97. Cosgrove SE, Vigliani GA, Fowler VG Jr et al (2009) Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 48:713–721. doi:10.1086/597031

    Article  PubMed  Google Scholar 

  98. Alp E (2016) Right first time! Ann Transl Med 4:331. doi:10.21037/atm.2016.08.52

    Article  PubMed  PubMed Central  Google Scholar 

  99. Micozzi A, Gentile G, Minotti C et al (2017) Carbapenem-resistant Klebsiella pneumoniae in high-risk haematological patients: factors favouring spread, risk factors and outcome of carbapenem-resistant Klebsiella pneumoniae bacteremias. BMC Infect Dis 17:203. doi:10.1186/s12879-017-2297-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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  1. Indiana University Bloomington, Bloomington, IN, 47405, USA

    Karen Bush

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  1. Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA

    Jed F. Fisher , Shahriar Mobashery  & Marvin J. Miller ,  & 

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Bush, K. (2017). Synergistic Antibiotic Combinations. In: Fisher, J.F., Mobashery, S., Miller, M.J. (eds) Antibacterials. Topics in Medicinal Chemistry, vol 25. Springer, Cham. https://doi.org/10.1007/7355_2017_23

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