Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram-negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development.
References
[1]
Boucher, H.; Talbot, G.H.; Bradley, J.S. Bad bugs, no drugs: no ESKAPE! An Update from the Infectious Diseases Society of America. Clin. Infect. Dis. 2009, 425, 1–12, doi:10.1086/595011.
[2]
Rice, L.B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 2008, 197, 1079–1081, doi:10.1086/533452.
[3]
Arias, C.A.; Murray, B.E. Antibiotic-resistant bugs in the 21st century – a clinical super challenge. N. Engl. J. Med. 2012, 360, 439–443, doi:10.1056/NEJMp0804651.
[4]
Livermore, D.M. Has the era of unbeatable infections arrived? J. Antimicrob. Chemother. 2009, 64, 29–36, doi:10.1093/jac/dkp255.
[5]
Carlet, J.; Jarlier, V.; et al. Ready for a world without antibiotics? The Pensieres Antibiotic Resistance Call to Action. Antimicrob. Resist. Infect. Contr. 2012, 1, 11, doi:10.1186/2047-2994-1-11.
Coates, A.R.M.; Halls, G.; Hu, Y. Novel classes of antibiotics or more of the same? Brit. J. Pharmacol. 2009, 163, 184–194, doi:10.1111/j.1476-5381.2011.01250.x.
[8]
Talbot, G.H.; Bradley, J.; Edwards, J.E., Jr.; Gilbert, D.; Scheld, M.; Bartlett, J.G. Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the Infectious Diseases Society of America. Clin. Infect. Dis. 2006, 42, 657–668.
[9]
Talbot, G.H. What is the pipeline for Gram-negative pathogens? Expert Rev. Anti. Infect. Ther. 2008, 6, 39–49, doi:10.1586/14787210.6.1.39.
[10]
Laudano, J.B. Ceftaroline fosamil: a new broad-spectrum cephalosporin. J. Antimicrob. Chemother. 2011, 66, 11–18, doi:10.1093/jac/dkr095.
[11]
Lopez-Rojas, R.; Sanchez-Cespedes, J.; Docobo-Perez, F.; Dom？nguez-Herrera, J.; Vila, J.; Pachon, J. Pre-clinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin. Int. J. Antimicrob. Agents 2011, 38, 355–359, doi:10.1016/j.ijantimicag.2011.06.006.
[12]
Sutcliffe, J.A. Antibiotics in development targeting protein synthesis. Ann. N. Y. Acad. Sci. 2011, 1241, 122–152, doi:10.1111/j.1749-6632.2011.06323.x.
[13]
Caron, W.; Mousa, S. Prevention strategies for antimicrobial resistance: a systematic review of the literature. Infection and Drug Resistance 2010, 3, 25–33.
[14]
Hughes, J.M. Preserving the lifesaving power of antimicrobial agents. JAMA 2011, 305, 1027–1028, doi:10.1001/jama.2011.279.
[15]
Rashmi, S. Antibacterial resistance: Current problems and possible solutions. Indian J. Med. Sci. 2005, 59, 120–129, doi:10.4103/0019-5359.15091.
[16]
World Health Organization. Global Strategy for Containment of Antimicrobial Resistance. World Health Organization, 2001. Available online: http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_DRS_2001_2_EN/en/ (access on 6 June 2013).
[17]
Sharma, R.; Sharma, C.L.; Kapoor, B. Antibacterial resistance: Current problems and possible solutions. IJMS 2005, 59, 120–129.
[18]
Huttner, B.; Goossens, H.; Verheji, T.; Harbath, S. Characteristics and outcomes of public campaigns aimed at improving the use of antibiotics in outpatients in high-income countries. Lancet 2010, 10, 17–31.
[19]
Gould, I.M. A review of the role of antibiotic policies in the control of antibiotic resistance. JAC 1999, 43, 459–465.
[20]
Collignon, P.J. Antibiotic resistance. Med. J. Aust. 2002, 177, 325–329.
[21]
Molstad, S.; Erntell, M.; Hanberger, H.; et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect. Dis. 2008, 8, 125–132.
[22]
Nicole, L.E. Infection control programmes to contain antimicrobial resistance. WHO, Department of Communicable Disease Surveillance and Response, 2001.
[23]
Essack, S.Y. Strategies for the Prevention and Containment of Antibiotic Resistance. S. A. Fam. Pract. 2006, 48, 51a–51d.
[24]
Drlica, C. The mutant selection window and antimicrobial resistance. JAC 2003, 52, 11–17.
[25]
Vaidya, V.K. Horizontal Transfer of Antimicrobial Resistance by Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae. J. Lab. Physicians. 2011, 3, 37–42, doi:10.4103/0974-2727.78563.
[26]
Barker, K. Antibiotic resistance: a current perspective. Br. J. Clin. Pharmacology. 1999, 48, 109–124, doi:10.1046/j.1365-2125.1999.00997.x.
[27]
Olofsson, S.K.; Cars, O. Optimizing drug exposure to minimize selection of antibiotic resistance. Clin. Infect. Dis. 2007, 1, S129–S136, doi:10.1086/519256.
[28]
Blaser, J.; Stone, B.B.; Griner, M.C.; Zinner, S.H. Comparative study with enoxacin and netilmicin in a pharmacodynamics model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance. Antimicrob. Agents Chemother. 1987, 31, 1054–1060, doi:10.1128/AAC.31.7.1054.
[29]
Marchbanks, C.R.; McKiel, J.R.; Gilbert, D.H.; et al. Dose ranging and fractionation of intravenous ciprofloxacin againsts Pseudomonas aruginosa and Staphylococcus aureus in an in vitro model of infection. Antimicrob. Agents Chemother. 1993, 37, 1756–1763, doi:10.1128/AAC.37.9.1756.
[30]
Drusano, G.I.; Johnson, D.E.; Rosen, M.; Standiford, H.C. Pharmacodynamics of a fluroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas species. Antimicrob. Agents Chemother. 1993, 37, 483–490, doi:10.1128/AAC.37.3.483.
[31]
Stearne, L.E.; van Boxtel, D.; Lemmens, N.; Goessens, W.H.; Mouton, J.W.; Gyssens, I.C. Comparative study of the effects of ceftizoxime, piperacillin, and piperacillin-tazobactam concentrations on antibacterial activity and selection of antibiotic-resistant mutants of Enterobacter cloacae and Bacteroides fragilis in vitro and in vivo in mixed-infection abscesses. Antimicrob. Agents Chemother. 2004, 48, 1688–1698, doi:10.1128/AAC.48.5.1688-1698.2004.
[32]
Wiuff, C.; Lykkesfeldt, J.; Svendsen, O.; Aarestrup, F.M. The effects of oral and intramuscular administration and dose escalation of enrofloxacin on the selection of quinolone resistance among Salmonella and coliforms in pigs. Res. Vet. Sci. 2003, 75, 185–193, doi:10.1016/S0034-5288(03)00112-7.
[33]
Guillemot, D.; Carbon, C.; Balkau, B.; et al. Low dosage and long treatment duration of b-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998, 279, 365–370.
[34]
Davidson, R.; Cavalcanti, R.; Brunton, J.L.; et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N. Engl. J. Med. 2002, 346, 747–750, doi:10.1056/NEJMoa012122.
[35]
Thomas, J.K.; Forrest, A.; Bhavnani, S.M.; et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob. Agents Chemother. 1998, 42, 521–527.
[36]
Mitchison, D. Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins. Int. J. Tuberc. Lung Dis. 2012, 16, 1186–1189, doi:10.5588/ijtld.11.0818.
[37]
Mitchison, D. The diagnosis and therapy of tuberculosis during the past 100 years. Am. J. Respir. Crit. Care Med. 2005, 171, 699–706, doi:10.1164/rccm.200411-1603OE.
[38]
Mitchison, D. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int. J. Tuberc. Lung Dis. 1998, 2, 10–15.
[39]
Blondeau, J.M.; Zhao, X.; Hansen, G.; Drilica, K. Mutant Prevention Concentrations of Fluoroquinolones for Clinical Isolates of Streptococcus pneumoniae. Antimicrob. Chemother. 2001, 45, 433–438, doi:10.1128/AAC.45.2.433-438.2001.
[40]
Cui, J.; Liu, Y.; Wang, R.; Tong, W.; Drlica, K.; Zhao, X. The mutant selection window in rabbits infected with Staphylococcus aureus. J. Infect. Dis. 2006, 194, 1601–1608, doi:10.1086/508752.
[41]
Zhu, Y.L.; Hu, L.F.; Mei, Q.; Cheng, J.; Liu, Y.Y.; Ye, Y.; Li, J.B. Testing the mutant selection window in rabbits infected with methicillin-resistant Staphylococcus aureus exposed to vancomycin. J. Antimicrob. Chemother. 2012, 67, 2700–2706, doi:10.1093/jac/dks280.
[42]
Williams, J.; Sefton, A. The Prevention of Antibiotic Resistance during Treatment. Infection 1999, 27, 29–31, doi:10.1007/BF02561667.
[43]
Lee, M.; Lee, J.; Carroll, M.W.; et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N. Engl. J. Med. 2012, 367, 1508–1518, doi:10.1056/NEJMoa1201964.
[44]
Craig, W.A. Does the dose matter? Clin. Infect. Dis. 2001, 15, S233–S237, doi:10.1086/321854.
[45]
Drusano, G.L. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin. Infect. Dis. 2003, 36, S42–S50, doi:10.1086/344653.
[46]
Geli, P.; Laxminarayan, R.; Dunne, M.; Smith, D.L. ‘‘One-Size-Fits-All’’? Optimizing Treatment Duration for Bacterial Infections. PLOS one. 2012, 7, 1–10.
[47]
Rashid, M.U.; Weintraub, A.; Nord, C.E. Effect of new antimicrobial agents on the ecological balance of human microflora. Anaerobe. 2012, 18, 249–253, doi:10.1016/j.anaerobe.2011.11.005.
[48]
Brunner, M.; Derendorf, H.; Muller, M. Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs. Curr. Opin. Pharmacol. 2005, 5, 495–499, doi:10.1016/j.coph.2005.04.010.
[49]
Cars, O. Pharmacokinetics of antibiotics in tissues and tissue fluids: a review. Scand. J. Infect. Dis. Suppl. 1990, 74, 23–33.
[50]
Cars, O.; Ogren, S. Antibiotic tissue concentrations: methodological aspects and interpretation of results. Scand. J. Infect. Dis. Suppl. 1985, 44, 7–15.
[51]
Gullberg, E.; Cao, S.; Berg, O.G.; Ilb？ck, C.; Sandegren, L.; Hughes, D. Selection of Resistant Bacteria at Very Low Antibiotic Concentrations. PLoS Pathog. 2011, 7, e1002158, doi:10.1371/journal.ppat.1002158.
[52]
Zhao, X.; Drlica, K. Restricting the Selection of Antibiotic-Resistant Mutants: A General Strategy Derived from Fluoroquinolone Studies. Clin. Infect. Dis. 2001, 333, S147–S156, doi:10.1086/321841.
[53]
Oh, H.; Nord, C.E.; Barkholt, L.; Hedberg, M.; Edlund, C. Ecological disturbances in intestinal microflora caused by clinafloxacin, an extended- spectrum quinolone. Infection. 2000, 28, 272–277, doi:10.1007/s150100070018.
[54]
Lode, H.; Von der H？h, N.; Ziege, S.; Borner, K.; Nord, C.E. Ecological effects of linezolid versus amoxicillin/clavulanic acid on the normal intestinal microflora. Scand. J. Infect. Dis. 2001, 33, 899–903, doi:10.1080/00365540110076714.
[55]
Pletz, M.W.R.; Rau, M.; Bulitta, J.; De Roux, A.; et al. Ertapenem Pharmacokinetics and Impact on Intestinal Microflora, in Comparison to Those of Ceftriaxone, after Multiple Dosing in Male and Female Volunteers. Antimicrob. Agents Chemother. 2004, 48, 3765–3772, doi:10.1128/AAC.48.10.3765-3772.2004.
[56]
DiNubile, M.J.; Chow, J.W.; Satishchandran, V.; Polis, A.; Motyl, M.R.; Abramson, M.A.; Teppler, H. Acquisition of Resistant Bowel Flora during a Double-Blind Randomized Clinical Trial of Ertapenem versus Piperacillin-Tazobactam Therapy for Intraabdominal Infections. Antimicrob. Agents Chemother. 2005, 49, 3217–3221.
[57]
Isha, C.; Nimrata, S.; Rana, A.C.; Surbhi, G. Oral sustained release drug delivery system: an overview. Int. Res. J. Pharm. 2012, 3, 57–62.
[58]
Hoffman, A.; Horwitz, E.; Hess, S.; et al. Implications on emergence of antimicrobial resistance as a critical aspect in the design of oral sustained release delivery systems of antimicrobials. Pharm. Res. 2008, 25, 667–671, doi:10.1007/s11095-007-9373-6.
[59]
Goren, M.G.; Carmeli, Y.; Schwaber, M.J.; Chmelnitsky, I.; Schechner, V.; Navon-Venezia, S. Transfer of Carbapenem-Resistant Plasmid from Klebsiella pneumoniae ST258 to Escherichia coli in Patient. Emerg. Infect. Dis. 2010, 16, 1014–1017.
[60]
Goldstein, E.J. Beyond the target pathogen: ecological effects of the hospital formulatory. Curr. Opin. Infect. Dis. 2011, 1, S21–S31, doi:10.1097/01.qco.0000393485.17894.4c.
[61]
Hurdle, J.G.; O’Neill, A.J.; Mody, L.; Chopra, I.; Bradley, S.F. In vivo transfer of high-level mupirocin resistance from Staphylococcus epidermidis to methicillin-resistant Staphylococcus aureus associated with failure of mupirocin prophylaxis. J. Antimicrob. Chemother. 2005, 56, 1166–1168.
[62]
Paster, B.J.; Olsen, I.; Aas, J.A.; Dewhirst, F.E. The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontol 2000 2006, 42, 80–87, doi:10.1111/j.1600-0757.2006.00174.x.
[63]
Keijser, B.J.F.; Zaura, E.; Huse, S.M.; van der Vossen, J.M.B.M.; Schuren, F.H.J.; Montijn, R.C.; ten Cate, J.M.; Crielaard, W. Pyrosequencing analysis of the oral microflora of healthy adults. J. Dent. Res. 2008, 87, 1016–1020, doi:10.1177/154405910808701104.
[64]
Gill, S.R.; Pop, M.; Deboy, R.T.; Eckburg, P.B.; Turnbaugh, P.J.; Samuel, B.S.; Gordon, J.I.; Relman, D.A.; Fraser-Liggett, C.M.; Nelson, K.E. Metagenomic analysis of the human distal gut microbiome. Science 2006, 312, 1355–1359, doi:10.1126/science.1124234.
[65]
Gao, Z.; Tseng, C.H.; Pei, Z.; Blaser, M.J. Molecular analysis of human forearm superficial skin bacterial biota. Proc. Natl. Acad. Sci. USA 2007, 104, 2927–2932, doi:10.1073/pnas.0607077104.
[66]
Fierer, N.; Hamady, M.; Lauber, C.L.; Knight, R. The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc. Natl. Acad. Sci. USA 2008, doi:10.1073/pnas.0807920105.
[67]
Mitchison, D. Problems of drug resistance. Br. Med. Bull. 1954, 69, 640–641.
[68]
Fox, W.; Sutherland, I.; Daniels, M. A five-year assessment of patients in a controlled trial of streptomycin in pulmonary tuberculosis. Q. J. Med. 1954, 23, 347–366.
[69]
Grüneberg, R.N. The microbiological rationale for the combination of sulphonamides with trimethoprim. J. Antimicrob. Chemother. 1979, 5, 27–36, doi:10.1093/jac/5.Supplement_B.27.
[70]
Boyd, N.; Nailor, M.D. Combination antibiotic therapy for empiric and definitive treatment of gram-negative infections: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2011, 31, 1073–1084, doi:10.1592/phco.31.11.1073.
[71]
Dagan, R.; Bar-David, Y. Comparison of amoxicillin and clavulanic acid (augmentin) for the treatment of nonbullous impetigo. Am. J. Dis. Child. 1989, 143, 916–918.
[72]
Solapure, S.; Dinesh, N.; Shandil, R.; Ramachandran, S.S.; et al. In vitro and in vivo efficacy of beta-lactams against replicating and slowly growing/non replicating M. tuberculosis. Antimicro. Agents Chemo. 2013, 57, 2506–2510.
[73]
Bliziotis, I.; Samonis, G.; Vardakas, K.; Chrysanthopoulou, S.; Falagas, M. Effect of Aminoglycoside and b-Lactam Combination Therapy versus b-Lactam Monotherapy on the Emergence of Antimicrobial Resistance: A Meta-analysis of Randomized, Controlled Trials. Clin. Infect. Dis. 2005, 41, 149–158, doi:10.1086/430912.
[74]
Gerber, A.U.; Vastola, A.P.; Brandel, J.; Craig, W.A. Selection of aminoglycoside-resistant variants of Pseudomonas aeruginosa in an in vivo model. J. Infect. Dis. 1982, 146, 691–697, doi:10.1093/infdis/146.5.691.
[75]
Mouton, J. Combination Therapy as a Tool to Prevent Emergence of Bacterial Resistance. Infection. 1999, 27, 24–28, doi:10.1007/BF02561666.
[76]
Michalsen, H.; Bergan, I. Azlocillin with and without an aminoglycoside against respiratory tract infections in children with cystic fibrosis. Scand. J. Infect. Dis. 1981, 29, 92–97.
Unemo, M.; Shafer, W.M. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann. N. Y. Acad. Sci. 2011, 1230, E19–E28, doi:10.1111/j.1749-6632.2011.06215.x.
[79]
Bonhoeffer, S.; Lipsitch, M.; Levin, B.R. Evaluating treatment protocols to prevent antibiotic resistance. Proc. Natl. Acad. Sci. USA 1997, 94, 12106–12111, doi:10.1073/pnas.94.22.12106.
[80]
Hurdle, J.; O’Neill, A.; Chopra, I.; Lee, R. Targeting bacterial membrane function: an unexploited mechanism for treating persistent infections. Nature Reviews. 2011, 9, 62–75, doi:10.1038/nrmicro2474.
[81]
Silver, L.L. Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 2007, 6, 41–55, doi:10.1038/nrd2202.
[82]
Leung, A.K.; Newman, R.; Kemar, A.; Davies, D.H. Rapid antigen detection testing in diagnosing group A beta-hemolytic streptococcal pharyngitis. Expert Rev. Mol. Diagn. 2006, 6, 761–766, doi:10.1586/14737159.6.5.761.
[83]
Madurell, J.; Balagué, M.; Gomez, M.; Cots, J.M.; Llor, C. Impact of rapid antigen detection testing on antibiotic prescription in acute pharyngitis in adults. Faringocat Study: a multicentric randomized controlled trial. BMC Fam. Pract. 2010, 11, 25–29.
[84]
Burkhardt, O.; Ewig, S.; Giesdorf, S.; Giersdorf, S.; Harmann, O.; Wegscheider, K.; Hummers-Pradier, E.; Welte, T. Procalcotonin guidance and reduction of antibiotic use in acute respiratory tract infection. Eur. Respir. J. 2010, 36, 601–607, doi:10.1183/09031936.00163309.
[85]
Harris, A.D.; Furuno, J.P.; et al. Targeted Surveillance of Methicillin-Resistant Staphylococcus aureus and Its Potential Use To Guide Empiric Antibiotic Therapy. Antimicrob. Chemother. 2010, 54, 3143–3148.
[86]
Masterton, R.G. Surveillance studies: how can they help the management of infection? JAC 2000, 46, 53–58.
[87]
Enne, V.I.; Livermore, D.M.; Stephens, P.; Hall, L.M.C. Persistence of sulphonamide resistance in Escherichia coli in the UK despite national prescribing restriction. Lancet 2001, 357, 1325–1328, doi:10.1016/S0140-6736(00)04519-0.
[88]
Bennett, K.M.; Scarborough, J.E.; Sharpe, M.; et al. Implementation of antibiotic rotation protocol improves antibiotic susceptibility profile in a surgical intensive care unit. J. Trauma. 2007, 63, 307–311, doi:10.1097/TA.0b013e318120595e.
[89]
Brown, E.; Nathwani, D. Antibiotic cycling: a systematic review of the evidence of efficacy. JAC 2005, 55, 6–9.
