Antimicrobial Therapy

Transcription

1 Antimicrobial Therapy Whole Hospital Meeting Wednesday 4 th November 2015 Jeremy Gardner Consultant Medical Microbiologist and Infection Control Doctor

2 Cases/100,000 Deaths/Year Comparison With Other Major Diseases Incidence of Severe Sepsis Mortality of Severe Sepsis , , AIDS* Colon Breast Cancer CHF Severe Sepsis 150, ,000 50,000 0 AIDS* Breast Cancer AMI Severe Sepsis National Center for Health Statistics, American Cancer Society, *American Heart Association Angus DC et al. Crit Care Med. 2001;29(7):

3 SURVIVING SEPSIS CAMPAIGN BUNDLES TO BE COMPLETED WITHIN 3 HOURS: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30 ml/kg crystalloid for hypotension or lactate 4mmol/L TO BE COMPLETED WITHIN 6 HOURS: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation to maintain a mean arterial pressure [MAP] 65 mm Hg) 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/l (36 mg/dl): - Measure central venous pressure (CVP)* - Measure central venous oxygen saturation (ScvO2)* 7) Remeasure lactate if initial lactate was elevated* *Targets for quantitative resuscitation included in the guidelines are CVP of 8 mm Hg, ScvO2 of 70%, and normalization of lactate

4 Time Zero Time Zero = time of presentation ED, Medical Floors, ICU Both bundles time based Most important time based elements: Antibiotic timing Resuscitation timing (EGDT)

5 Change in Mortality Over Time Site quarter Hospital mortality % % % % % % % % Mortality Benefit: 7% ARR 19% RRR P <.001 Levy MM et al. CCM 38(2): , February 2010.

6 Perspective Severe Sepsis Acute coronary syndrome No. cases per 100,000 per annum NNT basic care Sepsis Six (our data) 6 First hour antibiotics 5 Clopidogrel 48 β-blockade 42 Aspirin 26 NNT invasive care EGDT (Rivers) 6 Thrombolysis 15 Resusc Bundle (SSC) 18 PCI over thrombolysis 33

7 Antibiotic Therapy We recommend that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (1B) and severe sepsis without septic shock (1C). (Best Practice versus Stand of Care)

8 Antibiotics Multiple large, observational studies have shown the time to administration of antibiotics to be strongly associated with improve survival. Not aware of a single physician that recommends withholding or slowing down the time to antibiotics in a patient with severe sepsis. time to needle or door to balloon metric.

9 Antibiotics No randomized-controlled data Time from EGDT qualification to ABX Time from hypotension to appropriate ABX Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department*. Critical Care Medicine 2010;38(4): Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Critical Care Medicine 2006;34(6):

10 Time to Antibiotics Following Onset Septic Shock Kumar A, et al. Crit Care Med 2006; 34:

11 Running average survival in septic shock Running Average Survival in Septic Shock based Based on on antibiotic Antibiotic delay Delay (n=4195) (n=4195) fraction running average survival cumulative fraction of total survivors Funk and Kumar Critical Care Clinics 2011 (in press) AbRx Delay (hrs)

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13 Source Control No randomized-controlled data In necrotizing fasciitis, multiple case series have shown improvement with an aggressive operative approach. Sudarsky LA, Laschinger JC, Coppa GF, Spencer FC. Improved results from a standardized approach in treating patients with necrotizing fasciitis. Ann Surg 1987;206(5): Moss RL, Musemeche CA, Kosloske AM. Necrotizing fasciitis in children: Prompt recognition and aggressive therapy improve survival. J Pediatr Surg 1996;31: Freischlag JA, Ajalat G, Busuttil RW: Treatment of necrotizing soft tissue infections: The need for a new approach. Am J Surg 149: , 1985 Expert opinion supports identifying the source of infection and aggressively managing it when possible. Marshall JC, Maier RV, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med 2004;32:S513-26

14 Source Control Don t be satisfied with a diagnosis of sepsis and no source. If a source exists and is potentially removable, get the ball rolling.

15 Antibiotic Therapy Initial empiric anti-infective therapy activity against all likely pathogens and adequate concentrations into suspected or potential sources of infection (1B) Reassess antibiotic regimen daily for deescalation (1B)

16 Difficult diagnosis Not all patients have classic SIRS Clinical diagnosis requiring experience and high index of suspicion for interpretation of history/symptoms/signs Signs often subtle Some groups at special risk eg infants, age > 65, neutropenia, haemodialysis, diabetes mellitus, alcoholism, lung disease, patients with invasive devices Laupland et al Crit Care Med 2004

17 Common signs & symptoms of sepsis Tachypnoea 99% Tachycardia 97% Fever > 38 degrees 70% Hypothermia 13% Metabolic acidosis 38% Acute oliguria 54% Acute encephalopathy 35% Accurate and routine measurement of respiratory rate is essential Brun-Buisson C et al, JAMA: 274(12), 27 Sept, 1995

18 Diagnosis

19 C-Reactive Protein Acute phase protein produced by the liver Raised in Infection Immune disorders Auto-immune disease Inflammatory syndromes Tissue destruction Haemolysis Pancreatitis Surgery Crush injury Rhabdomyolysis Ischaemia Transfusion related Neoplastic disease especially haematological malignancy Metabolic disturbance e.g. gout, porphyria Thrombo-embolic events

20 C-Reactive Protein

21 The right antibiotic is crucial Take blood cultures before antibiotics but do not delay antibiotics to undertake investigations or await results Start antibiotic therapy within 60 minutes Use bolus administration where possible REMEMBER: one dose is safer than not treating at all PRESCRIBE IT... GET IT... GIVE IT... NOW!!!

22 Antibiotics Loading dose high to start with LD = V x C p Volume of distribution (V): hydrophillic increase in sepsis lipophillic increase in obese Required plasma concentration (C p ): MICs Renal function plays NO ROLE in calculation of loading dose McKenzie. Antibiotic dosing in critical illness. J Antimicrob Chemother 2011; 66 Supp 2: ii25 ii31

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24 Antibiotics Roberts J and Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009; 37: SEPSIS Increased cardiac output Leaky capillaries Multi-organ failure Increased clearance Increased volume of distribution Decreased clearance Low plasma concentrations Adequate initial dosing important High plasma concentrations Reassess and adjust

25 Blood Cultures

26 Commonly used classification of bacteremias into 3 categories: transient (bacteremia lasts for a short amount of time and can be caused by actions such as brushing of teeth or after gastrointestinal biopsy), intermittent (recurring bacteremia due to discontinuous seeding of the same organisms, which can be caused by infections such as abscesses), and persistent or sustained (bacteremia occurring over a prolonged period that is usually associated with infections such as infective endocarditis). Seifert H Clin Infect Dis. 2009;48:S238-S by the Infectious Diseases Society of America

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28 Diagnosis 1. To optimize identification of causative organisms, we recommend at least two blood cultures be obtained before antimicrobial therapy is administered as long as such cultures do not cause significant delay (>45 minutes) in antimicrobial administration, with at least one drawn percutaneously and one drawn through each vascular access device, unless the device was recently (<48 hr.) inserted (Grade 1C).

29 Blood cultures

30 2. Blood cultures Take blood cultures BEFORE starting antibiotics Take two blood cultures from separate sites if possible Obtain other cultures: urine, CSF, faeces, wound swabs, sputum, other fluids from within cavities, Consult specialty teams early for source control

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32 Blood cultures

33 Blood cultures

34 Blood cultures

35 Blood cultures

36 Blood cultures

37 Blood cultures Blood culture reported GPC likely staph. - Significant? Contaminant? - Coagulase positive or negative Significant bacteraemia: Local and/or systemic signs of infection or sepsis Both BC bottles positive Early detection BC pos < 14 hrs Previous S. aureus colonisation or isolation from BC < 3 months Marwick CA, Ziglam HM, Nathwani D. Your patient has a blood culture positive for Staphylococcus aureus - what do you do? J R Coll Physicians Edinb 2006; 36:

38 Blood cultures

39 Factors to consider when choosing antibiotics patient's recent antibiotic therapy Hospital flora presence of underlying diseases available culture data current AND past risk for drug resistant pathogens: receipt of antibiotics within the preceding 90 days current hospitalization of 5 days antibiotic resistance in the community immunosuppressive disease and/or therapy presence of risk factors for resistance

40 Choosing an antibiotic: Think about Location: Where did the patient become ill? Travel? Exposure? Where did the infection anatomically originate? Where in the body, has or will the infection spread to? Think about the bug you are treating:

41 Resistance & prescribing MRSA consider vancomycin (or linezolid or teicoplanin) VRE consider linezolid or daptomycin ESBL consider carbapenem or alternative agent e.g. cipro or gent if sensitivities are known CPE d/w Microbiology re tigecycline, colistin, fosfomycin etc Group A strep consider high dose clinda

42 Mortality & Multidrug-Resistant Organisms Association between development of antimicrobial resistance in Staphylococcus aureus, enterococci, and Gram-negative bacilli and mortality 1 Pseudomonas aeruginosa is increasingly resistant to fluoroquinolones, with a number of consequences, including infection-related mortality 2 Enterococcal infections have been associated with mortality rates exceeding 30% 3 1. Cosgrove SE. Clin Infect Dis. 2006;42(suppl 2):S82-S McGowan JE Jr. Am J Infect Control. 2006;34:S29-S Lautenbach E et al. Clin Infect Dis. 2003;36:

43 Percent of subjects Mortality associated with carbapenem resistant (CR) vs susceptible (CS) Klebsiella pneumoniae (KP) p<0.001 p<0.001 CRKP CSKP Overall Mortality Attributable Mortality OR 3.71 ( ) OR 4.5 ( ) Patel G et al. Infect Control Hosp Epidemiol 2008;29:

44 CLIN INFECT DIS 49(8): Figure 1. Predicted mortality for patients with and without antimicrobial resistant infection (ARI). APACHE, Acute Physiology and Chronic Health Evaluation.

45 Impact of Previous Therapy on Outcome of Gram-Negative Severe Sepsis Crit Care Med 2011; 39:1859

46 Mortality Associated with Initial Inappropriate Therapy Serious Infections Rello et al Infection-related mortality Kollef et al Crude mortality Ibrahim et al Infection-related mortality Luna et al Crude mortality Initial appropriate therapy Initial inappropriate therapy Mortality (%) Rello et al. Am J Respir Crit Care Med 1997;156: ; Kollef et al. Chest 1998;113: Ibrahim et al. Chest 2000;118: ; Luna et al. Chest 1997;111:

47 Guideline recommendations Combination empirical therapy for the following patients (grade 2B): Neutropenic with severe sepsis and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens (Acinetobacter or Pseudomonas bacteremia) Severe infections associated with respiratory failure and septic shock (Pseudomonas bacteremia) Septic shock from bacteremic Streptococcus pneumoniae Crit Care Med 2013;41:

48 Combination therapy vs. monotherapy for septic shock Monotherapy (n=1223) Mortality rate * Combination Rx (n=1223) HR (95% CI) 28-Day, % ( ) ICU, % ( ) Hospital, % ( ) # deaths All Gram +, % ( ) All Gram -, % ( ) * Propensity score adjusted Crit Care Med 2010;38:

49 Barriers to timely antibiotics Delayed recognition of sepsis and septic shock Infection Hypotension Inappropriate antimicrobial therapy Failure to use stat order Unrecognized risk factors for MDR pathogens No specifications for order of administration Logistical delays Crit Care Clin 2011;27:53-76

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52 Antibiotic allergy

53 Antibiotic allergy In the setting of severe sepsis / septic shock carbapenems (e.g. meropenem) can be used in those with a history of penicillin allergy provided No features of immediate hypersensitivity No severe prior reaction i.e. a prior history of a non-severe, delayed rash does not preclude the use of meropenem

54 Penicillin allergy If history of immediate hypersensitivity or severe prior reaction d/w Microbiology Reasonable approach would be: Vancomycin + cipro + metro + single dose of gentamicin Review / rationalise and deescalate with progress and results of investigations

55 Penicillins (ß-lactams) Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep pneumo Streptococci EF Anaerobes GC Men Resp Coliforms Pyo ESBL Benzylpenicillin / Penicillin V R R G G R G A A A R R R R Flucloxacillin R G G G R R R R R R R R R Amoxicillin R R G G G A R A A A R R R Co-amoxiclav R G G G G G G G G G R R R Anti-pseudomonal Tazocin R G G G G G G G G G G A R Carbapenems Ertapenem R G G G A G G G G G R G R Imipenem R G G G G G G G G G G G R Meropenem R G G G A G G G G G G G R

56 Cephalosporins (ß-lactams) Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep pneumo Streptococci EF Anaerobes GC Men Resp Coliforms Pyo ESBL 1 st generation Cefalexin R G G G R A R R R A R R R 2 nd generation Cefuroxime R G G G R A R A G G A A A 3 rd generation Ceftriaxone & Cefotaxime R G G G R A R G G G R R R Cefixime R R G G R A R A G G R R R Antipseudomonal Ceftazidime R A A A R A R A G G G R R

57 Other cell wall antibiotics Antibiotic Gram Positive Gram Negative Atypicals MRSA Staph Strep pneumo Streptococci EF Anaerobes GC Men Resp Coliforms Pyo ESBL Glycopeptides Vancomycin & Teicoplanin G G G G G G R R R R R R R Daptomycin G G R* G G G R R R R R R R Aztreonam R R R R R R R G G G G R R Colisin R R R R R R R R A G G G R *Inactive in the lung

58 Countess of Chester Total spend 2010/2011: 1.9 million 2011/2012: 2.15 million 2012/2013: 2.2 million 2013/ million Percent on antibiotics on point prevalence audits ( ) Tazocin dose units 2010/2011: 30, /2014: 50,000

59 Antimicrobial Stewardship Optimize clinical outcomes Potential for cost reduction Minimize Toxicity Resistance Dellit TH, et al. Clin Inf Dis. 2007

60 Kaplan-Meier Estimates of the Probability of Survival Probability of survival is for the 60 days after ventilator-assisted pneumonia onset as a function of the duration of antibiotics No excess mortality No more recurrent infections More antibiotic-free days Chastre, J. et al. JAMA 2003;290:

61 Antimicrobial stewardship

62 Antimicrobial Prescribing Empiric Initial administration of a broad-spectrum antibiotic regimen that attempts to improve outcomes and minimize resistance. Defined or Targeted Modification of antimicrobial therapy once the cause of infection is identified. Therapy may also be discontinued if the diagnosis of infection becomes unlikely. 1 Focus on de-escalation of antibiotic therapy with the goal of minimizing resistance and toxicity, and improving costeffectiveness. 2,3 1. Kollef MH. Drugs. 2003;63: Kollef MH. Crit Care Med. 2001;29: Evans RS et al. N Engl J Med. 1998;338:

63 What about risk? Meta-analysis of 24 studies in Critical Care Antibiotic stewardship was not associated with increases in nosocomial infection rates, length of stay or mortality. Kaki et all Impact of antimicrobial stewardship in critical care: a systematic review J Antimicrob Chemother Jun;66(6): Epub 2011 Apr 2

64 UK: Start Smart - Then Focus

65 UK: Start Smart - Then Focus

66 Take home messages Go hard / go early with antibiotics in severe sepsis/ septic shock Blood (and other cultures) Source control Consider risk for multi-drug resistant organisms Start smart, Then focus De-escalate!

67 Summary Sepsis is a medical emergency- and our second biggest killer Awareness and recognition are the key Reliable, early antibiotics and fluids will save more lives than Critical Care will... even if CC were infinitely resourced

68 Any questions

69 Hospital Mortality by Time to Antibiotics

70 Hospital Mortality by Time to Antibiotics

71 Antibiotic Therapy We recommend that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (1B) and severe sepsis without septic shock (1C). Remark: Although the weight of evidence supports prompt administration of antibiotics following the recognition of severe sepsis and septic shock, the feasibility with which clinicians may achieve this ideal state has not been scientifically validated.

72 Definitions A continuum of severity describing the host systemic inflammatory response

73 SIRS SIRS systemic inflammatory response syndrome Must have at least 2 of the following: Temperature >38.5ºC or <36ºC Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <32 mmhg WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 % immature (band) forms SIRS is the body s response to infection, inflammation, stress.

74 Sepsis and Severe Sepsis Sepsis SIRS + suspected or confirmed infection (documented via cultures or visualized via physical exam/imaging) Severe Sepsis Sepsis + at least one sign of organ hypo-perfusion or dysfunction Areas of mottled skin Capillary refill > 3 secs UOP < 0.5cc/kg /hr Lactate > 2mmol /L Disseminated intravascular coagulation AKI Altered mental status Plt < 100 Abnormal EEG ARDS or acute lung injury (ALI) Cardiac dysfunction on echo Troponin Leak

75 Mortality by antibiotics Cohort size Mortality % RRR % (NNT) Total 567 (100%) Delayed Antibiotics Antibiotics within 1 h 217 (38.4%) (61.6%) (5.77) Ron Daniels 2010

76 McKenzie. Antibiotic dosing in critical illness. J Antimicrob Chemother 2011; 66 Supp 2: ii25 ii31

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80 Blood cultures

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84 Standardized order sets Appropriate antibiotics, % 28-day mortality, % Before (n=60) After (n=60) P value Crit Care Med 2006;34:

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86 Site of Infection Most important factor to consider in antimicrobial selection Defines the most likely organisms Especially helpful in empiric antimicrobial selection Determines the dose and route of administration of antimicrobial Efficacy determined by adequate concentrations of antimicrobial at site of infection Serum concentrations vs. tissue concentrations and relationship to MIC

87 Streptococcus pneumoniae Pneumococcus

88 Gram positive cocci looking like Staphylococci

89 Gram positive cocci looking like Streptococci

90 Gram positive bacilli

91 Gram negative bacilli

92 Gram negative cocci

93 Strep not Staph!

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96 Prophylaxis CMV: 3 months of antiviral (valganciclovir [valcyte], valacyclovir [valtrex]) for D+R- and R+ PCP: 6-12 mo TMP/SMX (or dapsone, pentamidine) UTI: 1-3 mo TMP/SMX (or quinolone) for K txp Candida: all KP, selected liver transplant recipients 1-3 mo fluconazole

97 Evaluation of the Patient Baseline patient data critical for appropriate work-up Donor/recipient serologies (CMV, EBV, HSV, VZV, Toxoplasma) Underlying disease Time post-transplant Allograft function Prophylactic medications Rejection (and its treatment)

98 Evaluation of the Patient (cont.) Early and aggressive diagnostic investigation - adequate tissue - routine staging Appropriate notification and coordination with pathology and microbiology laboratories

99 Timetable of Infections After Organ Transplantation General guidelines, NOT absolute Epidemiology altered by prophylaxis Unusual timing may be a clue to unusual exposure

100 Early Period (first post-transplant month) Nosocomial/ surgical infections Multi-drug resistant organisms (e.g., GNR, MRSA, VRE) Importance of adjunctive therapy (anatomical problems, adequate drainage) Opportunistic infections are uncommon (except Aspergillus, Candida, HSV in absence of prophylaxis)

101 Middle Period (from post-transplant months 2-6) Greatest risk period for classic opportunists (e.g., PCP, Aspergillus, Toxoplasma, Cryptococcus, etc.) Immunomodulating viruses (e.g., CMV, EBV, HHV-6)

102 Late Period (after the 6 th post-transplant month) Typical community-acquired infections in patients with good allograft function Continued risk of opportunistic infections in patients with poor allograft infection and/or chronic rejection

103 General Concepts (cont.) Signs and symptoms of infection are muted by immunosuppression Specific, predictable risk periods for specific pathogens (unusual timing may be a clue to exposure) Link between immunosuppression and infection risk Consider the possibility of donor-derived infection (viral, fungal, bacterial, mycobacterial, etc.)

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106 Hospital Mortality (%) Importance of Initial, Appropriate Antibiotic Therapy selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections. ATS/IDSA Guidelines A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality * *P< * All-Cause Mortality Inadequate antimicrobial treatment (n=169) ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America. Infection-Related Mortality Adequate antimicrobial treatment (n=486) Adapted from Kollef MH et al. Chest. 1999;115: ATS/IDSA. Am J Respir Crit Care Med. 2005;171:

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108 Stewardship optimizes patient safety: decreased patient-level resistance Cipro Standard Antibiotic duration LOS ICU 3 days 10 days 9 days 15 days Antibiotic resistance/ superinfection 14% 38% Singh N et al. Am J Respir Crit Care Med. 2000;162: Study terminated early because attending physicians began to treat standard care group with 3 days of therapy

109 Spiraling Spiralling Empiricism Diagnostic Uncertainty Broad- Spectrum Coverage Rise in MDRO HAIs MDRO Selection