Antibiotic Resistance of Pathogens Causing Community-Acquired Pneumonia

Abstract

Community-acquired pneumonia remains an important cause of disease and death in both developed and developing countries and therefore continues to have a major medical impact. The mortality remains high despite the ready availability of potent antimicrobial agents to which the organisms are susceptible. However, management of these infections is potentially complicated by the emerging resistance of many of the common pathogens to the different classes of antibiotics that are usually prescribed. Furthermore, it is also being recognized that antibiotic resistance or treatment failures may occur not only through traditional microbial antibiotic resistance mechanisms but also through less well defined mechanisms, particularly those developed by the microbes in relation to their quorum sensing/biofilm machinery. Much recent research in this field has been focused on evaluating the clinical impact of antibiotic resistance on optimal antibiotic treatment and antimicrobial choices, as well as alternative strategies to deal with antibiotic resistance and treatment failures.

Keywords

antibiotic resistance - β-lactam antibiotics - biofilm formation - community-acquired pneumonia - fluoroquinolones - macrolides - quorum sensing

• References

• 1 Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67 (1) 71-79
• 2 File Jr TM, Marrie TJ. Burden of community-acquired pneumonia in North American adults. Postgrad Med 2010; 122 (2) 130-141
• 3 Isturiz RE, Luna CM, Ramirez J. Clinical and economic burden of pneumonia among adults in Latin America. Int J Infect Dis 2010; 14 (10) e852-e856
• 4 Song J-H, Thamlikitkul V, Hsueh P-R. Clinical and economic burden of community-acquired pneumonia amongst adults in the Asia-Pacific region. Int J Antimicrob Agents 2011; 38 (2) 108-117
• 5 Ramirez JA, Anzueto AR. Changing needs of community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (Suppl. 03) iii3-iii9
• 6 Huang SS, Johnson KM, Ray GT , et al. Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine 2011; 29 (18) 3398-3412
• 7 Ewig S, Torres A. Community-acquired pneumonia as an emergency: time for an aggressive intervention to lower mortality. Eur Respir J 2011; 38 (2) 253-260
• 8 Feikin DR, Feldman C, Schuchat A, Janoff EN. Global strategies to prevent bacterial pneumonia in adults with HIV disease. Lancet Infect Dis 2004; 4 (7) 445-455
• 9 Welte T, Köhnlein T. Global and local epidemiology of community-acquired pneumonia: the experience of the CAPNETZ Network. Semin Respir Crit Care Med 2009; 30 (2) 127-135
• 10 Woodhead M. The European vision of community-acquired pneumonia. Semin Respir Crit Care Med 2009; 30 (2) 136-145
• 11 Niederman MS. Community-acquired pneumonia: the U.S. perspective. Semin Respir Crit Care Med 2009; 30 (2) 179-188
• 12 Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents 2010; 36 (3) 197-204
• 13 Polverino E, Torres Marti A. Community-acquired pneumonia. Minerva Anestesiol 2011; 77 (2) 196-211
• 14 Metlay JP, Singer DE. Outcomes in lower respiratory tract infections and the impact of antimicrobial drug resistance. Clin Microbiol Infect 2002; 8 (Suppl. 02) 1-11
• 15 Jacobs MR, Anon J, Appelbaum PC. Mechanisms of resistance among respiratory tract pathogens. Clin Lab Med 2004; 24 (2) 419-453
• 16 Lynch III JP, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med 2010; 16 (3) 217-225
• 17 Feldman C. Clinical relevance of antimicrobial resistance in the management of pneumococcal community-acquired pneumonia. J Lab Clin Med 2004; 143 (5) 269-283
• 18 Lynch III JP, Zhanel GG. Streptococcus pneumoniae: does antimicrobial resistance matter?. Semin Respir Crit Care Med 2009; 30 (2) 210-238
• 19 Feldman C, Anderson R. Bacteraemic pneumococcal pneumonia: current therapeutic options. Drugs 2011; 71 (2) 131-153
• 20 Felmingham D, Feldman C, Hryniewicz W , et al. Surveillance of resistance in bacteria causing community-acquired respiratory tract infections. Clin Microbiol Infect 2002; 8 (Suppl. 02) 12-42
• 21 Klugman KP, Low DE, Metlay J, Pechere J-C, Weiss K. Community-acquired pneumonia: new management strategies for evolving pathogens and antimicrobial susceptibilities. Int J Antimicrob Agents 2004; 24 (5) 411-422
• 22 Alpuche C, Garau J, Lim V. Global and local variations in antimicrobial susceptibilities and resistance development in the major respiratory pathogens. Int J Antimicrob Agents 2007; 30 (Suppl. 02) S135-S138
• 23 Goto H, Shimada K, Ikemoto H, Oguri T ; Study Group on Antimicrobial Susceptibility of Pathogens Isolated from Respiratory Infections. Antimicrobial susceptibility of pathogens isolated from more than 10,000 patients with infectious respiratory diseases: a 25-year longitudinal study. J Infect Chemother 2009; 15 (6) 347-360
• 24 File Jr TM. The science of selecting antimicrobials for community-acquired pneumonia (CAP). J Manag Care Pharm 2009; 15 (2, Suppl) S5-S11
• 25 Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect 2001; 7 (11) 589-596
• 26 Garau J. Role of beta-lactam agents in the treatment of community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 2005; 24 (2) 83-99
• 27 Owens Jr RC, Shorr AF. Rational dosing of antimicrobial agents: pharmacokinetic and pharmacodynamic strategies. Am J Health Syst Pharm 2009; 66 (12, Suppl 4) S23-S30
• 28 Van Bambeke F, Reinert RR, Appelbaum PC, Tulkens PM, Peetermans WE. Multidrug-resistant Streptococcus pneumoniae infections: current and future therapeutic options. Drugs 2007; 67 (16) 2355-2382
• 29 Jacobs MR. Antimicrobial-resistant Streptococcus pneumoniae: trends and management. Expert Rev Anti Infect Ther 2008; 6 (5) 619-635
• 30 Song J-H, Chung DR. Respiratory infections due to drug-resistant bacteria. Infect Dis Clin North Am 2010; 24 (3) 639-653
• 31 Feldman C, Brink AJ, von Gottberg A , et al. Antimicrobial susceptibility of pneumococcal isolates causing bacteraemic pneumococcal pneumonia: analysis using current breakpoints and fluoroquinolone pharmacodynamics. Int J Antimicrob Agents 2010; 36 (1) 95-97
• 32 Yu VL, Chiou CC, Feldman C , et al; International Pneumococcal Study Group. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003; 37 (2) 230-237
• 33 Amsden GW. Pneumococcal macrolide resistance—myth or reality?. J Antimicrob Chemother 1999; 44 (1) 1-6
• 34 Lonks JR, Garau J, Medeiros AA. Implications of antimicrobial resistance in the empirical treatment of community-acquired respiratory tract infections: the case of macrolides. J Antimicrob Chemother 2002; 50 (Suppl S2) 87-92
• 35 Lynch III JP, Martinez FJ. Clinical relevance of macrolide-resistant Streptococcus pneumoniae for community-acquired pneumonia. Clin Infect Dis 2002; 34 (Suppl. 01) S27-S46
• 36 Nuermberger E, Bishai WR. The clinical significance of macrolide-resistant Streptococcus pneumoniae: it's all relative. Clin Infect Dis 2004; 38 (1) 99-103
• 37 Fuller JD, McGeer A, Low DE. Drug-resistant pneumococcal pneumonia: clinical relevance and approach to management. Eur J Clin Microbiol Infect Dis 2005; 24 (12) 780-788
• 38 Pletz MW, van der Linden M, von Baum H, Duesberg CB, Klugman KP, Welte T ; CAPNETZ study group. Low prevalence of fluoroquinolone resistant strains and resistance precursor strains in Streptococcus pneumoniae from patients with community-acquired pneumonia despite high fluoroquinolone usage. Int J Med Microbiol 2011; 301 (1) 53-57
• 39 Lismond A, Carbonnelle S, Tulkens PM, Van Bambeke F. Efflux of novel quinolones in contemporary Streptococcus pneumoniae isolates from community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (4) 948-951
• 40 Fuller JD, Low DE. A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance. Clin Infect Dis 2005; 41 (1) 118-121
• 41 Arnold FW, Summersgill JT, Lajoie AS , et al; Community-Acquired Pneumonia Organization (CAPO) Investigators. A worldwide perspective of atypical pathogens in community-acquired pneumonia. Am J Respir Crit Care Med 2007; 175 (10) 1086-1093
• 42 Isozumi R, Yoshimine H, Morozumi M, Ubukata K, Ariyoshi K. Adult community-acquired pneumonia caused by macrolide resistant Mycoplasma pneumoniae. Respirology 2009; 14 (8) 1206-1208
• 43 Morozumi M, Takahashi T, Ubukata K. Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia. J Infect Chemother 2010; 16 (2) 78-86
• 44 Miyashita N, Maruyama T, Kobayashi T , et al. Community-acquired macrolide-resistant Mycoplasma pneumoniae pneumonia in patients more than 18 years of age. J Infect Chemother 2011; 17 (1) 114-118
• 45 Bébéar C, Pereyre S, Peuchant O. Mycoplasma pneumoniae: susceptibility and resistance to antibiotics. Future Microbiol 2011; 6 (4) 423-431
• 46 Hoban D, Felmingham D. The PROTEKT surveillance study: antimicrobial susceptibility of Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract infections. J Antimicrob Chemother 2002; 50 (Suppl S1) 49-59
• 47 Tristram S, Jacobs MR, Appelbaum PC. Antimicrobial resistance in Haemophilus influenzae. Clin Microbiol Rev 2007; 20 (2) 368-389
• 48 McGregor K, Chang BJ, Mee BJ, Riley TV. Moraxella catarrhalis: clinical significance, antimicrobial susceptibility and BRO beta-lactamases. Eur J Clin Microbiol Infect Dis 1998; 17 (4) 219-234
• 49 Murphy TF, Parameswaran GI. Moraxella catarrhalis, a human respiratory tract pathogen. Clin Infect Dis 2009; 49 (1) 124-131
• 50 Stefani S, Bongiorno D, Cafiso V , et al. Pathotype and susceptibility profile of a community-acquired methicillin-resistant Staphylococcus aureus strain responsible for a case of severe pneumonia. Diagn Microbiol Infect Dis 2009; 63 (1) 100-104
• 51 Cataldo MA, Taglietti F, Petrosillo N. Methicillin-resistant Staphylococcus aureus: a community health threat. Postgrad Med 2010; 122 (6) 16-23
• 52 Hidron AI, Low CE, Honig EG, Blumberg HM. Emergence of community-acquired methicillin-resistant Staphylococcus aureus strain USA300 as a cause of necrotising community-onset pneumonia. Lancet Infect Dis 2009; 9 (6) 384-392
• 53 David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010; 23 (3) 616-687
• 54 Lobo LJ, Reed KD, Wunderink RG. Expanded clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus pneumonia. Chest 2010; 138 (1) 130-136
• 55 Marques MR, Nunes A, Sousa C, Moura F, Gouveia J, Ramos A. Community-acquired pneumonia in an intensive care unit. Rev Port Pneumol 2010; 16 (2) 223-235
• 56 Sader HS, Sampaio JL, Zoccoli C, Jones RN. Results of the 1997 SENTRY Antimicrobial surveillance program in three Brazilian medical centres. Braz J Infect Dis 1999; 3 (2) 63-79
• 57 Einhorn AE, Neuhauser MM, Bearden DT, Quinn JP, Pendland SL. Extended-spectrum beta-lactamases: frequency, risk factors, and outcomes. Pharmacotherapy 2002; 22 (1) 14-20
• 58 Kang C-I, Song J-H, Chung DR , et al; Korean Network for Study of Infectious Diseases (KONSID). Risk factors and treatment outcomes of community-onset bacteraemia caused by extended-spectrum β-lactamase-producing Escherichia coli. Int J Antimicrob Agents 2010; 36 (3) 284-287
• 59 Tsai SS, Huang JC, Chen ST , et al. Characteristics of Klebsiella pneumoniae bacteremia in community-acquired and nosocomial infections in diabetic patients. Chang Gung Med J 2010; 33 (5) 532-539
• 60 Teng CP, Chen HH, Chan J, Lye DCB. Ertapenem for the treatment of extended-spectrum β-lactamase-producing Gram-negative bacterial infections. Int J Antimicrob Agents 2007; 30 (4) 356-359
• 61 Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science 1999; 284 (5418) 1318-1322
• 62 Hall-Stoodley L, Stoodley P. Evolving concepts in biofilm infections. Cell Microbiol 2009; 11 (7) 1034-1043
• 63 Ojha AK, Baughn AD, Sambandan D , et al. Growth of Mycobacterium tuberculosis biofilms containing free mycolic acids and harbouring drug-tolerant bacteria. Mol Microbiol 2008; 69 (1) 164-174
• 64 Williams DW, Kuriyama T, Silva S, Malic S, Lewis MAO. Candida biofilms and oral candidosis: treatment and prevention. Periodontol 2000 2011; 55 (1) 250-265
• 65 Deep A, Chaudhary U, Gupta V. Quorum sensing and bacterial pathogenicity: From molecules to disease. J Lab Physicians 2011; 3 (1) 4-11
• 66 Nguyen KT, Piastro K, Gray TA, Derbyshire KM. Mycobacterial biofilms facilitate horizontal DNA transfer between strains of Mycobacterium smegmatis. J Bacteriol 2010; 192 (19) 5134-5142
• 67 Anderson R, Feldman C. Key virulence factors of Streptococcus pneumoniae and non-typeable Haemophilus influenzae: roles in host defence and immunization. SA J Epidemiol Infect 2011; 26: 6-12
• 68 Federle MJ, Bassler BL. Interspecies communication in bacteria. J Clin Invest 2003; 112 (9) 1291-1299
• 69 Yang L, Liu Y, Wu H, Hóiby N, Molin S, Song ZJ. Current understanding of multi-species biofilms. Int J Oral Sci 2011; 3 (2) 74-81
• 70 Elliott D, Burns JL, Hoffman LR. Exploratory study of the prevalence and clinical significance of tobramycin-mediated biofilm induction in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 2010; 54 (7) 3024-3026
• 71 Mathee K, Ciofu O, Sternberg C , et al. Mucoid conversion of Pseudomonas aeruginosa by hydrogen peroxide: a mechanism for virulence activation in the cystic fibrosis lung. Microbiology 1999; 145 (Pt 6) 1349-1357
• 72 McInnis CE, Blackwell HE. Thiolactone modulators of quorum sensing revealed through library design and screening. Bioorg Med Chem 2011; 19 (16) 4820-4828
• 73 Eberhard A, Burlingame AL, Eberhard C, Kenyon GL, Nealson KH, Oppenheimer NJ. Structural identification of autoinducer of Photobacterium fischeri luciferase. Biochemistry 1981; 20 (9) 2444-2449
• 74 Fuqua C, Greenberg EP. Listening in on bacteria: acyl-homoserine lactone signalling. Nat Rev Mol Cell Biol 2002; 3 (9) 685-695
• 75 Galloway WRJD, Hodgkinson JT, Bowden SD, Welch M, Spring DR. Quorum sensing in Gram-negative bacteria: small-molecule modulation of AHL and AI-2 quorum sensing pathways. Chem Rev 2011; 111 (1) 28-67
• 76 Zeng L-R, Xie J-P. Molecular basis underlying LuxR family transcription factors and function diversity and implications for novel antibiotic drug targets. J Cell Biochem 2011; 112 (11) 3079-3084
• 77 Patankar AV, González JE. Orphan LuxR regulators of quorum sensing. FEMS Microbiol Rev 2009; 33 (4) 739-756
• 78 Senadheera D, Cvitkovitch DG. Quorum sensing and biofilm formation by Streptococcus mutans. Adv Exp Med Biol 2008; 631: 178-188
• 79 Brackman G, Cos P, Maes L, Nelis HJ, Coenye T. Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo. Antimicrob Agents Chemother 2011; 55 (6) 2655-2661
• 80 Ng WL, Bassler BL. Bacterial quorum-sensing network architectures. Annu Rev Genet 2009; 43: 197-222
• 81 Xavier KB, Bassler BL. Interference with AI-2-mediated bacterial cell-cell communication. Nature 2005; 437 (7059) 750-753
• 82 Neiditch MB, Federle MJ, Miller ST, Bassler BL, Hughson FM. Regulation of LuxPQ receptor activity by the quorum-sensing signal autoinducer-2. Mol Cell 2005; 18 (5) 507-518
• 83 Yoshida A, Ansai T, Takehara T, Kuramitsu HK. LuxS-based signaling affects Streptococcus mutans biofilm formation. Appl Environ Microbiol 2005; 71 (5) 2372-2380
• 84 Vidal JE, Ludewick HP, Kunkel RM, Zähner D, Klugman KP. The LuxS-dependent quorum-sensing system regulates early biofilm formation by Streptococcus pneumoniae strain D39. Infect Immun 2011; 79 (10) 4050-4060
• 85 Armbruster CE, Swords WE. Interspecies bacterial communication as a target for therapy in otitis media. Expert Rev Anti Infect Ther 2010; 8 (10) 1067-1070
• 86 Cloak OM, Solow BT, Briggs CE, Chen C-Y, Fratamico PM. Quorum sensing and production of autoinducer-2 in Campylobacter spp., Escherichia coli O157:H7, and Salmonella enterica serovar Typhimurium in foods. Appl Environ Microbiol 2002; 68 (9) 4666-4671
• 87 Anderson GG, O'Toole GA. Innate and induced resistance mechanisms of bacterial biofilms. Curr Top Microbiol Immunol 2008; 322: 85-105
• 88 Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents 2010; 35 (4) 322-332
• 89 Roberts AP, Mullany P. Oral biofilms: a reservoir of transferable, bacterial, antimicrobial resistance. Expert Rev Anti Infect Ther 2010; 8 (12) 1441-1450
• 90 Antonova ES, Hammer BK. Quorum-sensing autoinducer molecules produced by members of a multispecies biofilm promote horizontal gene transfer to Vibrio cholerae. FEMS Microbiol Lett 2011; 322 (1) 68-76
• 91 Król JE, Nguyen HD, Rogers LM, Beyenal H, Krone SM, Top EM. Increased transfer of a multidrug resistance plasmid in Escherichia coli biofilms at the air-liquid interface. Appl Environ Microbiol 2011; 77 (15) 5079-5088
• 92 Vaidya VK. Horizontal transfer of antimicrobial resistance by extended spectrum β-lactamase-producing Enterobacteriaceae. J Lab Physicians 2011; 3 (1) 37-42
• 93 Budhani RK, Struthers JK. Interaction of Streptococcus pneumoniae and Moraxella catarrhalis: investigation of the indirect pathogenic role of beta-lactamase-producing moraxellae by use of a continuous-culture biofilm system. Antimicrob Agents Chemother 1998; 42 (10) 2521-2526
• 94 Weimer KE, Juneau RA, Murrah KA , et al. Divergent mechanisms for passive pneumococcal resistance to β-lactam antibiotics in the presence of Haemophilus influenzae. J Infect Dis 2011; 203 (4) 549-555
• 95 Miyahara E, Nishie M, Takumi S , et al. Environmental mutagens may be implicated in the emergence of drug-resistant microorganisms. FEMS Microbiol Lett 2011; 317 (2) 109-116
• 96 Bagaitkar J, Demuth DR, Daep CA, Renaud DE, Pierce DL, Scott DA. Tobacco upregulates P. gingivalis fimbrial proteins which induce TLR2 hyposensitivity. PLoS ONE 2010; 5 (5) e9323
• 97 Goldstein-Daruech N, Cope EK, Zhao K-Q , et al. Tobacco smoke mediated induction of sinonasal microbial biofilms. PLoS ONE 2011; 6 (1) e15700
• 98 Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M. Immunosenescence and infectious diseases. Microbes Infect 2001; 3 (10) 851-857
• 99 McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults?. Curr Opin Immunol 2009; 21 (4) 418-424
• 100 Yoshikawa TT. Antimicrobial resistance and aging: beginning of the end of the antibiotic era?. J Am Geriatr Soc 2002; 50 (7, Suppl) S226-S229
• 101 Girard TD, Opal SM, Ely EW. Insights into severe sepsis in older patients: from epidemiology to evidence-based management. Clin Infect Dis 2005; 40 (5) 719-727
• 102 Tachfouti N, Nejjari C, Benjelloun MC , et al. Association between smoking status, other factors and tuberculosis treatment failure in Morocco. Int J Tuberc Lung Dis 2011; 15 (6) 838-843
• 103 Nuorti JP, Butler JC, Farley MM , et al; Active Bacterial Core Surveillance Team. Cigarette smoking and invasive pneumococcal disease. N Engl J Med 2000; 342 (10) 681-689
• 104 Stanley PJ, Wilson R, Greenstone MA, MacWilliam L, Cole PJ. Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency. Thorax 1986; 41 (7) 519-523
• 105 Manzel LJ, Shi L, O'Shaughnessy PT, Thorne PS, Look DC. Inhibition by cigarette smoke of nuclear factor-κB-dependent response to bacteria in the airway. Am J Respir Cell Mol Biol 2011; 44 (2) 155-165
• 106 Kulkarni R, Rampersaud R, Aguilar JL, Randis TM, Kreindler JL, Ratner AJ. Cigarette smoke inhibits airway epithelial cell innate immune responses to bacteria. Infect Immun 2010; 78 (5) 2146-2152
• 107 Phipps JC, Aronoff DM, Curtis JL, Goel D, O'Brien E, Mancuso P. Cigarette smoke exposure impairs pulmonary bacterial clearance and alveolar macrophage complement-mediated phagocytosis of Streptococcus pneumoniae. Infect Immun 2010; 78 (3) 1214-1220
• 108 Feng Y, Kong Y, Barnes PF , et al. Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infect Immun 2011; 79 (1) 229-237
• 109 Zhang Y. Mechanisms of antibiotic resistance in the microbial world. www.moleculartb.org/gb/pdf/transcriptions/11_YZHANG.pdf
• 110 Lönn-Stensrud J, Landin MA, Benneche T, Petersen FC, Scheie AA. Furanones, potential agents for preventing Staphylococcus epidermidis biofilm infections?. J Antimicrob Chemother 2009; 63 (2) 309-316
• 111 Brackman G, Celen S, Hillaert U , et al. Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp. PLoS ONE 2011; 6 (1) e16084
• 112 Bunders CA, Richards JJ, Melander C. Identification of aryl 2-aminoimidazoles as biofilm inhibitors in gram-negative bacteria. Bioorg Med Chem Lett 2010; 20 (12) 3797-3800
• 113 Steenackers HP, Ermolat'ev DS, Savaliya B , et al. Structure-activity relationship of 2-hydroxy-2-aryl-2,3-dihydro-imidazo[1,2-a]pyrimidinium salts and 2N-substituted 4(5)-aryl-2-amino-1H-imidazoles as inhibitors of biofilm formation by Salmonella typhimurium and Pseudomonas aeruginosa. Bioorg Med Chem 2011; 19 (11) 3462-3473
• 114 Budzyńska A, Rózalski M, Karolczak W, Wieckowska-Szakiel M, Sadowska B, Rózalska B. Synthetic 3-arylideneflavanones as inhibitors of the initial stages of biofilm formation by Staphylococcus aureus and Enterococcus faecalis. Z Naturforsch C 2011; 66 (3-4) 104-114
• 115 Bunders C, Cavanagh J, Melander C. Flustramine inspired synthesis and biological evaluation of pyrroloindoline triazole amides as novel inhibitors of bacterial biofilms. Org Biomol Chem 2011; 9 (15) 5476-5481
• 116 Sintim HO, Smith JAJ, Wang J, Nakayama S, Yan L. Paradigm shift in discovering next-generation anti-infective agents: targeting quorum sensing, c-di-GMP signaling and biofilm formation in bacteria with small molecules. Future Med Chem 2010; 2 (6) 1005-1035
• 117 Kirchdoerfer RN, Garner AL, Flack CE , et al. Structural basis for ligand recognition and discrimination of a quorum-quenching antibody. J Biol Chem 2011; 286 (19) 17351-17358
• 118 Chaignon P, Sadovskaya I, Ragunah Ch, Ramasubbu N, Kaplan JB, Jabbouri S. Susceptibility of staphylococcal biofilms to enzymatic treatments depends on their chemical composition. Appl Microbiol Biotechnol 2007; 75 (1) 125-132
• 119 Høiby N, Ciofu O, Johansen HK , et al. The clinical impact of bacterial biofilms. Int J Oral Sci 2011; 3 (2) 55-65
• 120 Stables MJ, Newson J, Ayoub SS, Brown J, Hyams CJ, Gilroy DW. Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria. Blood 2010; 116 (16) 2950-2959
• 121 O'Neill LAJ, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 2009; 61 (2) 177-197
• 122 Nicholls EF, Madera L, Hancock REW. Immunomodulators as adjuvants for vaccines and antimicrobial therapy. Ann N Y Acad Sci 2010; 1213: 46-61
• 123 Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP: master regulator of innate immune cell function. Am J Respir Cell Mol Biol 2008; 39 (2) 127-132