The discovery of antimicrobial chemotherapeutics

Transcription

1 58 Commentary Volume 8 No. 1, 2011 COMMENTARY Bacterial Resistance to Antibiotics: A Growing Public Health Problem Justin Dhat-Ming Tilak, BSc (Hons) THE EMERGENCE OF CLINICAL ANTIMICROBIAL RESISTANCE The discovery of antimicrobial chemotherapeutics and their introduction into the clinical setting ranks among the most significant advances in the history of medicine. 1 Infectious disease is no longer the leading cause of death in the industrialized world, due in large part to the effectiveness of antimicrobial drugs. 2,3 The rapid and widespread emergence of clinical antibiotic resistance among bacterial pathogens, however, presents a formidable challenge to infectious disease management. 4 Antibiotic-resistant bacterial strains are prevalent around the globe, 4 including Canada. 5 The development of these strains has been identified as a serious public health issue, particularly in hospital settings. 6 Noteworthy antibiotic-resistant pathogens found in Canadian hospitals include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), β-lactam- and fluoroquinolone-resistant Enterobacteriaceae (e.g. Escherichia coli and Klebsiella pneumoniae), and multidrug-resistant gram-negative bacilli (e.g. Pseudomonas aeruginosa), among others (Table 1). 6-8 Although lower than those observed in the United States, antibiotic resistance rates in Canada have increased dramatically in recent years. In 2008, MRSA accounted for 27.0% of all Staphylococcus aureus isolates in Canadian hospitals, 8 rising from 6.0% in Similarly, 21.4% of Escherichia coli urinary tract isolates were resistant to the fluoroquinolone ciprofloxacin, 8 up from 1.1% in Rates of multidrug resistance are also high, particularly in intensive care units. 11 From , 12.6% of Pseudomonas aeruginosa isolates from Canadian intensive care units demonstrated resistance to three or more antibiotic classes. 11 KEY POINTS The prevalence of antibiotic resistance among bacterial pathogens in Canada continues to rise. The mechanisms of bacterial antibiotic resistance are numerous and diverse. Clinical resistance has been observed to nearly all available antibiotics. Infections due to antibiotic-resistant bacteria frequently result in adverse clinical outcomes and increased healthcare costs. The continued effectiveness of antimicrobial chemotherapy depends on increased awareness of the consequences of antimicrobial resistance, effective strategies to prevent the emergence and spread of resistant organisms, as well as the development of new antimicrobial compounds. Table 1. Bacterial Pathogens Demonstrating Significant Levels of Antibiotic Resistance in Canadian Hospitals 6-8 Classification Species Gram-positive Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Gram-negative Acinetobacter baumannii Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa THE DIVERSITY OF MECHANISMS CONFERRING ANTIBIOTIC RESISTANCE The mechanisms of bacterial antibiotic resistance are numerous and diverse, and the clinical resilience of many pathogens is attributable to their expression of several of these mechanisms. 12 All species possess some degree of intrinsic antibiotic resistance, and exposure to a certain drug

2 MUMJ Commentary 59 then provides selective pressures to promote the emergence of acquired resistance through mutation or horizontal gene transfer. No antibiotic is immune to bacterial resistance, as evidenced by the discovery of resistance to nearly every clinically-available antibiotic (Table 2). 12,14 Table 2. Major Antibiotics, Targets, and Associated Resistance Mechanisms 12,14 Antibiotic Class Aminoglycosides Amikacin Gentamicin β-lactams Penicillins Cephalosporins Carbapenems Monobactams Example Agents Bacterial Target Amoxicillin Cloxacillin Cefazolin Ceftazidime Meropenem Aztreonam Fluoroquinolones Ciprofloxacin Levofloxacin Resistance Mechanisms Protein synthesis Enzymatic Cell wall synthesis Enzymatic Decreased uptake Active efflux DNA synthesis Glycopeptides Vancomycin Cell wall synthesis Glycylcyclines Tigecycline Protein synthesis Lincosamides Clindamycin Protein synthesis Lipopeptides Daptomycin Cell membrane Macrolides Azithromycin Clarithromycin Protein synthesis Nitroimidazoles Metronidazole DNA synthesis Unclear Oxazolidinones Linezolid Protein synthesis Phenicols Chloramphenicol Protein synthesis Enzymatic Polymyxins Colistin Cell membrane Unclear Pyrimidines Trimethoprim Folate metabolism Rifamycins Rifampin RNA synthesis Streptogramins Quinupristin Dalfopristin Protein synthesis Enzymatic Active efflux Sulfonamides Sulfamethoxazole Folate metabolism Tetracyclines Doxycycline Tetracycline Protein synthesis The production of antibiotic-inactivating enzymes is one of the best known mechanisms of resistance, 15 and is typified by the β-lactamases. 16 A major group of β-lactamases is the extended-spectrum β-lactamases (ESBLs), which inactivate many penicillins, cephalosporins, and monobactams, but generally not carbapenems. 17 Additionally, plasmids encoding ESBLs often contain genes encoding resistance to other antibiotic classes, namely aminoglycosides 18 and fluoroquinolones, 19 and thus are significant contributors to multidrug resistance. 20 The rising prevalence of ESBLs among the Enterobacteriaceae has forced a greater reliance on the use of carbapenems. 21 Yet this treatment option is also threatened by pathogen acquisition of carbapenem-inactivating enzymes. 22 Among the notable carbapenemases is the recently discovered (and widely publicized) New Delhi metallo-β-lactamase-1 (NDM-1), which has been identified in Escherichia coli and Klebsiella pneumoniae. 23 NDM-1-carrying strains have now been isolated in many countries, 24 including Canada. 25 In addition to β-lactam resistance, enzymatic also plays a major role in resistance to aminoglycosides. 26 Other mechanisms of resistance include decreased uptake and increased active efflux, both of which prevent the accumulation of the antibiotic at the target site. 27 In gram-negative bacteria, resistance to certain β-lactams is mediated through decreases in porin production, 28,29 as β-lactams must cross the outer cell membrane through porins in order to reach their target: penicillin-binding proteins. 30 Active efflux involves the energy-dependent removal of antibiotics from the cell by efflux pumps. 27 Although first described as a mechanism of tetracycline resistance in Escherichia coli, 31 class-specific and multidrug efflux systems conferring resistance to most antibiotic classes have now been characterized in many bacterial pathogens. 32 Multidrug efflux pumps are major contributors to antibiotic resistance in gram-negative bacilli, including Acinetobacter baumannii 33 and Pseudomonas aeruginosa. 34 The alteration of target sites to prevent the binding of antibiotics is another mechanism of resistance. 35 A clinicallysignificant example is MRSA, in which the production of an altered penicillin-binding protein with decreased affinity for methicillin confers resistance to nearly all β-lactams, including those resistant to by most staphylococcal β-lactamases (e.g. methicillin, oxacillin, cloxacillin). 36,37 Modified penicillin-binding proteins also account for β-lactam resistance in other gram-positive bacteria. 38,39 Other notable examples of target site alteration include fluoroquinolone resistance in various species, macrolide resistance in Streptococcus pneumoniae, 43 and vancomycin resistance in VRE. 44 THE CLINICAL AND ECONOMIC IMPACT OF ANTIBIOTIC RESISTANCE Antibiotic resistance among bacterial pathogens has major clinical implications for infectious disease treatment. The spread of resistant organisms in the clinical setting presents a

3 60 Commentary Volume 8 No. 1, 2011 considerable public health concern, as infections with such organisms are often associated with poor clinical outcomes. 45,46 Patients infected with resistant organisms frequently require lengthier hospitalizations and suffer higher mortality rates, particularly in the case of bloodstream infections caused by MRSA, 47 VRE, 48 and ESBL-producing Enterobacteriaceae. 49,50 The adverse clinical outcomes associated with resistant infections are due in large part to limitations in therapeutic options, as well as decreased efficacy of remaining antibiotic options (i.e. vancomycin). Resistance frequently compromises the effectiveness of empirically-determined treatments, resulting in increased rates of treatment failure Failure of first-line therapies may necessitate further investigations, additional antibiotic treatments, surgical procedures, or may result in patient death. 45 The management of resistant infections is further complicated by the fact that antibiotics used to treat resistant infections are often associated with more severe toxicities. 53 One example is colistin, a treatment of last resort for infections caused by multidrug-resistant gram-negative bacilli, which has known nephrotoxicity. 54 However, colistin use continues due to a desperate need for effective antibiotics against gram-negative bacilli. 55,56 Research trends in antimicrobial development compound the issue of limited treatment options, as the development of new antimicrobial agents continues to decline. 57 The dwindling number of chemotherapeutic options, particularly in the case of multidrug-resistant pathogens, highlights the unsettling possibility that infections refractory to all available treatments may soon arise in the clinic. 58,59 Not only does antibiotic resistance negatively impact clinical outcomes, but it is also associated with increased healthcare costs. 46,53 These costs are due to prolonged patient hospitalizations, delayed recoveries, and the need to implement infection control initiatives aimed at preventing the spread of resistant organisms. In 2002, the direct hospitalization costs incurred in Canada as a result of antibiotic-resistant bacterial infections were estimated at between CDN $14 and $26 million, a notable CDN $9 to $14 million more than it would have cost had those infections been susceptible to traditional antibiotic therapies. 60 Patient screening for resistant organisms and precautions to prevent their spread were estimated to have cost an additional CDN $26 million. 60 This estimate does not include the cost of treating resistant infections that occur outside of hospitals. 60 Purchasing new and advanced antimicrobial drugs also presents a substantial financial strain to the healthcare system. In the case of Staphylococcus aureus, treatments for methicillin-resistant strains are significantly more expensive than those for methicillinsensitive strains (Table 3). 61 Table 3. The Cost of Antibiotics for the Treatment of Staphylococcus Aureus in Pathogen Antibiotic Daily Cost (CDN) MSSA Cloxacillin $0.70-$14.40 MRSA Vancomycin $92.54 Linezolid $ Daptomycin Tigecycline $ $ MSSA methicillin-sensitive Staphylococcus aureus; MRSA methicillin-resistant Staphylococcus aureus. CONCLUDING REMARKS The issue of antimicrobial resistance is an escalating challenge to public health. Antimicrobial drugs are among the most revolutionary pharmaceuticals in modern medicine, but the emergence of resistance among bacterial pathogens continues to compromise their clinical effectiveness. Antibioticresistant infections are associated with increased patient morbidity and mortality, as well as increased healthcare costs. The need for increased awareness of antimicrobial resistance and its consequences has led to its selection by the World Health Organization as the theme for World Health Day Although there are unique trends in antimicrobial resistance in Canada, it is truly a global health problem. 63 While the focus of this article has been limited to bacterial antibiotic resistance, the worldwide existence and impact of antimicrobial resistance among viral, 64 fungal, 65 and parasitic (including protozoal 66 and helminthic 67 ) pathogens should not be overlooked. Controlling antimicrobial resistance requires a multifaceted approach. The selective pressures of antimicrobial exposure emphasize the need for caution and stewardship in antimicrobial prescription, 68 while the increasing prevalence of resistant organisms in hospitals underscores the need for surveillance of resistance rates and implementation of strong infection control practices. 69 The lack of viable treatment options for multidrug-resistant organisms also stresses the need for the continued development of novel antimicrobial compounds. 70 Such initiatives will ensure antimicrobial chemotherapy will continue to fulfill its essential role in infectious disease treatment in the future.

4 MUMJ Commentary 61 REFERENCES 1. Bud R. Medical Milestones Antibiotics: The epitome of a wonder drug. BMJ 2007; 334: S6. 2. Cohen ML. Changing patterns of infectious disease. Nature 2000; 406: Armstrong GL, Conn LA, Pinner RW. Trends in infectious disease mortality in the United States during the 20th century. JAMA 1999; 281: Levy SB & Marshall B. Antibacterial resistance worldwide: Causes, challenges and responses. Nat Med 2004; 10: S122-S Conly J. Antimicrobial resistance in Canada. CMAJ 2002; 167: Mulvey MR & Simor AE. Antimicrobial resistance in hospitals: How concerned should we be? CMAJ 2009; 180: Zhanel GG, Karlowsky JA, DeCorby M, et al. Prevalence of antimicrobial-resistant pathogens in Canadian hospitals: Results of the Canadian Ward Surveillance Study (CANWARD 2007). Can J Infect Dis Med Microbiol 2009; 20: 9A-19A. 8. Zhanel GG, DeCorby M, Adam H, et al. Prevalence of antimicrobial-resistant pathogens in Canadian hospitals: Results of the Canadian Ward Surveillance Study (CANWARD 2008). Antimicrob Agents Chemother 2010; 54: Simor AE, Ofner-Agostini M, Bryce E et al. The evolution of methicillin-resistant Staphylococcus aureus in Canadian hospitals: 5 years of national surveillance. CMAJ 2001; 165: Jones RN, Kugler KC, Pfaller MA, et al. Characteristics of pathogens causing urinary tract infections in hospitals in North America: Results from the SENTRY Antimicrobial Surveillance Program, Diagn Microbiol Infect Dis 1999; 35: Zhanel GG, DeCorby M, Laing N, et al. Antimicrobial-resistant pathogens in intensive care units in Canada: Results of the Canadian National Intensive Care Unit (CAN-ICU) study, Antimicrob Agents Chemother 2008; 52: Alekshun MN & Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell 2007; 128: Normark BH & Normark S. Evolution and spread of antibiotic resistance. J Intern Med 2002; 252: Archer GL & Polk RE. Treatment and prophylaxis of bacterial infections. In: Fauci AS, Braunwald E, Kasper DL et al. (eds). Harrison s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008; Wright GD. Bacterial resistance to antibiotics: Enzymatic degradation and. Adv Drug Deliv Rev 2005; 57: Bush K & Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother 2010; 54: Paterson DL & Bonomo RA. Extended-spectrum β-lactamases: A clinical update. Clin Microbiol Rev 2005; 18: Galani I, Xirouchaki E, Kanellakopoulou, et al. Transferable plasmid mediating resistance to multiple antimicrobial agents in Klebsiella pneumoniae isolates in Greece. Clin Microbiol Infect 2002; 8: Robicsek A, Jacoby GA, Hooper DC. The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect Dis 2006; 6: Giamarellou K. Multidrug resistance in gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs). Clin Microbiol Infect 2005; 11: S1-S Pitout JDD & Laupland KB. Extended-spectrum β-lactamases-producing Enterobacteriaceae: An emerging public-health concern. Lancet Infect Dis 2008; 8: Toye B, Krajden S, Fuksa M, et al. Carbapenem resistance in Canada. CMAJ 2009; 180: Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: A molecular, biological, and epidemiological study. Lancet Infect Dis 2010; 10: Pillai DR, McGeer A, Low DE. New Delhi metallo-β-lactamase-1 in Enterobacteriaceae: Emerging resistance. CMAJ 2011; 183: Mulvey MR, Grant JM, Plewes K, Roscoe D, and Boyd DA. New Delhi metalloβ-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada. Emerg Infect Dis 2011; 17: Ramirez MS & Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat 2010; 13: Kumar A & Schweizer HP. Bacterial resistance to antibiotics: Active efflux and reduced uptake. Adv Drug Deliv Rev 2005, 57: Rodriguez-Martinez JM, Poirel L, Nordmann P. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2009; 53: Doumith M, Ellington MJ, Livermore DM, et al. Molecular mechanisms disrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK. J Antimicrob Chemother 2009; 63: Pages J-M, James CE, Winterhalter M. The porin and the permeating antibiotic: A selective diffusion barrier in gram-negative bacteria. Nat Rev Microbiol 2008; 6: Poole K. Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 2005; 56: Li, XZ & Nikaido H. Efflux-mediated drug resistance in bacteria: An update. Drugs 2009; 69: Perez F, Hujer AM, Hujer KM, et al. Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2007, 51: Poole K & Srikumar R. Multidrug efflux in Pseudomonas aeruginosa: Components, mechanisms and clinical significance. Curr Top Med Chem 2001; 1: Lambert PA. Bacterial resistance to antibiotics: Modified target sites. Adv Drug Deliv Rev 2005; 57: Lowe FD. Antimicrobial resistance: The example of Staphylococcus aureus. J Clin Invest 2003; 111: Poole K. Resistance to β-lactam antibiotics. Cell Mol Life Sci 2004; 61: Grebe T & Hakenbeck R. Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of β-lactam antibiotics. Antimicrob Agents Chemother 1996; 40: Rybkine T, Mainardi JL, Sougakoff W, et al. Penicillin-binding protein 5 sequence alterations in clinical isolates of Enterococcus faecium with different levels of β-lactam resistance. J Infect Dis 1998; 178: Adam HJ, Schurek KN, Nichol KA, et al. Molecular characterization of increasing fluoroquinolone resistance in Streptococcus pneumoniae isolates in Canada, 1997 to Antimicrob Agents Chemother 2007; 51: Higgins PG, Fluit AC, Milatovic D, et al. Mutations in GyrA, ParC, MexR and NfxB in clinical isolates of Pseudomonas aeruginosa. Int J Antimicrob Agents 2003; 21: Morgan-Linnell SK, Boyd LB, Steffen D, et al. Mechanisms accounting for fluoroquinolone resistance in Escherichia coli clinical isolates. Antimicrob Agents Chemother 2009; 53: Wierzbowski AK, Nichol K, Laing N, et al. Macrolide resistance mechanisms among Streptococcus pneumoniae isolated over 6 years of Canadian Respiratory Organism Susceptibility Study (CROSS) ( ). J Antimicrob Chemother 2007; 60: Gold HS. Vancomycin-resistant enterococci: Mechanisms and clinical observations. Clin Infect Dis 2001; 33: French GL. Clinical impact and relevance of antibiotic resistance. Adv Drug Deliv Rev 2005; 57: Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: Mortality, length of hospital stay, and health care costs. Clin Infect Dis 2006; 42: S82-S Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: A Meta-analysis. Clin Infect Dis 2003; 36: Linden PK, Pasculle AW, Manez R, et al. Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clin Infect Dis 1996; 22: Tumbarello M, Spanu T, Sanguinetti M, et al. Bloodstream infections caused by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae: Risk factors, molecular epidemiology, and clinical outcome. Antimicrob Agents Chemother 2006; 50: Tumbarello M, Spanu T, Di Bidino R, et al. Cost of bloodstream infections caused by Escherichia coli and influence of extended-spectrum-β-lactamase production and inadequate initial antibiotic therapy. Antimicrob Agents Chemother 2010; 54: Peralta G, Sanchez MB, Garrido JC, et al. Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with Escherichia coli bacteraemia. J Antimicrob Chemother 2007; 60: Micek SC, Lloyd AE, Richie DJ, et al. Pseudomonas aeruginosa bloodstream infection: Importance of appropriate initial antimicrobial treatment. Antimicrob Agents Chemother 2005; 49: Cosgrove SE & Carmeli Y. The impact of antimicrobial resistance on health and economic outcomes. Clin Infect Dis 2003; 36: Levin AS, Barone AA, Penco J, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999; 28: Falagas ME & Kasaikou SK. Colistin: The revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis 2005; 40: Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis 2006; 6: Spellberg B, Powers JH, Brass EP, et al. Trends in antimicrobial drug development: Implications for the future. Clin Infect Dis 2004; 38: Falagas ME & Bliziotis IA. Pandrug-resistant gram-negative bacteria: The dawn of the post-antibiotic era? Int J Antimicrob Agents 2007; 29: Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother 2009; 64: i29-i Canadian Committee on Antibiotic Resistance. Antimicrobial resistance: A deadly burden no country can afford to ignore. Can Commun Dis Rep 2003; 29: Canadian Expert Drug Advisory Committee. (2008). CEDAC final recommendation on reconsideration and reasons for recommendation Daptomycin. Retrieved January 18, 2011, from the World Wide Web: cdr/complete/cdr_complete_cubicin_%20september pdf. 62. World Health Organization. (2011). World Health Day 7 April 2011: Antimicrobial resistance and its global spread. Retrieved January 18, 2011, from the World Wide Web: Smith RD & Coast J. Antimicrobial resistance: A global response. Bull World Health Organ 2002; 80: Richman DD. Antiviral drug resistance. Antiviral drug resistance. Antiviral Res 2006; 71: Kanafani ZA & Perfect JR. Resistance to antifungal agents: Mechanisms and clinical impact. Clin Infect Dis 2008; 46: Borst P & Ouellette M. New mechanisms of drug resistance in parasitic protozoa. Annu Rev Microbiol 1995; 49:

5 62 Commentary Volume 8 No. 1, Geerts S & Gryseels B. Antihelmintic resistance in human helminths: A review. Trop Med Int Health 2001; 6: Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America: Guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis 2007; 44: Shlaes DM, Gerding DN, John Jr JF, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the prevention of antimicrobial resistance in hospitals. Infect Control Hosp Epidemiol 1997; 18: Norrby SR, Nord CE, Finch R. Lack of development of new antimicrobial drugs: A potential serious threat to public health. Lancet Infect Dis 2005; 5: Author Biography Justin D. Tilak is a first-year student at the Michael G. DeGroote School of Medicine, McMaster University. He received his Bachelor of Science degree at Queen s University.