Fundamental Concepts in the Use of Antibiotics Todd Miano, PharmD, MSCE Critical Care Pharmacist Pharmacoepidemiology Fellow Perelman School of Medicine at the University of Pennsylvania Case TM is a 24 year old male admitted to ICU after TBI and leg fracture from MVA ICU day 3 Worsening respiratory failure, leading to hemodynamic instability Chest X-ray shows pneumonia What antibiotics should we give the patient? Case TM is a 67 year old male admitted to ICU overnight via rapid response Originally admitted 16 days earlier for colectomy Abdominal pain, fever, and acidosis on floor, leading to hemodynamic instability What antibiotics should we give the patient? 1
Mortality, percent Importance of Effective Empiric Antibiotics 35 30 30.7 25 20 15 10 16.6 26.1 17.8 Appropriate Inappropriate 5 0 MRSA Pseudomonas Schramm GE, Johnson JA, et al.crit Care Med. 2006; 34: 2069-74. Micek ST, Lloyd AE, et al. Antimicrob Agents Chemother. 2005;49:1306-11. Septic Shock: every hour counts Kumar A, Roberts D, et al. Crit Care Med. 2006; 34:1589-96. Trends in Gram Negative Resistance Multi-drug resistance, percent 18 16 14 12 10 8 6 4 2 0 1994-95 1996-97 1998-99 2000-01 2002 Pseudomonas Klebsiella Enterobacter D agata EM. Infect Control Hosp Epidemiol 2004; 25: 842-846 2
Case TM is a 48 year old male admitted to SICU overnight via rapid response Worsening respiratory failure on floor, leading to hemodynamic instability Rapid response team suspects pneumonia What antibiotics should we give the patient? What information do we need to make this decision? Choosing an Antibiotic What is the suspected source of infection? What are the common pathogens associated with that infection? Which antibiotics have activity against the likely pathogens? What is the patient s risk for resistant organisms? Types of Bacteria Gram positive Staphylococcus, Streptococcus, Enterococcus Gram negative Haemophilus spp, E.coli, klebsiella spp, enterobacter spp, proteus spp, pseudomonas aeruginosa Anaerobes Bacteroides Fragilis Atypicals Respiratory pathogens Chlamydia pneumoniae, mycoplasma pneumoniae, Legionella pneumoniae 3
Site Determines Pathogen Mouth Peptococcus Peptostreptococcus Actinomyces Skin/Soft Tissue S. aureus S. pyogenes S. epidermidis Pasteurella Bone and Joint S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram-negative rods Abdomen E. coli, Proteus Klebsiella Enterococcus Bacteroides sp. Urinary Tract E. coli, Proteus Klebsiella Enterococcus Staph saprophyticus Upper Respiratory S. pneumoniae H. influenzae M. catarrhalis S. pyogenes Lower Respiratory Community S. pneumoniae H. influenzae K. pneumoniae Legionella pneumophila Mycoplasma, Chlamydia Lower Respiratory Hospital K. pneumoniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus Meningitis S. pneumoniae N. meningitidis H. influenza Group B Strep E. coli Listeria Culture Results: Incremental Information Gram Stain specimen is visualized with microscope Size and shape Ability of organism to absorb stain Inflammatory cells Epithelial cells Preliminary information that can help guide antibiotic selection Pseudomonas aeruginosa 4
xxxxxxxxxxx xxxxxxxxxxx Gram Positive vs. Gram Negative Cell Membrane Cell Wall Outer Membrane (LPS) Gram negative only Bacterial Classification Gram Stain Positive Negative Cocci Bacilli Cocci Bacilli Clusters Staphylococci Coagulase-positive --S. aureus Small --Listeria --Propionibacterium --Corynebacterium --Garderella --N. meningitidis --N. gonorrhoeae Lactose Fermenter Oxidase-positive --Aeromonas --Pasteurella --Vibrio Coagulase-negative --S. epidermidis Pairs and Chains Streptococci Alpha-hemolytic --S. pneumoniae --S. viridans Beta-hemolytic --S. pyogenes --S. agalactiae Enterococci --E. feacium --E. feacalis Large Spore-forming --Clostridium --Bacillus Nonspore-forming --Lactobacillus Branching or Filamentous --Nocardia --Actinomyces Oxidase negative --Escherichia coli --Klebsiella spp. --Enterobacter spp. --Citrobacter spp. Non-Lactose Fermenter Oxidase-positive --Pseudomonas aeruginosa Oxidase negative --Proteus spp. --Serratia marcescens --Morganella morganni --Salmonella spp. --Stenotrophomonos maltophilia --Acinetobacter spp. Coccobacilli --Haemophilus influenzae --Moraxella catarrhalis Final Culture Results Pathogen vs. contaminant Normal flora for the site of infection? Coag negative staphylococcus on the skin Enterococcus in the lungs and urine Yeast in the lungs and urine Bacterial susceptibility Minimum Inhibitory Concentration (MIC) Minimum concentration required to inhibit bacterial growth in-vitro Wikler MA, Ambrose PG. The Breakpoint; in Antibiotics in Laboratory Medicine, 5 th Edition 2005 5
Susceptibility-Broth Dilution Automated Testing What Do I Do With the MIC? Compare it to the Breakpoint MIC value that separates bacteria that are likely to respond to a specific drug treatment from those that are not CLSI, EUCAST, FDA Determined by consideration of the following factors Microbiologic data Animal modeling data PK/PD modeling data Human clinical trial data 6
Using the Breakpoint Used to guide antibiotic selection Sensitive- isolates are inhibited by the usually achievable concentrations when the recommended dosage is used for the site of infection. Resistant- isolates are not inhibited by the usually achievable concentrations with normal dosage, and clinical efficacy against the isolate has not been reliably shown in studies Intermediate- isolates with MICs that approach usually attainable concentrations and for which response rates may be lower than for susceptible isolates. Implies clinical efficacy in body sites where the drugs are physiologically concentrated or when a higher than normal dosage can be used http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/amt.html Concentration Time Curve Resistant Concentration (mg/dl) Intermediate Susceptible Time (hours) Antibiotic review: bear with me 7
Beta-Lactams Includes 4 classes of antibiotics Share common chemical structure and mechanism of action All agents in this class are bacteriocidal Penicillins Cephalosporins Carbapenems Monobactams Beta-lactams Inhibit Cell Wall Synthesis Cell Wall xxxxxxxxxxx Bacterial cell wall is made of repeating layers of peptidoglycan that are cross-linked by proteins. The cross linking reaction is catalyzed by penicillin-binding protein (PBP) Beta-lactams inhibit the action of PBP Mechanisms of Resistance Cell Wall xxxxxxxxxxx Gram Positive 1. Beta-lactamase 2. Change of binding site on PBP 3. Decreased penetration of outer membrane (GN) 4. Efflux of drug across outer membrane (GN) Outer Membrane (LPS) Gram negative only xxxxxxxxxxx Gram Negative (GN) 8
Penicillins Penicillin was first discovered by Alexander Fleming The discovery was an accident When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic. But I suppose that was exactly what I did". Classes Natural Penicillins Penicillin G, Penicillin V Spectrum of activity Gram positive organisms» Streptococcus spp. and Enterococcus spp.» Limited Staphylococcus aureus Synthetic penicillins Nafcillin, oxacillin, dicloxacillin Spectrum of activity Good Streptococcus spp. Drug of choice for MSSA Aminopenicillins Ampicillin and Amoxicillin Spectrum of activity Similar gram positive activity to penicillin. Better enterococcus activity Addition of Gram negative activity Some Haemophilus spp. Some E. coli Some Proteus spp. 9
Beta-lactamase Inhibitor Combinations Ampicillin/sulbactam E.coli, klebsiella, anaerobes Increased Staph activity Piperacillin/tazobactam Same as above; add pseudomonas Cephalosporins Divided into four sub-classes (generations) based upon spectrum of activity All agents share the same core structure Activity is altered by changing the side chain at position R1 or R2 Generations Gram Positive Gram Negative 1 st 2 nd 3 rd 4 th 10
First generation Cefazolin, cephalexin Spectrum of activity Gram positive organisms» Streptococcus spp. and potent Staphylococcus aureus (MSSA) Gram negative organisms» E. coli, Klebsiella spp and Proteus spp. Third generation Ceftriaxone, ceftazidime Spectrum of activity Good gram positive spectrum for ceftriaxone» Potent Streptococcus spp. and MSSA Gram negative organisms» Good E. coli, Klebsiella spp, Proteus spp, Haemophilus spp,» in-vitro activity against Enterobacter spp, Citrobacter spp, Serratia spp. 3 rd Generation Resistance Extended-spectrum β-lactamase production (ESBL) AmpC inducible beta-lactamase Inducible resistance mechanism Enzymatic destruction of all first, second, and third generation cephalosporins False susceptibility results Classically found in Enterobacter, Citrobacter, and Serratia spp. 11
Fourth Generation Cefepime Broad gram positive activity Streptococcus spp. and MSSA activity Broad gram negative activity Good E. coli, Klebsiella spp, Proteus spp, Haemophilus spp, Enterobacter spp, Citrobacter spp, Serratia spp, Pseudomonas aeruginosa Resistance Stable to some ESBLs Stable against most AmpC PBP changes (i.e., MRSA) Carbapenems Broadest Spectrum beta-lactam Gram positive spectrum Streptococcus spp, MSSA, some Enterococcus spp. Covers many gram resistant gram negatives Cover almost all Gram negative organisms Active against ESBL and AmpC producers Good anaerobic coverage Resistance Carbapenem Resistant Enterorbacteriaceae (CRE) Produce enzymes that hydrolyze carbapenems and most other beta-lactams Mid-Atlantic US is a endemic region Starting to be transmitted to other species Resistance mechanism also seen in pseudomonas aeruginosa 12
Fluoroquinolones MOA- rapidly bactericidal; inhibits bacterial DNA synthesis through binding of DNA gyrase and topoisomerase IV MOA- rapidly bactericidal; inhibits bacterial DNA synthesis through binding of DNA gyrase and topoisomerase IV Levofloxacin Classified as a respiratory fluoroquinolone Potent activity against Streptococcus pneumoniae and atypical organisms in-vitro activity against S.aureus and Enterococcus spp. Resistance develops rapidly Has activity against most gram negatives Activity most potent against enterobacter and citrobacter 13
Aminoglycosides Mechanism of action Penetrate the cell wall and membrane, binding irreversibly to the 30S subunit of bacterial ribosome Proteins which are produced are abnormal and nonfunctional leading to bacterial death Retain the broadest coverage against nosocomial gram negative pathogens Vancomycin One of the most prescribed antibiotics in hospitalized patients Been in use for more than 40 years Still retains broad gram positive activity Active against nearly all gram positive species All streptococcus spp All staphylococcus spp. Most enterococcus spp. Drug of choice for MRSA Resistance Vancomycin resistant enterococcus (VRE) 50% of HUP isolates Risk factors Current or recent vancomycin use GI tract colonization with VRE Duration of hospital stay ICU stay Intra-abdominal surgery Invasive device usage: HD, ventilator, catheter 14
Drug to Treat VRE Two broad spectrum gram positive agents MRSA, VRE, streptococcus Linezolid Inhibits protein synthesis; bacteriostatic Adverse effects- thrombocytopenia Daptomycin Disrupts bacterial cell membrane; bacteriocidal Adverse effects- myopathies Not effective for infection in the lung Empiric Selection? HUP Antibiogram Organism N AS CFZ CFP Mer P/T Lev Gent Tob AMK Bact P. aeruginosa 353 0 0 81 69 72 68 62 91 91 0 E. coli 178 69 56 92 99 86 87 87 81 100 71 K. pneumoniae 149 67 45 70 77 68 70 76 70 92 65 Enterobacter cloacae 61 0 0 87 93 67 87 85 77 98 82 Proteus mirabilis 61 98 86 98 100 100 92 97 97 100 92 Serratia marcescens 58 0 0 95 97 84 95 98 97 100 93 Enterobacter aeurogenes Acinetobacter baumanii 39 0 0 97 100 87 100 97 100 100 95 33 100 0 29 31 22 27 37 41 36 34 15
16
HUP Antibiogram Antibiograms Combine Clinically Distinct Populations Cefepime Susceptibility- 90% Amikacin Susceptibility- 98% Percent Susceptible Cefepime Amikacin 0-5 days 6-10 days 11-15 days > 15 days Increasing MDR risk Risk Factors for Multi-drug Resistant Pathogens Previous antibiotics exposure Prolonged hospitalization ( > 4 days) Immunosuppressive disease or treatment Previous healthcare exposure (>72 hours) within past 90 days Previous hospitalization Nursing home Chronic dialysis Deresinski S. CID 2007;45:S177-83 17
Percent MDR Antibiotic exposure Antibiotic exposure Antibiotic exposure 2 5 10 15 Time (days) Community Nosocomial Some ABX are Worse than Others Pseudomonas Meropenem exposure- OR = 11 Ciprofloxacin exposure- OR = 4 What does previous antibiotic exposure mean? One dose same risk as 7 day course?? Threshold for resistance may vary by agent 3 days Levofloxacin, Meropenem, Ceftriaxone, Ceftazidime Greater potential to produce resistance 7 days Cefepime and Zosyn Lower potential to produce resistance Lodise TP et al Antimicrob Agents Chemother. 2007;51:417-22. Hyle EP, Gasink LB et al J Infect. 2007;55:414-418 18
MDR risk: length of stay powerful predictor Risk increases sharply at 30 days Resistance to > 4 antibiotics MDR pathogens Klebsiella pneumoniae producing carbapenemase (KPC) E. coli and K. pneumoniae producing extended spectrum beta-lactamase (ESBL) Pan-resistant acinetobacter and pseudomonas Lodise TP et al Antimicrob Agents Chemother. 2007;51:417-22. High MDR Risk? Should Double Cover Gram Negatives? Double coverage for Gram negatives? Percent Beardsley JR et al CHEST 2006 19
Activity against MDR Psuedomonas Percent Specific bug : drug considerations ESBL- meropenem, amikacin MDR pseudomonas- amikacin, tobramycin Acinetobacter- unasyn, colistin CRE- colistin, amikacin, tigecycline (careful now) New antibiotics? HUP Treatment Guidelines 20
AND the last step De-escalation Empiric treatment with broad spectrum therapy is essential for a given patient s outcome De-escalation is essential for the population. It s an important tool to preserve the activity our our current agents Fundamental Concepts in the Use of Antibiotics Todd Miano, PharmD, MSCE Critical Care Pharmacist Pharmacoepidemiology Fellow Perelman School of Medicine at the University of Pennsylvania a 21