Antibiotic Resistance in Nosocomial Respiratory Infections Gerald A. Denys,
PhD, D(ABMM)*,
Ryan F. Relich,
PhD, MLS(ASCP)CM
KEYWORDS Health care–associated infections Hospital-acquired pneumonia Ventilator-associated pneumonia Nosocomial Multidrug resistant pathogens KEY POINTS Nosocomial respiratory infections are the most common acquired infections in patients with severe underlying conditions and are responsible for high morbidity and mortality in this patient population. Multidrug-resistant (MDR) pathogens are associated with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Empiric treatment of HAP and VAP is based on onset of disease and presence or absence of risk factors associated with multidrug-resistant pathogens. Molecular assays directly applicable to respiratory specimen testing have the potential to improve adequacy of empiric therapy and spare use of broad-spectrum antibiotics. Effective strategies for the prevention of HAP and VAP and newer antimicrobial agents are needed to combat MDR pathogens.
INTRODUCTION
The emergence of multidrug resistance among bacterial species is a worldwide public health threat that is evolving at an alarming rate. Pathogens, including extended-spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species, and multidrug-resistant Acinetobacter baumannii, are associated with both hospital-acquired and community-acquired infections.1 Antimicrobial-resistant pathogens that are associated with nosocomial infections, or health care–associated infections (HAI) pose an ongoing challenge to hospitals, both in terms of patient treatment and in the prevention of transmission of resistant pathogens from patient to patient.1,2
Disclosures: The authors have no potential conflicts of interest to report. Division of Clinical Microbiology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Room 6027B, Indianapolis, IN 46202, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.02.004 0272-2712/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
labmed.theclinics.com
2
Denys & Relich
Of the HAIs, lower respiratory tract (LRT) infections are among the most frequently acquired, particularly among patients in the intensive care unit (ICU).3 Because of the unique combination of critically ill, and often immunosuppressed, hosts and chronically high antibiotic selective pressures, the ICU is an important environment for the emergence of antimicrobial drug resistance and the spread of drug-resistant organisms. Despite advances in antimicrobial therapy, supportive care, and infection control measures, hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) cause considerable morbidity and mortality. In addition, these infections are associated with increased costs to health care systems.1,4,5 The incidence of HAP ranges from 5 to more than 20 cases per 1000 hospital admissions.6,7 In patients not in the ICU, the highest rates are seen in the elderly, the immunosuppressed, surgical patients, and those receiving enteral feeding through a nasogastric tube.6 Approximately onethird of HAPs are ICU-acquired, with VAP accounting for approximately 90% of the cases. VAP occurs in 9% to 40% of intubated and mechanically ventilated individuals, which represents the most frequent ICU-acquired infection.8,9 The current incidence of VAP ranges from 2 to 16 cases per 1000 ventilator days, with a mortality rate ranging from of 3% to 17%.7 The estimated cost per HAP or VAP infection is in excess of $40,000, with a mortality rate ranging from 10% to 50%.10 This article describes the etiology, epidemiology, pathogenesis, diagnosis, and treatment of HAP and VAP associated with antibiotic-resistant bacterial pathogens. ETIOLOGY
The etiology of HAP and VAP depends on whether the patient has risk factors for the acquisition of multidrug-resistant (MDR) pathogens. Factors, including the duration of mechanical ventilation, length of hospital and ICU stay, previous exposure to antibiotics, and local endemic pathogens in a given ICU, influence the likelihood of MDR pathogen infection.1,11 A summary of the risk factors for infection with MDR pathogens is presented in Box 1.10,12 The frequency of specific MDR pathogens varies among Box 1 Risk factors associated with multidrug-resistant (MDR) pathogens causing hospital-acquired pneumonia and ventilator-associated pneumonia Antibiotic use in previous 3 months Hospitalization in the previous 3 months or 5 days Exposure to the intensive care unit Exposure to specific hospital unit with high frequency of antibiotic resistance Previous residence in nursing home or long-term care facility Home infusion therapy (including antibiotics) Hemodialysis Home wound care in past 30 days Family member with MDR pathogen Immunosuppression Data from Sydnor ER, Perl TM. Hospital epidemiology and infection control in acute-care settings. Clin Microbiol Rev 2011;24:141–73; and Papazian L, Donati SY. Hospital-acquired pneumonia. In: Cohen J, Powderly WG, Opel SM, editors. van der Meer JWM, Didier, Sobel JD, section editors. Cohen, Powderly and Opal’s infectious diseases. 3rd edition. Philadelphia: Mosby Elsevier; 2010. p. 294–9.
Resistance in Nosocomial Respiratory Infections
hospitals, specific hospital units, and patient populations (eg, medical, surgical, or trauma), including those patients who have recently been exposed to antibiotics. These pathogens may originate from the patient’s endogenous flora, other patients, hospital staff, contaminated medical devices, or the environment.13 Guidelines for the treatment of nosocomial pneumonia defines HAP into early-onset pneumonia, which occurs within the first 5 days of admission, and those who develop late-onset nosocomial pneumonia, which occurs 5 days or more after admission.1 Late-onset HAP mostly involves hospital-acquired MDR pathogens, a result of antibiotic selective pressure, cross-transmission, and colonization from ICU environmental sources.1,11,14 However, MDR pathogens may be isolated in early-onset HAP when risk factors exist before ICU admission.14 Table 1 lists the predominant bacterial agents causing nosocomial pneumonia. In general, organisms causing early-onset HAP reflect antibiotic-susceptible community isolates, such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, S aureus, nonresistant Enterobacteriaceae, anaerobic bacteria, and Legionella pneumophila. Patients who develop late-onset pneumonia are more likely to be infected with MDR organisms, including Pseudomonas aeruginosa, A baumannii, ESBL-producing and carbapenemase-producing Enterobacteriaceae, and MRSA. EPIDEMIOLOGY
More than 60% of reported HAP and VAP are caused by gram-negative bacilli; however, 20% to 40% are now caused by S aureus, most of which are methicillin-resistant strains.6 Pneumonia due to hospital-acquired MRSA has been increasing worldwide for the past 10 years; reports indicate that community-acquired MRSA clones (eg, US300/400) emerging in hospitals cause HAP and VAP.15 Increasing resistance to vancomycin (minimum inhibitory concentration [MIC] 2 mg/mL) or vancomycin intermediate-resistant S aureus (MIC 4–8 mg/mL) have been seen worldwide and are associated with poor clinical outcomes.16,17 In addition, recent reports of linezolid resistance in MRSA isolates is a significant concern.18,19 Among the Enterobacteriaceae, resistance to third-generation and fourth-generation cephalosporins is expressed by acquired ESBLs and/or AmpC b-lactamases. Another emerging resistance concern is the increase of carbapenemase-producing strains associated with Table 1 Predominant bacterial agents causing nosocomial pneumonia Early-Onset HAP (
PhD, D(ABMM)*,
Ryan F. Relich,
PhD, MLS(ASCP)CM
KEYWORDS Health care–associated infections Hospital-acquired pneumonia Ventilator-associated pneumonia Nosocomial Multidrug resistant pathogens KEY POINTS Nosocomial respiratory infections are the most common acquired infections in patients with severe underlying conditions and are responsible for high morbidity and mortality in this patient population. Multidrug-resistant (MDR) pathogens are associated with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Empiric treatment of HAP and VAP is based on onset of disease and presence or absence of risk factors associated with multidrug-resistant pathogens. Molecular assays directly applicable to respiratory specimen testing have the potential to improve adequacy of empiric therapy and spare use of broad-spectrum antibiotics. Effective strategies for the prevention of HAP and VAP and newer antimicrobial agents are needed to combat MDR pathogens.
INTRODUCTION
The emergence of multidrug resistance among bacterial species is a worldwide public health threat that is evolving at an alarming rate. Pathogens, including extended-spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus species, and multidrug-resistant Acinetobacter baumannii, are associated with both hospital-acquired and community-acquired infections.1 Antimicrobial-resistant pathogens that are associated with nosocomial infections, or health care–associated infections (HAI) pose an ongoing challenge to hospitals, both in terms of patient treatment and in the prevention of transmission of resistant pathogens from patient to patient.1,2
Disclosures: The authors have no potential conflicts of interest to report. Division of Clinical Microbiology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Room 6027B, Indianapolis, IN 46202, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.02.004 0272-2712/14/$ – see front matter Ó 2014 Published by Elsevier Inc.
labmed.theclinics.com
2
Denys & Relich
Of the HAIs, lower respiratory tract (LRT) infections are among the most frequently acquired, particularly among patients in the intensive care unit (ICU).3 Because of the unique combination of critically ill, and often immunosuppressed, hosts and chronically high antibiotic selective pressures, the ICU is an important environment for the emergence of antimicrobial drug resistance and the spread of drug-resistant organisms. Despite advances in antimicrobial therapy, supportive care, and infection control measures, hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) cause considerable morbidity and mortality. In addition, these infections are associated with increased costs to health care systems.1,4,5 The incidence of HAP ranges from 5 to more than 20 cases per 1000 hospital admissions.6,7 In patients not in the ICU, the highest rates are seen in the elderly, the immunosuppressed, surgical patients, and those receiving enteral feeding through a nasogastric tube.6 Approximately onethird of HAPs are ICU-acquired, with VAP accounting for approximately 90% of the cases. VAP occurs in 9% to 40% of intubated and mechanically ventilated individuals, which represents the most frequent ICU-acquired infection.8,9 The current incidence of VAP ranges from 2 to 16 cases per 1000 ventilator days, with a mortality rate ranging from of 3% to 17%.7 The estimated cost per HAP or VAP infection is in excess of $40,000, with a mortality rate ranging from 10% to 50%.10 This article describes the etiology, epidemiology, pathogenesis, diagnosis, and treatment of HAP and VAP associated with antibiotic-resistant bacterial pathogens. ETIOLOGY
The etiology of HAP and VAP depends on whether the patient has risk factors for the acquisition of multidrug-resistant (MDR) pathogens. Factors, including the duration of mechanical ventilation, length of hospital and ICU stay, previous exposure to antibiotics, and local endemic pathogens in a given ICU, influence the likelihood of MDR pathogen infection.1,11 A summary of the risk factors for infection with MDR pathogens is presented in Box 1.10,12 The frequency of specific MDR pathogens varies among Box 1 Risk factors associated with multidrug-resistant (MDR) pathogens causing hospital-acquired pneumonia and ventilator-associated pneumonia Antibiotic use in previous 3 months Hospitalization in the previous 3 months or 5 days Exposure to the intensive care unit Exposure to specific hospital unit with high frequency of antibiotic resistance Previous residence in nursing home or long-term care facility Home infusion therapy (including antibiotics) Hemodialysis Home wound care in past 30 days Family member with MDR pathogen Immunosuppression Data from Sydnor ER, Perl TM. Hospital epidemiology and infection control in acute-care settings. Clin Microbiol Rev 2011;24:141–73; and Papazian L, Donati SY. Hospital-acquired pneumonia. In: Cohen J, Powderly WG, Opel SM, editors. van der Meer JWM, Didier, Sobel JD, section editors. Cohen, Powderly and Opal’s infectious diseases. 3rd edition. Philadelphia: Mosby Elsevier; 2010. p. 294–9.
Resistance in Nosocomial Respiratory Infections
hospitals, specific hospital units, and patient populations (eg, medical, surgical, or trauma), including those patients who have recently been exposed to antibiotics. These pathogens may originate from the patient’s endogenous flora, other patients, hospital staff, contaminated medical devices, or the environment.13 Guidelines for the treatment of nosocomial pneumonia defines HAP into early-onset pneumonia, which occurs within the first 5 days of admission, and those who develop late-onset nosocomial pneumonia, which occurs 5 days or more after admission.1 Late-onset HAP mostly involves hospital-acquired MDR pathogens, a result of antibiotic selective pressure, cross-transmission, and colonization from ICU environmental sources.1,11,14 However, MDR pathogens may be isolated in early-onset HAP when risk factors exist before ICU admission.14 Table 1 lists the predominant bacterial agents causing nosocomial pneumonia. In general, organisms causing early-onset HAP reflect antibiotic-susceptible community isolates, such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, S aureus, nonresistant Enterobacteriaceae, anaerobic bacteria, and Legionella pneumophila. Patients who develop late-onset pneumonia are more likely to be infected with MDR organisms, including Pseudomonas aeruginosa, A baumannii, ESBL-producing and carbapenemase-producing Enterobacteriaceae, and MRSA. EPIDEMIOLOGY
More than 60% of reported HAP and VAP are caused by gram-negative bacilli; however, 20% to 40% are now caused by S aureus, most of which are methicillin-resistant strains.6 Pneumonia due to hospital-acquired MRSA has been increasing worldwide for the past 10 years; reports indicate that community-acquired MRSA clones (eg, US300/400) emerging in hospitals cause HAP and VAP.15 Increasing resistance to vancomycin (minimum inhibitory concentration [MIC] 2 mg/mL) or vancomycin intermediate-resistant S aureus (MIC 4–8 mg/mL) have been seen worldwide and are associated with poor clinical outcomes.16,17 In addition, recent reports of linezolid resistance in MRSA isolates is a significant concern.18,19 Among the Enterobacteriaceae, resistance to third-generation and fourth-generation cephalosporins is expressed by acquired ESBLs and/or AmpC b-lactamases. Another emerging resistance concern is the increase of carbapenemase-producing strains associated with Table 1 Predominant bacterial agents causing nosocomial pneumonia Early-Onset HAP (
