EDITORIAL
For reprint orders, please contact: [email protected]
Antibiotic resistance in hospitals
“...the expanse of drug-resistant bacteria is increasing and spreading throughout outpatient and inpatient populations.” Amal Alsaeed1,2,3,4 & Joseph M Blondeau*,1,2,3,4 Anyone working in healthcare and attending to patients being treated for an infectious disease has some familiarity with antimicrobial resistance. Indeed more senior medical staff had lived through the golden age of potent and broad-spectrum antibiotics whereby it was felt that very few pathogens could not be successfully treated to now where drug-resistant bacteria contribute to increased mortality. Furthermore, the expanse of drug- resistant bacteria is increasing and spreading throughout outpatient and inpatient populations. In the 1980s, antimicrobial resistance was felt to be hospital-based problem. Patients came into healthcare facilities and acquired resistant bacteria from the environment, other patients, healthcare providers or had resistant pathogens selected in vivo during therapy for infection. In the 1990s, there was wider recognition of drugresistant bacteria increasing in prevalence in the outpatient population (i.e., penicillin-nonsusceptible Streptococcus pneumoniae, β-lactamase-positive Haemophilus influenzae and Moraxella catarrhalis, ampicillin-resistant Escherichia coli). Escalation of community-acquired drug-resistant
bacteria impacted empiric antimicrobial therapy and therapeutic failures were seen in the form of clinical deterioration and failure to clinically respond, which resulted in additional days of therapy with the same or a different antibiotic. One additional impact of increasing drug-resistant pathogens in the outpatient setting was patients requiring admission to the hospital (infection or noninfection related) and thus serving as a vector for carrying drug-resistant pathogens into healthcare facilities. This also impacted empiricor pathogen-specific drug selection for therapy for infected patients. Moving beyond the year 2000 to present day, antimicrobial resistance remains problematic both in community (as above and methicillin-resistant Staphylococcus aureus [MRSA] and extended-spectrum β-lactamase-producing Gram-negative bacilli, such as Klebsiella pneumoniae) and healthcare facility settings. In our hospitals, the list of problematic drug-resistant pathogens can include all those already mentioned and also include multidrugresistant E. coli, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, other genera of Enterobacteriaceae including
KEYWORDS
• antimicrobial resistance • hospital
“In the 1990s, there was wider recognition of drug-resistant bacteria increasing in prevalence in the outpatient population...”
Department of Clinical Microbiology, Royal University Hospital & The Saskatoon Health Region, Saskatoon, SK, Canada Departments of Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada 3 Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada 4 Department of Ophthalmology, University of Saskatchewan, Saskatoon, SK, Canada *Author for Correspondence: Tel.: +1 306 655 6943; Fax: +1 306 655 6947; [email protected] 1 2
10.2217/FMB.15.10 © 2015 Future Medicine Ltd
Future Microbiol. (2015) 10(3), 303–307
part of
ISSN 1746-0913
303
Editorial Alsaeed & Blondeau
“Bacteria become resistant to antimicrobial agents by well-known and defined mechanisms: enzymatic inactivation, altered target sites, efflux and altered membrane permeability resulting in decreased uptake.”
304
Enterobacter species, Proteus spp., Serratia spp., among others. Drug-resistant bacteria in hospitalized patients are particularly problematic. In our three acute care hospitals in Saskatoon, we have seen over the past two decades a shift in admission criteria whereby only the more moderately to severely ill patients are admitted and many more patients that would be otherwise admitted are now being treated at home through a variety of programs including home care nursing and outpatient antimicrobial therapy (including injectable), among others. For sicker hospitalized patients they are often predisposed to infection as a result of central lines, urinary catheters, immunosuppression (disease or therapy related), surgery, intubation, burns and/or antimicrobial therapy and prosthetic devices. When one considers a multidrug-resistant pathogen and a patient with well known allergies to specific drugs or drug classes and combine these with specific drug toxicities that prevent use of some antimicrobial agents (i.e., aminoglycoside or vancomycin and renal toxicity), options for therapy become limited very quickly. In such scenarios, less frequently used antim icrobial agents may be used – optimal therapy may be difficult to obtain and any antimicrobial that could potentially work would be used. Bacteria become resistant to antimicrobial agents by well-known and defined mechanisms: enzymatic inactivation, altered target sites, efflux and altered membrane permeability resulting in decreased uptake. Additionally some bugs are intrinsically resistant to some antimicrobials for one of two main reasons: the bacteria lack the drug target or the target is not accessible to the drug [1] . Unfortunately, some bacteria with acquired resistance may simultaneously possess multiple resistance mechanisms conferring multidrug-resistant strains – an unfortunate reality in many hospitals. It is the multidrugresistant bacterial pathogens and their continued evolution over the past 10 years that have compromised antimicrobial therapy in hospitalized patients. Weinstein stated that the forces driving antimicrobial drug resistance in hospitals were related to failures of hospital hygiene, selective pressures created by overuse of antibiotics and mobile genetic elements carrying resistance genes that get passed between some species of bacteria; 85% of 424 physicians surveyed agreed that antimicrobial resistance was
Future Microbiol. (2015) 10(3)
a major national problem [2] . Bergstrom et al., using a mathematical model suggested cycling of antimicrobial agents is unlikely to reduce the emergence or spread of drug-resistant bugs, however, drug mixing (receiving one of several drug classes simultaneously) may be more effective [3] . Nosocomial infection is argued to contribute to mortality, morbidity, length of stay and overall healthcare costs. Additionally, Mulvey and Simor argued that antibiotic-resistant organisms appeared to be biologically fit and associated with life-threatening infections with few therapeutic options [4] . Sievert et al. reported on antimicrobialresistant pathogens associated with healthcareassociated infections: eight pathogen groups represented 80% of reported pathogens and included S. aureus, Enterococcus spp., E. coli, Staphylococcus-coagulase negative, Candida spp., Klebsiella spp., P. aeruginosa and Enterobacter spp. [5] . MRSA is an enormous problem in hospitalized patients. Acquisition of the mecA gene results in the encoding of a novel penicillin-binding protein that is biologically active but not inhibited by β-lactam antimicrobials; resistance is rendered to penicillins, cephalosporins, monobactams and carbapenems. S. aureus is a most successful human pathogen causing mild self-limiting to life-threatening infections. Bacteremias are particularly problematic as a limited few antimicrobials are available for life-threatening infections. MRSA infections need to be further segregated into communicated-acquired versus hospitalacquired. Community-acquired strains occur in individuals with no history of association with a healthcare facility whereas the hospital-acquired strains have a healthcare-associated history. Antimicrobial susceptibility profiles are different between community- and hospital-acquired MRSA strains. Zhanel et al. reported 5.1% of 5282 bacterial isolates collected (2008) as part of the Canadian Ward Surveillance Study were MRSA, and these organisms represented 27% of all S. aureus isolates; 68.8% hospital-acquired and 27.6% community acquired [6] . More recently, Simor et al. reported that from 76 Canadian hospitals a median prevalence rate for MRSA colonization was 4.2% and median infection rates were 0.3%, with healthcare-associated MRSA being 79% [7] . Stefani et al. reported on the global epidemiology of MRSA and reported the following rates for hospital-acquired strains: USA, Brazil
future science group
Antibiotic resistance in hospitals and other South American countries: >50%; Canada: 5–10%; Europe: 10–50%; and China and Australia: 25–50% [8] . For some countries, data are limited or unavailable. Davis et al. reported 3.4% of 758 patients admitted to hospital were colonized with MRSA versus 21% with methicillin-susceptible S. aureus (MSSA) strains [9] . Some 19% of patients colonized with MRSA at admission and 25% of patients that became colonized during hospitalization developed MRSA infection – a statistically significant observation as compared to those with MSSA strains, 1.5 and 2%, respectively; p < 0.01 and p < 0.01 or not colonized (p < 0.01). Colonization increases the risk of infection but does that impact mortality? Van Hal and colleagues reviewed predictors of mortality in S. aureus bacteremia and indicated significant mortality, especially in the intensive care unit [10] . Regarding MRSA infections, despite some potential weaknesses in published studies, numerous reports indicated increased mortality for MRSA versus MSSA infections. Cosgrove et al. reported MRSA bacteremia was associated with higher mortality than MSSA bacteremia, and Hanberger et al. reported in intensive care unit patients, MRSA infection was independently associated with an almost 50% higher likelihood of hospital death when compared with MSSA strains [11,12] . Risk factors that may be associated with higher mortality due to MRSA included cirrhosis, renal insufficiency, admittance to an intensive care unit and having lived in a nursing home prior to hospitalization. Pastagia et al. reported that older age, residence in a nursing home, severe bacteremia and organ impairment were independently associated with increased risk of death due to MRSA infection [13] . Consultation with an infectious diseases specialist lowered the risk of death. Vancomycin remains the corner stone of therapy in more severe infections, however, concerns over therapeutic failure are concerning. Decreases in the susceptibility breakpoint may limit the utility of this drug and failures associated with increased MIC’s may necessitate alternative antimicrobials. As to which drug(s) may be a suitable alternative (tigecycline, daptomycin, ceftobiprole, telavancin or tedizolid) is still being debated and studied. Gram-negative infections have traditionally been treatable with a variety of drug classes including cephalosporins and carbapenems, aminoglycosides and f luoroquinolones. Of
future science group
these classes, systemic administration of amino glycosides was potentially associated with renal and otic toxicity and recognized toxicities are also known with other drug classes. In recent years, the discovery and spread of extended-spectrum β-lactamase-producing Gram-negative bacilli as well as carbapenemase-producing organism have compromised the use of extendedspectrum cephalosporins (i.e., third-generation agents such as ceftriaxone and cefotaxime) and carbapenems (imipenem, meropenem and ertapenem). In our institutions, extended-spectrum β-lactamase-producing organisms are seen most commonly in urinary tract infection but not exclusively. Inadequate initial antimicrobial therapy has been identified as a predictor of increased mortality. Therapy may be considered with tigecycline, carbapenems, amikacin and β-lactam/β-lactamase inhibitors or other agents including fluoroquinoilones when supported by susceptibility data. Considering carbapenemase-producing organisms, Tzouvelekis and colleagues indicated these organisms were causing an unprecedented public health nightmare, primarily infecting hospitalized patients and those in long-term care facilities [14] . Infection is often seen in debilitated and immunocompromised patients and associated with prolonged hospital stays and increased mortality. Mortality rates can exceed 50% depending on the patient population. Therapeutic options are limited, and tigecycline and colistin are often used. The value of combination regimens remains unresolved but is likely of value. Carbapenemase-producing Enterobacteriaceae have been reported from the USA and Canada, southern and northern Europe and Scandinavian countries, the Middle East, South America and China [15] . The New Delhi metallo-β-lactamase genotype has been described in Enterobacter cloacae, E. coli and K. pneumoniae and associated with urine and respiratory tract infections – many initial cases could be traced back to India and care in a hospital. Every healthcare facility has concerns with P. aeruginosa and multidrug-resistant strains are more concerning. From the Canadian Ward Surveillance Study, P. aeruginosa accounted for 7.1% of the 5282 bacterial strains collected from ten Canadian hospitals and of these 5.9% demonstrated multidrug-resistant phenotypes [6] . Overall, P. aeruginosa resistance was seen as follows: colistin: 0.8%; amikacin: 3.5%; cefepime:
www.futuremedicine.com
Editorial
“Infection is often seen in debilitated and immunocompromised patients and associated with prolonged hospital stays and increased mortality.”
305
Editorial Alsaeed & Blondeau 7.2%; gentamicin: 12.3%; fluoroquinolones: 19–24%; meropenem: 5.6%; and piperacillintazobactam: 8%. Risk factors for the acquisition and spread of these pathogens include deficiencies in infection control guidelines and use of broad-spectrum antibiotics, including carbapenems and fluoroquinolones [16] . Aloush et al. reported multidrug-resistant P. aeruginosa infections were associated with serious adverse clinical outcomes [17] . Multivariate analysis showed being bedridden, high invasive device scores, treatment with broad-spectrum cephalosporins and aminoglycosides were risk factors. Compared with controls, increased mortality, longer hospital stay and requirement for procedures were also identified. Where do we go from here? Numerous individuals and associations have been sounding the alarm bells for years over increasing antimicrobial resistance, patient morbidity and mortality, and the need to address this crisis. Unrealistic regulatory hurdles are not helpful and noninferiority trials often produce predictable results. The use of noninferiority trials is not ideal and often fail to identify useful differences between the agents being studied. Combinations of antimicrobials have been suggested for therapy but in my opinion we really don’t understand the true value of combination therapy or what measurements we need to be doing. In some References 1
2
3
Leclercq R, Courvalin P. Intrinsic and unusual resistance to macrolide, lincosamide, and streptogramin antibiotics in bacteria. Antimicrob. Agents Chemother. 35(7), 1273–1276 (1991). Weinstein RA. Controlling antimicrobial resistance in hospitals: infection control and use of antibiotics. Emerg. Infect. Dis. 7(2), 188–192 (2001).
Mulvey MR, Simor AE. Antimicrobial resistance in hospitals: how concerned should we be? CMAJ 180(4), 408–415 (2009).
5
Sievert DM, Ricks P, Edwards JR et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for
306
Financial & competing interest disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Disease Control and Prevention, 2009–2010. Infect. Control Hosp. Epidemiol. 34(1), 1–14 (2013). 6
7
Bergstrom CT, Lo M, Lipsitch M. Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc. Natl Acad. Sci. USA 101(36), 13285–13290 (2004).
4
instances, combination therapy has not been shown to impact clinical outcome; however, it might reduce the likelihood for resistance selection from bacteria with susceptible phenotypes – this has value. The need for new and novel antimicrobials is a given. Additionally, investigations on novel ways to deliver drugs that would be anatomically restricted yielding high drug concentrations with limited toxicities are encouraging. One example is the ongoing investigations with aerosolized amikacin for ventilator-associated pneumonia. Such high pulmonary drug concentrations may be very useful for treating bacteria with elevated MICs and designated as resistant by traditional measurements. This and other potential novel developments may provide valuable alternatives/combination to systemically administered drugs.
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. 54(11), 4684–4693 (2010). Simor AE, Williams V, Mcgeer A et al. Prevalence of colonization and infection with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus and of Clostridium difficile infection in Canadian hospitals. Infect. Control Hosp. Epidemiol. 34(7), 687–693 (2013).
8
Stefani S, Chung DR, Lindsay JA et al. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39(4), 273–282 (2012).
9
Davis KA, Stewart JJ, Crouch HK, Florez CE, Hospenthal DR. Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its
Future Microbiol. (2015) 10(3)
effect on subsequent MRSA infection. Clin. Infect. Dis. 39(6), 776–782 (2004). 10 Van Hal SJ, Jensen SO, Vaska VL, Espedido
BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus bacteremia. Clin. Microbiol. Rev. 25(2), 362–386 (2012). 11 Cosgrove SE, Sakoulas G, Perencevich EN,
Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillinsusceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin. Infect. Dis. 36(1), 53–59 (2003). 12 Hanberger H, Walther S, Leone M et al.
Increased mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) infection in the intensive care unit: results from the EPIC II study. Int. J. Antimicrob. Agents 38(4), 331–335 (2011). 13 Pastagia M, Kleinman LC, Lacerda De La
Cruz EG, Jenkins SG. Predicting risk for death from MRSA bacteremia. Emerg. Infect. Dis. 18(7), 1072–1080 (2012).
future science group
Antibiotic resistance in hospitals 14 Tzouvelekis LS, Markogiannakis A,
Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin. Microbiol. Rev. 25(4), 682–707 (2012). 15 Gupta N, Limbago BM, Patel JB, Kallen AJ.
epidemiology and prevention. Clin. Infect. Dis. 53(1), 60–67 (2011). 16 Falagas ME, Kopterides P. Risk factors for
the isolation of multi-drug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa: a systematic review of the literature. J. Hosp. Infect. 64(1), 7–15 (2006).
Editorial
17 Aloush V, Navon-Venezia S, Seigman-Igra Y,
Cabili S, Carmeli Y. Multidrug-resistant Pseudomonas aeruginosa: risk factors and clinical impact. Antimicrob. Agents Chemother. 50(1), 43–48 (2006).
Carbapenem-resistant Enterobacteriaceae:
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www.futuremedicine.com
307
For reprint orders, please contact: [email protected]
Antibiotic resistance in hospitals
“...the expanse of drug-resistant bacteria is increasing and spreading throughout outpatient and inpatient populations.” Amal Alsaeed1,2,3,4 & Joseph M Blondeau*,1,2,3,4 Anyone working in healthcare and attending to patients being treated for an infectious disease has some familiarity with antimicrobial resistance. Indeed more senior medical staff had lived through the golden age of potent and broad-spectrum antibiotics whereby it was felt that very few pathogens could not be successfully treated to now where drug-resistant bacteria contribute to increased mortality. Furthermore, the expanse of drug- resistant bacteria is increasing and spreading throughout outpatient and inpatient populations. In the 1980s, antimicrobial resistance was felt to be hospital-based problem. Patients came into healthcare facilities and acquired resistant bacteria from the environment, other patients, healthcare providers or had resistant pathogens selected in vivo during therapy for infection. In the 1990s, there was wider recognition of drugresistant bacteria increasing in prevalence in the outpatient population (i.e., penicillin-nonsusceptible Streptococcus pneumoniae, β-lactamase-positive Haemophilus influenzae and Moraxella catarrhalis, ampicillin-resistant Escherichia coli). Escalation of community-acquired drug-resistant
bacteria impacted empiric antimicrobial therapy and therapeutic failures were seen in the form of clinical deterioration and failure to clinically respond, which resulted in additional days of therapy with the same or a different antibiotic. One additional impact of increasing drug-resistant pathogens in the outpatient setting was patients requiring admission to the hospital (infection or noninfection related) and thus serving as a vector for carrying drug-resistant pathogens into healthcare facilities. This also impacted empiricor pathogen-specific drug selection for therapy for infected patients. Moving beyond the year 2000 to present day, antimicrobial resistance remains problematic both in community (as above and methicillin-resistant Staphylococcus aureus [MRSA] and extended-spectrum β-lactamase-producing Gram-negative bacilli, such as Klebsiella pneumoniae) and healthcare facility settings. In our hospitals, the list of problematic drug-resistant pathogens can include all those already mentioned and also include multidrugresistant E. coli, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, other genera of Enterobacteriaceae including
KEYWORDS
• antimicrobial resistance • hospital
“In the 1990s, there was wider recognition of drug-resistant bacteria increasing in prevalence in the outpatient population...”
Department of Clinical Microbiology, Royal University Hospital & The Saskatoon Health Region, Saskatoon, SK, Canada Departments of Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada 3 Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada 4 Department of Ophthalmology, University of Saskatchewan, Saskatoon, SK, Canada *Author for Correspondence: Tel.: +1 306 655 6943; Fax: +1 306 655 6947; [email protected] 1 2
10.2217/FMB.15.10 © 2015 Future Medicine Ltd
Future Microbiol. (2015) 10(3), 303–307
part of
ISSN 1746-0913
303
Editorial Alsaeed & Blondeau
“Bacteria become resistant to antimicrobial agents by well-known and defined mechanisms: enzymatic inactivation, altered target sites, efflux and altered membrane permeability resulting in decreased uptake.”
304
Enterobacter species, Proteus spp., Serratia spp., among others. Drug-resistant bacteria in hospitalized patients are particularly problematic. In our three acute care hospitals in Saskatoon, we have seen over the past two decades a shift in admission criteria whereby only the more moderately to severely ill patients are admitted and many more patients that would be otherwise admitted are now being treated at home through a variety of programs including home care nursing and outpatient antimicrobial therapy (including injectable), among others. For sicker hospitalized patients they are often predisposed to infection as a result of central lines, urinary catheters, immunosuppression (disease or therapy related), surgery, intubation, burns and/or antimicrobial therapy and prosthetic devices. When one considers a multidrug-resistant pathogen and a patient with well known allergies to specific drugs or drug classes and combine these with specific drug toxicities that prevent use of some antimicrobial agents (i.e., aminoglycoside or vancomycin and renal toxicity), options for therapy become limited very quickly. In such scenarios, less frequently used antim icrobial agents may be used – optimal therapy may be difficult to obtain and any antimicrobial that could potentially work would be used. Bacteria become resistant to antimicrobial agents by well-known and defined mechanisms: enzymatic inactivation, altered target sites, efflux and altered membrane permeability resulting in decreased uptake. Additionally some bugs are intrinsically resistant to some antimicrobials for one of two main reasons: the bacteria lack the drug target or the target is not accessible to the drug [1] . Unfortunately, some bacteria with acquired resistance may simultaneously possess multiple resistance mechanisms conferring multidrug-resistant strains – an unfortunate reality in many hospitals. It is the multidrugresistant bacterial pathogens and their continued evolution over the past 10 years that have compromised antimicrobial therapy in hospitalized patients. Weinstein stated that the forces driving antimicrobial drug resistance in hospitals were related to failures of hospital hygiene, selective pressures created by overuse of antibiotics and mobile genetic elements carrying resistance genes that get passed between some species of bacteria; 85% of 424 physicians surveyed agreed that antimicrobial resistance was
Future Microbiol. (2015) 10(3)
a major national problem [2] . Bergstrom et al., using a mathematical model suggested cycling of antimicrobial agents is unlikely to reduce the emergence or spread of drug-resistant bugs, however, drug mixing (receiving one of several drug classes simultaneously) may be more effective [3] . Nosocomial infection is argued to contribute to mortality, morbidity, length of stay and overall healthcare costs. Additionally, Mulvey and Simor argued that antibiotic-resistant organisms appeared to be biologically fit and associated with life-threatening infections with few therapeutic options [4] . Sievert et al. reported on antimicrobialresistant pathogens associated with healthcareassociated infections: eight pathogen groups represented 80% of reported pathogens and included S. aureus, Enterococcus spp., E. coli, Staphylococcus-coagulase negative, Candida spp., Klebsiella spp., P. aeruginosa and Enterobacter spp. [5] . MRSA is an enormous problem in hospitalized patients. Acquisition of the mecA gene results in the encoding of a novel penicillin-binding protein that is biologically active but not inhibited by β-lactam antimicrobials; resistance is rendered to penicillins, cephalosporins, monobactams and carbapenems. S. aureus is a most successful human pathogen causing mild self-limiting to life-threatening infections. Bacteremias are particularly problematic as a limited few antimicrobials are available for life-threatening infections. MRSA infections need to be further segregated into communicated-acquired versus hospitalacquired. Community-acquired strains occur in individuals with no history of association with a healthcare facility whereas the hospital-acquired strains have a healthcare-associated history. Antimicrobial susceptibility profiles are different between community- and hospital-acquired MRSA strains. Zhanel et al. reported 5.1% of 5282 bacterial isolates collected (2008) as part of the Canadian Ward Surveillance Study were MRSA, and these organisms represented 27% of all S. aureus isolates; 68.8% hospital-acquired and 27.6% community acquired [6] . More recently, Simor et al. reported that from 76 Canadian hospitals a median prevalence rate for MRSA colonization was 4.2% and median infection rates were 0.3%, with healthcare-associated MRSA being 79% [7] . Stefani et al. reported on the global epidemiology of MRSA and reported the following rates for hospital-acquired strains: USA, Brazil
future science group
Antibiotic resistance in hospitals and other South American countries: >50%; Canada: 5–10%; Europe: 10–50%; and China and Australia: 25–50% [8] . For some countries, data are limited or unavailable. Davis et al. reported 3.4% of 758 patients admitted to hospital were colonized with MRSA versus 21% with methicillin-susceptible S. aureus (MSSA) strains [9] . Some 19% of patients colonized with MRSA at admission and 25% of patients that became colonized during hospitalization developed MRSA infection – a statistically significant observation as compared to those with MSSA strains, 1.5 and 2%, respectively; p < 0.01 and p < 0.01 or not colonized (p < 0.01). Colonization increases the risk of infection but does that impact mortality? Van Hal and colleagues reviewed predictors of mortality in S. aureus bacteremia and indicated significant mortality, especially in the intensive care unit [10] . Regarding MRSA infections, despite some potential weaknesses in published studies, numerous reports indicated increased mortality for MRSA versus MSSA infections. Cosgrove et al. reported MRSA bacteremia was associated with higher mortality than MSSA bacteremia, and Hanberger et al. reported in intensive care unit patients, MRSA infection was independently associated with an almost 50% higher likelihood of hospital death when compared with MSSA strains [11,12] . Risk factors that may be associated with higher mortality due to MRSA included cirrhosis, renal insufficiency, admittance to an intensive care unit and having lived in a nursing home prior to hospitalization. Pastagia et al. reported that older age, residence in a nursing home, severe bacteremia and organ impairment were independently associated with increased risk of death due to MRSA infection [13] . Consultation with an infectious diseases specialist lowered the risk of death. Vancomycin remains the corner stone of therapy in more severe infections, however, concerns over therapeutic failure are concerning. Decreases in the susceptibility breakpoint may limit the utility of this drug and failures associated with increased MIC’s may necessitate alternative antimicrobials. As to which drug(s) may be a suitable alternative (tigecycline, daptomycin, ceftobiprole, telavancin or tedizolid) is still being debated and studied. Gram-negative infections have traditionally been treatable with a variety of drug classes including cephalosporins and carbapenems, aminoglycosides and f luoroquinolones. Of
future science group
these classes, systemic administration of amino glycosides was potentially associated with renal and otic toxicity and recognized toxicities are also known with other drug classes. In recent years, the discovery and spread of extended-spectrum β-lactamase-producing Gram-negative bacilli as well as carbapenemase-producing organism have compromised the use of extendedspectrum cephalosporins (i.e., third-generation agents such as ceftriaxone and cefotaxime) and carbapenems (imipenem, meropenem and ertapenem). In our institutions, extended-spectrum β-lactamase-producing organisms are seen most commonly in urinary tract infection but not exclusively. Inadequate initial antimicrobial therapy has been identified as a predictor of increased mortality. Therapy may be considered with tigecycline, carbapenems, amikacin and β-lactam/β-lactamase inhibitors or other agents including fluoroquinoilones when supported by susceptibility data. Considering carbapenemase-producing organisms, Tzouvelekis and colleagues indicated these organisms were causing an unprecedented public health nightmare, primarily infecting hospitalized patients and those in long-term care facilities [14] . Infection is often seen in debilitated and immunocompromised patients and associated with prolonged hospital stays and increased mortality. Mortality rates can exceed 50% depending on the patient population. Therapeutic options are limited, and tigecycline and colistin are often used. The value of combination regimens remains unresolved but is likely of value. Carbapenemase-producing Enterobacteriaceae have been reported from the USA and Canada, southern and northern Europe and Scandinavian countries, the Middle East, South America and China [15] . The New Delhi metallo-β-lactamase genotype has been described in Enterobacter cloacae, E. coli and K. pneumoniae and associated with urine and respiratory tract infections – many initial cases could be traced back to India and care in a hospital. Every healthcare facility has concerns with P. aeruginosa and multidrug-resistant strains are more concerning. From the Canadian Ward Surveillance Study, P. aeruginosa accounted for 7.1% of the 5282 bacterial strains collected from ten Canadian hospitals and of these 5.9% demonstrated multidrug-resistant phenotypes [6] . Overall, P. aeruginosa resistance was seen as follows: colistin: 0.8%; amikacin: 3.5%; cefepime:
www.futuremedicine.com
Editorial
“Infection is often seen in debilitated and immunocompromised patients and associated with prolonged hospital stays and increased mortality.”
305
Editorial Alsaeed & Blondeau 7.2%; gentamicin: 12.3%; fluoroquinolones: 19–24%; meropenem: 5.6%; and piperacillintazobactam: 8%. Risk factors for the acquisition and spread of these pathogens include deficiencies in infection control guidelines and use of broad-spectrum antibiotics, including carbapenems and fluoroquinolones [16] . Aloush et al. reported multidrug-resistant P. aeruginosa infections were associated with serious adverse clinical outcomes [17] . Multivariate analysis showed being bedridden, high invasive device scores, treatment with broad-spectrum cephalosporins and aminoglycosides were risk factors. Compared with controls, increased mortality, longer hospital stay and requirement for procedures were also identified. Where do we go from here? Numerous individuals and associations have been sounding the alarm bells for years over increasing antimicrobial resistance, patient morbidity and mortality, and the need to address this crisis. Unrealistic regulatory hurdles are not helpful and noninferiority trials often produce predictable results. The use of noninferiority trials is not ideal and often fail to identify useful differences between the agents being studied. Combinations of antimicrobials have been suggested for therapy but in my opinion we really don’t understand the true value of combination therapy or what measurements we need to be doing. In some References 1
2
3
Leclercq R, Courvalin P. Intrinsic and unusual resistance to macrolide, lincosamide, and streptogramin antibiotics in bacteria. Antimicrob. Agents Chemother. 35(7), 1273–1276 (1991). Weinstein RA. Controlling antimicrobial resistance in hospitals: infection control and use of antibiotics. Emerg. Infect. Dis. 7(2), 188–192 (2001).
Mulvey MR, Simor AE. Antimicrobial resistance in hospitals: how concerned should we be? CMAJ 180(4), 408–415 (2009).
5
Sievert DM, Ricks P, Edwards JR et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for
306
Financial & competing interest disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Disease Control and Prevention, 2009–2010. Infect. Control Hosp. Epidemiol. 34(1), 1–14 (2013). 6
7
Bergstrom CT, Lo M, Lipsitch M. Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc. Natl Acad. Sci. USA 101(36), 13285–13290 (2004).
4
instances, combination therapy has not been shown to impact clinical outcome; however, it might reduce the likelihood for resistance selection from bacteria with susceptible phenotypes – this has value. The need for new and novel antimicrobials is a given. Additionally, investigations on novel ways to deliver drugs that would be anatomically restricted yielding high drug concentrations with limited toxicities are encouraging. One example is the ongoing investigations with aerosolized amikacin for ventilator-associated pneumonia. Such high pulmonary drug concentrations may be very useful for treating bacteria with elevated MICs and designated as resistant by traditional measurements. This and other potential novel developments may provide valuable alternatives/combination to systemically administered drugs.
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. 54(11), 4684–4693 (2010). Simor AE, Williams V, Mcgeer A et al. Prevalence of colonization and infection with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus and of Clostridium difficile infection in Canadian hospitals. Infect. Control Hosp. Epidemiol. 34(7), 687–693 (2013).
8
Stefani S, Chung DR, Lindsay JA et al. Methicillin-resistant Staphylococcus aureus (MRSA): global epidemiology and harmonisation of typing methods. Int. J. Antimicrob. Agents 39(4), 273–282 (2012).
9
Davis KA, Stewart JJ, Crouch HK, Florez CE, Hospenthal DR. Methicillin-resistant Staphylococcus aureus (MRSA) nares colonization at hospital admission and its
Future Microbiol. (2015) 10(3)
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