2016 Updates to the Hospital Acquired- and Ventilator Associated-Pneumonia Guidelines

Transcription

1 2016 Updates to the Hospital Acquired- and Ventilator Associated-Pneumonia Guidelines Janessa M. Smith, PharmD, BCPS Clinical Pharmacy Specialist, Infectious Diseases The Johns Hopkins Hospital

2 Objectives List risk factors for development of pneumonia with multidrug resistant organisms Describe the role of an antibiogram in the empiric treatment of hospital acquired pneumonia (HAP) and ventilator associated pneumonia (VAP) Identify the role of pharmacokinetic and pharmacodynamic parameters in dose optimization Discuss the role of biomarkers in diagnosing and treating HAP and VAP

3 Epidemiology Pneumonia is the most common healthcare-associated infection (HAI) HAP and VAP account for 22% of HAI annually Up to 50% of patients with HAP develop serious complications Respiratory failure, pleural effusions, septic shock, renal failure and empyema All-cause mortality from VAP ranges from 20-50% and attributable mortality has been estimated at 13% Magill SSl. N Engl Med. 2014;370:2542; Sopena N. Chest. 2005;127:213; Melson WG. Lancet Infect Dis. 2013;13:665; Muscedere JG. Clin Infec Dis. 2010;51 (supp 1):S120; Kollef MH. Infec Control Hosp Epidemiol. 2012;33:250.

4 Impact on the Healthcare System VAP prolongs length of ventilation (7.6 to 11.5 days) and hospital stay (11.5 to 13.1 days) VAP estimated to result in excess health care costs of $40,000 per patient Limited data on the impact of HAP Magill SS, et al. N Engl Med. 2014;370:2542; Sopena N, et al., Chest. 2005;127:213; Melson WG, et al. Lancet Infect Dis. 2013;13:665; Muscedere JG, et al. Clin Infec Dis. 2010;51 (supp 1):S120; Kollef MH, et al. Infec Control Hosp Epidemiol.2012;33:250.

5 Definitions Pneumonia Presence of a new lung infiltrate plus clinical evidence of an infectious cause (fever, purulent sputum, leukocytosis and decline in oxygenation) VAP Pneumonia that develops >48 hours after endotracheal intubation HAP Pneumonia that develops >48 hours after hospital admission Am J Respir Crit Care Med. 2005;171:

6 Major Changes in the 2016 Update Recommend less invasive microbiologic methods for diagnosis Redefine risk factors for multidrug resistant organisms (MDRO) Emphasis on antibiograms to guide empiric therapy Emphasis on optimizing antimicrobial dosing based on pharmacokinetic (PK) and pharmacodynamic (PD) parameters Suggest duration of therapy of 7 days for all HAP/VAP treatment Kalil AC. Clin Infect Dis. 2016;63:1-51.

7 Microbiologic Methods to Diagnosis Recommendation Non-invasive sampling with semiquantitative cultures preferred Expectorated or induced sputum cultures Endonasotracheal cultures If invasive sampling methods used, should be quantitative and should be used to stop therapy if below diagnostic threshold: Bronchoalveolar lavage: <10 4 CFU/mL Protected brush specimen: <10 3 CFU/mL Rationale No evidence that invasive sampling impact clinical outcomes, including changes in antibiotics Non-invasive sampling can be done more rapidly and with fewer complications and resources Kalil AC. Clin Infect Dis. 2016;63:1-51.

8 Selecting Empiric Therapy Antibiotics should be started early and should target potential pathogens Potential pathogens determined by surveillance data and patient-specific risk factors Adequate early antibiotics Superfluous coverage Kalil AC. Clin Infect Dis. 2016;63:1-51.

9 Removal of HCAP Definition 2005 Guidelines HCAP: Healthcare-associated pneumonia Any patient who was hospitalized in an acute care hospital for > 48 hours within prior 90 days Residing in a nursing home or long-term care facility Received recent IV antibiotics, chemotherapy, or wound care in the prior 30 days Attended a hospital or hemodialysis clinic Role: to identify patients at risk for MDRO 2016 Guidelines Removed from guidelines Rationale: new evidence suggesting that many patients identified as HCAP did not have MDRO isolated as a cause of VAP or HAP Am J Respir Crit Care Med. 2005;171: ; Kalil AC. Clin Infect Dis. 2016;63:1-51.

10 Definition of MDRO Microorganisms that are resistant to one or more classes of antimicrobial agents E.g., MRSA, VRE, certain Gram-negative bacilli

11 MDRO Definition in Clinical Studies Reference Pneumonia Type Definition Gross (2014) HCAP/CAP MRSA, Pseudomonas aeruginosa, extended-spectrum beta-lactamase (ESBL)- producing Enterobacteriaceae, carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), Acinetobacter spp., and Stenotrophomonas maltophilia Chamlers (2014) HCAP/CAP MRSA, Gram-negative Enterobacteriaceae, and P. aeruginosa Valles (2014) HCAP MRSA, P. aeruginosa, S. maltophilia, A. baumannii, Klebsiella spp., and S. marcescens Depuydt (2008) VAP MRSA, ESBL, Acinetobacter spp., Pseudomonas spp., Stenotrophomonas spp. resistant to at least one of the following: ceftazidime, piperacillin, imipenem Giantsou (2005), Trouillet (1998), Martin-Loeches (2013) VAP P. aeruginosa, MRSA, A. baumannii, S. maltophilia Chamlers JD, et al. Clin Infec Dis. 2014;58:330.; Gross AE. Antimicrob Agents Chemother. 2014;58:5262.; Valles J.Intensive Care Med. 2014;40:572.; Depuydt P. Intensive Care Med.2008;34:675.; Giantsou E. Intensive Care Med. 2005;31:1488.; Trouillet JL. Am J Respir Crit Care Med. 1998; 157:531.Martin-Loeches I. Intensive Care Med.2013;39:672.

12 Trends in Antibiotic Use with HCAP 128 VA Hospitals evaluated trends in antibiotic prescribing and antibiotic resistance for pneumonia ,511 hospitalizations were included P-value Antibiotic Use Vancomycin 16% 31% <0.001 Piperacillin-tazobactam 16% 27% <0.001 Ceftriaxone 39% 33% <0.001 Azithromycin 39.5% 36% <0.001 MDRO Pathogens Isolated MRSA 2.5% 2% <0.001 P. aeruginosa 1.9% 2% 0.14 Acinetobacter spp. 0.2% 0.2% 0.17 Jones BE. Clin Infect Dis. 2015;61:

13 Sensitivity and Specificity of HCAP for Identifying MDRO HCAP more often associated with P. aeruginosa, S. aureus, Enterobacteriaceae but overall poor predictor of MDRO Meta-analysis of 24 studies comparing incidence of MDRO HCAP vs CAP found low sensitivity and specificity of HCAP definition Sensitivity Specificity All MDRO 53.7% 71.2% MRSA 69% 65.7% Enterobacteriaceae 42.9% 66.1% Pseudomonas aeruginosa 52.2% 67.7% Chamlers JD, et al. Clin Infec Dis. 2014;58:330.

14 Isolation of MDRO by HCAP Definition Retrospective review characterized the etiology of pneumonia and risk factors for MDRO CAP or HCAP Only 19% had an identifiable etiology Viral pneumonia was the most common cause, followed by S. pneumoniae Overall MDRO prevalence was 3.8% HCAP (n = 258) CAP (n = 263) Any MDRO 5.9% 1.9% MRSA 3.1% 1.1% P. aeruginosa 2.7% 0.8% MDRO independent predictors: Antibiotics in the last 90 days Duration of hospitalization in prior 90 and 180 days P. aeruginosa colonization/infection in the previous 12 months Gross AE. Antimicrob Agents Chemother. 2014;58:5262.

15 Risk Factors for Any MDRO Pneumonia MDRO-VAP vs non-mdro-vap Use of intravenous antibiotics in the past 90 days >5 days of hospitalization prior to VAP Acute respiratory distress syndrome before VAP Renal replacement therapy prior to VAP Septic shock at the time of VAP MDRO-HAP vs non-mdro-hap Use of intravenous antibiotics in the past 90 days

16 Risk factors for MRSA HAP/VAP More common in late-onset (>4 days of hospitalization) than early-onset Major risk factor for MRSA HAP/VAP is prior intravenous antibiotic exposure within 90 days Unclear which antibiotics put patients are higher risk as studies did not evaluate this The role of MRSA nasal surveillance is unclear

17 Case-Control Studies for MRSA HAP/VAP Reference Pneumonia Type Risk Factors OR (95% CI) Wooten (2013) Moreira (2008) Bouza (2012) MRSA vs MSSA pneumonia (all) MRSA vs MSSA VAP MRSA vs non-mrsa VAP Recent antibiotics (w/in 90 days) Tobacco use Illicit drug use Liver disease Previous antibiotic therapy Age >60 years Use of corticosteroids Antibiotic exposure Pleural effusion APACHE II score 7.01 ( ) 2.66 ( ) 3.52 ( ) 3.50 ( ) 5.93 ( ) 5.33 ( ) 5.79 ( ) 2.38 ( ) 2.74 ( ) 1.10 ( ) Wooten DA. Resp Med. 2013;107: ; Moreira MR. Braz J Infect Dis. 2008;12: ; Bouza E. J Hosp Infect. 2012;80:150-5.

18 MRSA Active Surveillance Screening of asymptomatic patients to identify carriers Swab of nares, oropharynx and/or perineum Identification of carriers for intervention to prevent spread of MRSA (e.g., contact precautions) Standard culture or PCR methods

19 Role of Surveillance in Empiric MRSA Treatment Concurrent or recent positive MRSA screen increases the likelihood of respiratory infection with MRSA Better negative predictive value (98%) vs positive predictive value (30%) May have a better role in deciding which patients do NOT need MRSA-active therapy About 30% of respiratory infections due to MRSA are in patients with positive MRSA surveillance studies Recent surveillance (<7 days) is more relevant as patients can acquire MRSA while hospitalized Robicsek A. J Clin Microbiol. 2008;46: Davis KA. Clin Infect Dis. 2004;39: Sarikonda KV. Crit Care Med. 2010;38:

20 Risk factors for MDR P. aeruginosa HAP/VAP Mechanical ventilation COPD Cystic fibrosis or bronchiectasis Prior antibiotic use Specifically carbapenems, broad spectrum cephalosporins and fluoroquinolones Montero M. Eur J Clin Microbiol Infect Dis. 2010;29:335-9.; Parker CM. J Crit Care. 2008;23:18-26.

21 Antibiogram Summary of antimicrobial susceptibilities of bacterial isolates within an institution over a defined period of time Used to track resistance rate over time and to inform clinicians about empiric antibiotic selection IDSA Guidelines on Implementing an Antimicrobial Stewardship Program recommend using a stratified antibiogram over a non-stratified antibiogram Stratified by location (e.g., ICU vs non-icu) or patient age Barlam TF. Clin Infect Dis. 2016;62:e51-77.

22 Example Antibiogram

23 Empiric Treatment of VAP Initial therapy for VAP should be based on local antibiogram, ideally ICU-specific In absence of local antibiogram data, clinicians should refer to large national and international surveys of organisms and resistance patterns Surveillance studies indicate the most common organisms: S. aureus (20-30%) P. aeruginosa (10-20%) Other enteric Gram-negative organisms (20-40%) A. baumanii (5-10%) Sievert DM. Infect Control Hosp Epidemiol. 2013;34:1-14.

24 Sievert DM. Infect Control Hosp Epidemiol. 2013;34:1-14.

25 Empiric Treatment of VAP S. aureus For empiric coverage, use an agent with activity against Gramnegative bacilli and MSSA Cefepime, piperacillin-tazobactam, levofloxacin, imipenem or meropenem Therapeutic regimen should include an agent targeted at MRSA if: Patient has been exposed to intravenous antibiotics within the prior 90 days Patient being treated in a unit with >10-20% of S. aureus isolates are MRSA or if the prevalence of MRSA is unknown Weak recommendation with low-quality evidence Empiric therapy targeted at MRSA should include Vancomycin or Linezolid

26 Targeted Therapy S. aureus MRSA MSSA Vancomycin Linezolid Oxacillin Nafcillin Cefazolin

27 MRSA Agents Vancomycin vs Linezolid Author Patient population Results Stevens et al. (2002) Kohno et al. (2007) Wunderink et al (2008) Wunderink et al (2012) NS, Not statistically significant Suspected MRSA infection (MRSA pneumonia, n = 64) Suspected MRSA infection (MRSA pneumonia, n = 54) VAP, MRSA (n = 146) HAP or HCAP, MRSA (n = 448) Clinical cure, MRSA pneumonia (NS): Linezolid 52.2% Vancomycin 53.8% Clinical cure, MRSA pneumonia (NS): Linezolid 60% Vancomycin 47.4% Clinical response (NS): Linezolid 66.7% Vancomycin 52.9% Clinical success (p = 0.042): Linezolid 57.6% Vancomycin 46.6% Stevens DL. Clin Infect Dis.2002;34: ; Kohno S. J Antimicrob Chemother. 2007;60: Wunderink RG. Chest. 2008;134: ; Wunderink RG. Clin Infect Dis. 2012;54:621-9.

28 Empiric Treatment of VAP Pseudomonas spp. Two agents targeted at Pseudomonas spp. should be used in the following situations: Patients with prior intravenous antibiotic exposure in the past 90 days Units where >10% of isolates are resistant to an agent being considered for monotherapy or resistance rates are unknown Patients with structural lung disease (e.g., bronchiectasis or cystic fibrosis) Weak recommendation with low-quality evidence Combination therapy increases the likelihood that at least one of the agents used will be active against the pathogen. Monotherapy should be used once an organism has been isolated and susceptibilities are known.

29 Empiric Treatment of VAP Pseudomonas spp. Avoid aminoglycosides and Colistin if alternative agents are available Given poor lung penetration, toxicities, and poorer clinical response Patients randomized to aminoglycoside-containing regimens had similar mortality rates but lower clinical response rates compared to aminoglycoside-free regimens

30 Empiric Treatment of HAP Bacterial etiologies of HAP Non-glucose fermenting Gram-negative bacilli: 19%, Pseudomonas spp. 13% and Acinetobacter spp. 4% Enteric Gram-negative organisms: 16% S. aureus: 16% MRSA 10%, MSSA 6% Kalil AC. Clin Infect Dis. 2016;63:1-51.

31 Empiric Treatment of HAP S. aureus For empiric coverage, use an agent with activity against Gramnegative bacilli and MSSA Cefepime, piperacillin-tazobactam, levofloxacin, imipenem or meropenem) Therapeutic regimen should include an agent targeted at MRSA if: Patient has been exposed to intravenous antibiotics within the prior 90 days Patient being treated in a unit with >20% of S. aureus isolates are MRSA or if the prevalence of MRSA is unknown Patients with high risk of mortality (e.g., patients requiring ventilatory support or with septic shock) Weak recommendation with low-quality evidence Empiric therapy targeted at MRSA should include Vancomycin or Linezolid

32 Empiric Treatment of HAP Pseudomonas spp. Two agents targeted at Pseudomonas spp. should be used in the following situations: Patients with prior intravenous antibiotic exposure in the past 90 days Patients with high risk of mortality (e.g., patients requiring ventilatory support or with septic shock) Patients with structural lung disease (e.g., bronchiectasis or cystic fibrosis) Weak recommendation with low-quality evidence Combination therapy increases the likelihood that at least one of the agents used will be active against the pathogen. Monotherapy should be used once an organism has been isolated and susceptibilities are known.

33 PK/PD Dose Optimization Antibiotic dosing should be determined using PK/PD data, rather than manufacturer s prescribing information Clinical studies have found that PK/PD-optimized dosing results in: Reduced mortality (12% vs 24%, RR 0.49) Reduced ICU length of stay (mean difference -2.48) Improved clinical cure rate (81% vs 64%, RR 1.40)

34 Antimicrobial Therapy PK/PD Pharmacokinetics (drug concentrations) What does the BODY do to the drug? Absorption Distribution Metabolism Elimination PK-PD Drug concentrations and effect Pharmacodynamics (antimicrobial effects) What does the drug do to the BUG? Bacteriostatic/Bactericidal Post-antibiotic effect Minimum inhibitory concentration Owens RC, et al. Am J Health-Syst Pharm 2009;66:S23-30.

35 Static vs Cidal Bacteriostatic Inhibits growth and replication of the organism Require the aid of host defenses to clear infecting microorganisms Agents that alter bacterial physiology such as inhibition of folate synthesis (e.g. sulfonamides) Bactericidal Directly cause cell death Agents that interfere with the development of the cell wall or membrane (e.g. beta-lactams, vancomycin) Agents that inhibit nucleic acid synthesis (e.g. fluoroquinolones) or protein synthesis (e.g. aminoglycosides) Levison ME, et al. Infect Dis Clin North Am 2009:23:

36 Minimum inhibitory concentration (MIC) The minimal concentration of antibiotic that inhibits bacterial growth The MIC usually represents attainable concentrations in serum Concentrations at the site of infection may be higher (e.g. urine) or lower (e.g. CSF) Antimicrobials have variable lung penetration March 27,

37 Interpreting MIC Values GREATER THAN 10,000 COLONIES PER ML. ESCHERICHIA COLI ANTIBIOTIC MIC (mcg/ml) INTERPRETATION Ampicillin <= Susceptible Amp/Sulbactam / Susceptible Piper/Tazo / Susceptible Cefazolin <= Susceptible Cefoxitin Susceptible Ceftriaxone <= Susceptible Cefepime <= Susceptible Aztreonam <= Susceptible Meropenem <= Susceptible Ertapenem <= Susceptible Trimeth/Sulfa <=0.5/ Susceptible Tetracycline Intermediate Gentamicin <= Susceptible Tobramycin <= Susceptible Amikacin <= Susceptible Ciprofloxacin > Resistant Nitrofurantoin <= Susceptible Susceptible: strain can be treated with antibiotic at recommended doses and schedules. Useful to know when treating an organism in an area that is difficult to penetrate (CSF, osteomyelitis) Intermediate:antibiotic level can usually be obtained in the tissue or blood, but response may be diminished Resistant: growth not inhibited by usually achievable concentrations at normal doses

38 PK-PD Principles of Antibiotics Time-Dependent ft>mic: The cumulative percentage of a 24 hour period that the drug exceeds the MIC E.g., β-lactams fauc/mic The ratio of the area under the curve to the MIC E.g., vancomycin, fluoroquinolones Concentration-Dependent fcmax/mic The ratio of maximal drug concentration to the MIC E.g., aminoglycosides Mandell, Douglas and Bennet s Principles and Practice of Infectious Diseases. 7th ed. 38

39 PK-PD Measures of Antibiotics Aminoglycosides fc max /MIC Drug Concentration Fluoroquinolones fauc/mic Beta-lactams ft>mic Time MIC Figure adapted from Amsden G et al. Pharmacokinetics and Pharmacodynamics of Anti-infectives. Mandell, Douglas and Bennett s Principles and Practice of Infectious Diseases. 7th ed Print. 39

40 PK-PD Targets of Beta-Lactams Drug Class Bacteriostatic %ft > MIC Bactericidal %ft > MIC Post-Antibiotic Effect Penicillins ~30% ~50% 0.1 hours for Gram-negatives hours for Gram-positives Cephalosporins 35-40% 60-70% None for Gram-negative hours for Gram-positives Carbapenems 20% 40% 0.9 for Gram-negatives hours for Gram-positive Post-Antibiotic Effect: time of growth suppression after drug exposure has fallen below MIC Drusano GL. Clin Inect Dis 2007;45:S Ambrose P. et al. Clin Infect. Dis 2007;44: George JM, et al. Pharmacotherapy 2012;32:

41 Administration Strategies for Antibiotics Time (hours)

42 PK/PD Optimization for Pneumonia Agent PK/PD Parameter Manufacturer Dosing Optimized Regimen Levofloxacin AUC/MIC >87 HAP/VAP: 750 mg once daily 750 mg once daily Ciprofloxacin AUC/MIC >125 Nosocomial pneumonia: 400 mg IV Q8H 400 mg Q8H Ceftazidime % T>MIC Uncomplicated pneumonia: 1 g Q8H Cefepime 100% T>MIC Pneumonia (P. aeruginosa): 2 g Q8H Meropenem 54% T>MIC, Cmin:MIC>5 OR 75% T>MIC Pneumonia (not P. aeruginosa): 1-2 g Q8-12H Not in labeling 2 g Q8H over 3 hour infusion 2 g Q8H over 3 hour infusion 1 g Q8H over 3 hour infusion

43 Cefepime Probability of varying regimens achieving >50% T>MIC With an MIC of 8 mcg/ml Standard infusion over 30- minutes 1 g Q12H: 50% 2 g Q12H: 75% 1 g Q8H: 70% 2 g Q8H: 85% Prolonged infusion over 3-hours 2 g Q8H: 95% Nicasio AM. Antimicrob Agents Chemother.2009;53:

44 Duration of Therapy Both HAP and VAP should be treated for 7 days, rather than a longer duration Strong recommendation, moderate quality evidence Short courses (7-8 days) are associated with: Increased 28-day antibiotic-free days (mean 4.02 days) Reduced recurrent VAP due to MDRO (42.1% vs 62.3%) No differences in mortality, recurrent pneumonia, treatment failure, hospital length of stay or duration of mechanical ventilation

45 De-escalation of Therapy De-escalation refers to changing from an empiric broad-spectrum antibiotic to a narrower antibiotic regimen Antibiotic therapy should be de-escalated, rather than fixed

46 Procalcitonin (PCT) Produced by parenchymal tissue throughout the body when stimulated by endotoxin and bacterial infection PCT should not be used to diagnosis HAP/VAP When combined with clinical criteria, it has a sensitivity of 67% and specificity of 83% PCT combined with clinical criteria can guide discontinuation of antibiotics Resulted in shorter duration of antibiotic therapy (9.1 vs 12.1 days; P <.00001) with no effect on clinical outcomes Kalil AC. Clin Infect Dis. 2016;63:1-51.; Stolz D. Eur Respir J. 2009;34: ; Bouadma L. Lancet. 2010;375:

47 strem-1 Member of immunoglobulin superfamily strongly expressed on neutrophils and monocytes infiltrating tissues invaded by bacteria and fungi Measured in BAL fluid, cutoff values have not been validated strem-1 should not be used to diagnose HAP/VAP Sensitivity of 84% and specificity of 49% as a diagnostic tool

48 Clinical Pulmonary Infection Score (CPIS) 0 Points 1 Point 2 Points Temperature (C) or 39 Peripheral WBC 4,000-11,000 <4,000 or >11,000, >50% bands: add 1 point Tracheal secretions None Non-purulent Purulent Chest x-ray No infiltrate Diffuse or patchy infiltrates Localized infiltrate Progression of infiltrate from prior radiographs None Culture of ET suction No growth/light growth Heavy growth, same bacteria on Gram stain: add 1 point Progression Oxygenation (PaO2/FiO2) >240 or ARDS 240 and no ARDS If CPIS 6, VAP unlikely. If CPIS remains 6 after 3 days, antibiotics can be stopped in most cases

49 CPIS Recommend clinical criteria alone to determine initiation and discontinuation of antibiotics CPIS should not be used to diagnose HAP or VAP Low diagnostic sensitivity (65%) and specificity (64%) for VAP

50 Summary Empiric antibiotic therapy for HAP and VAP should be based on patient-specific risk factors for MDRO Local, stratified antibiograms should be used to guide empiric treatment of HAP and VAP Antimicrobial dosing should be optimized based on PK/PD parameters, when feasible PCT levels, combined with clinical criteria, may be used to guide discontinuation of antibiotics

51 2016 Updates to the Hospital Acquired- and Ventilator Associated-Pneumonia Guidelines Janessa M. Smith, PharmD, BCPS Clinical Pharmacy Specialist, Infectious Diseases The Johns Hopkins Hospital