Objectives 6/28/2012. Infection, Antibiotic Use & Antimicrobial Resistance A Common Thread?

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1 Infection, Antibiotic Use & Antimicrobial Resistance A Common Thread? Jennifer Schmitz, PharmD, BCPS Clinical Pharmacist, Infectious Diseases Via Christi Hospitals Wichita, Inc. September 21, 2012 Objectives Review the signs of infection Examine normal flora and common pathogens Compare antimicrobial agents with regard to mechanism of action, spectrum of activity and uses Evaluate susceptibility reports Describe the scope of bacterial resistance and factors that can impact resistance patterns 1

2 Infection Organism Drug Patient Clinical Indicators of Infection Localized: Inflammation (redness, swelling, warmth, induration, pain) Exudate (drainage, sputum production) Lesion Clinical Indicators of Infection Systemic Fever Chills/rigors Increased heart rate Increased respiratory rate Malaise Hypotension Mental status changes 2

3 Clinical Indicators of Infection Laboratory Increased or decreased WBC (with increase immature WBC) Microbiology (Positive Gram stain, cultures) Increased inflammatory markers (ESR, CRP) Positive serology test (antigen or antibody) WBC=white blood cells; ESR=erythrocyte sedimentation rate; CRP=C-reactive protein Complete Blood Count (CBC) White blood cells (WBC) Typically elevated in infection Low WBC can also indicate severe infection Different types Neutrophils-acute responders to infection Bands-immature neutrophils Shift to the left=increase in immature neutrophils Elevated number may indicate acute infection Lymphocytes Elevated in viral infections 3

4 Patient factors Site of infection Immune function Comorbidities Organ function Past medical history Allergies Drug interactions Drug factors Spectrum of activity Absorption/bioavailability Distribution throughout the body Metabolism Excretion Bactericidal vs. bacteriostatic activity Organism Factors: Quantity Threshold for infection Virulence Resistance (inherent as well as local Resistance (inherent as well as local patterns) 4

5 Resistance vs. Virulence Virulence The potential for an organism to cause severe disease Example of a virulent organism Strep. pyogenes Resistance Refers to susceptibility to antimicrobial agents Example of a resistant organism Enterococcus species Some organisms are both virulent & resistant Example: S. aureus Treatment of Infectious Diseases 1 st Rule: source control Eliminate/remove foci of infection Drain/debride abscess; remove lines, catheters, screws, plates Patient history Living situation, alcohol/drug use Pets Hospitalization/chronic illness Travel Vaccinations Balance efficacy with safety Empiric Antimicrobial Therapy Broad-spectrum coverage of likely pathogens before microbiology results are available How do we know what the likely pathogens are? 5

6 Normal Flora The body is colonized with numerous different types of micro-organisms Colonization = presence of bacteria that are not causing disease Colonization should NOT be treated with antimicrobials Mouth Viridans grp Streptococci Anaerobes Peptococcus Peptostreptococcus Eikenella Normal Flora Skin Staphylococcus epidermidis Staphylococcus aureus Streptococcus species Corynebacterium Small Intestine Upper (duodenem, jejunem) Lactobacillus Enterococcus Lower (ileum) Enterobacteriaceae E. coli Enterobacter Klebsiella Anaerobes Peptostreptococcus Bacteroides Fusobacterium Upper Airway Streptococcus pneumoniae Haemophilus influenzae Neisseria sp. S. aureus (nose) Large Intestine Enterobacteriaceae E. coli Enterobacter Klebsiella Enterococcus Anaerobes Bacteroides, Clostridium 6

7 Sterile sites Blood Cerebral spinal fluid Peritoneal, pleural, pericardial fluid Urine Common pathogens by infection site Often the normal flora of the site are the first suspects when infection occurs The green underlined organisms are also part of normal flora for the site What other organisms should be suspected? Common Pathogens-Mouth/Dental Peptococcus Peptostreptococcus Actinomyces israeli Treponema pallidum 7

8 Common Pathogen-Skin & Soft Tissue Staphylococcus aureus (a.k.a., S. aureus) Staphylococcus epidermidis (a.ka., Coagnegative Staph, CoNS, Staph epi) Streptococcus pyogenes (a.k.a, Group A strep) Pasturella multocida common colonizer of the mouths of dogs and cats Common Pathogens-Bone & Joint Staphylococcus aureus Staphylococcus epidermidis Neisseria gonorrhea Strep species Gram negative rods (depends on situation) Common Pathogens-Abdomen E. coli Proteus species Klebsiella species Enterococcus species Enterococcus species Bacteroides species Fusobacterium species 8

9 Common Pathogens-Urinary Tract E. coli Proteus mirabilis Klebsiella species Enterococcus species Common Pathogens- Upper Respiratory Tract Includes sinusitis, pharyngitis, bronchitis, inner ear infections Streptococcus pneumoniae (a.k.a-strep pneumo) Haemophilus influenzae Moraxella catarrhalis Streptococcus pyogenes (Strep throat) Common Pathogens- Lower Respiratory Tract (Pneumonia) Streptococcus pneumoniae (a.k.a-strep pneumo) Haemophilus influenzae Klebsiella pneumoniae Legionella pneumoniae Mycoplasma pneumoniae Chamydophila pneumoniae Mycobacterium tuberculosis 9

10 Common Pathogens- Hospital-acquired pneumonia Klebsiella pneumoniae Pseudomonas aeruginosa Enterobacter species Serratia species Acinetobacter species S. aureus Bacterial Morphology (Shape) Key Gram Positive Organisms Staphylococcus S. aureus Coagulase-negative Staph S. epidermidis Enterococcus E. faecalis E. faecium Streptococci S. pyogenes S. agalactiae S. pneumoniae Viridans group Strep S. mitis S. mutans S. sanguinis S. intermedius Corynebacterium 10

11 Key Gram Negative Organisms Enterobacteriacae E. coli Klebsiella pneumoniae Klebsiella oxytoca Enterobacter species Serratia species Proteus species Morganella morganii Moraxella catarrhalis Neisseria meningiditis Neisseria gonorrhoea Nonenterobacteriacae Haemophilus influenzae Pseudomonas aeruginosa Acinetobacter species Pasturella multocida Key Anaerobic Organisms Above the diaphragm Peptococcus Peptostreptococcus Prevotella Actinomyces Below the diaphragm Clostridium perfringens Clostridium difficile Clostridium tetani Bacteroides species Fusobacterium Key Atypical Organisms Legionella pnuemophila Mycoplasma pneumoniae Chlamydia pneumophila Mycobacterium tuberculosis 11

12 Targeted antimicrobial therapy Narrow spectrum coverage of identified pathogens once susceptibility tests are available Deciding on Targeted Therapy Patient factors Organism factors Susceptibility Interpreting MIC s Interpreting S, I, R Values should not be compared between antibiotics (especially different classes) Drug factors 12

13 Antimicrobial Agents Mechanisms of Action Inhibit cell wall synthesis: Penicillins, Cephalosporins Carbapenems (meropenem), Vancomycin Inhibit protein synthesis: azithromycin, doxycycline, gentamicin, tobramycin Inhibit nucleic acid replication and transcription: Fluoroquinolones (levofloxacin, ciprofloxacin) Damage plasma membrane: Polymixin B Inhibition synthesis of essential metabolites: trimethoprim/ sulfamethoxazole (Bactrim) Classes of Antimicrobials Beta-lactams Penicillins Cephalosporins Carbapenem Monobactams Macrolides Folic acid antagonists Tetracyclines Aminoglycosides 13

14 Spectrum of Activity Chart DISCLAIMER The following information refers to general patterns of activity and cannot be applied in all situations Every ypatient and infection must be individually evaluated to determine the most appropriate therapy Spectrum of Activity and Uses 14

15 SUSCEPTIBILITIES 15

16 Pharmacokinetics Pharmacokinetics- How the drug interacts with the body ADME Absorption Distribution Metabolism Excretion ADME IV Drug A Bloodstream Tissue Drug A-OH Eliminatio n ADME Drug A Bloodstream Tissue Drug A-OH Elimination 16

17 Minimum Inhibitory Concentration (MIC) Lowest concentration of antimicrobial at which an isolate cannot produce visible growth Antibiotic Concentration mg/l Susceptibility Reports: What s S-I-R? S=Susceptible Isolate is inhibited by usually achievable concentrations of the antimicrobial agent at the site of infection when given at recommended dosages Antibiotics listed as S might work Susceptibility Reports: What s S-I-R? I=Intermediate MIC approaches usually attainable blood and tissue concentrations and clinical responses may not be optimal Antibiotics listed as I might not work R=Resistant Isolate is not inhibited by usually attainable concentrations Antibiotics listed as R probably won t work 17

18 Can t Compare Apples to Oranges! Trimethoprim/sulfamethoxazole (Bactrim) achieves high concentrations in the urine and is narrower spectrum than cipro. The lower MIC is not a reason to select cipro over trim/sulfa. Antimicrobial Resistance 18

19 Objectives Discuss the scope of the antibiotic resistance problem Review types and mechanisms of resistance as well as how resistant organisms develop Examine how resistant organisms come into hospitals Evaluate strategies to optimize use of antimicrobials and reduce the impact of antibiotic resistance Scope of the problem Antimicrobials are used in 40% of inpatient days and 70% of ICU days Antimicrobials account for upwards of 30% of hospital pharmacy budgets Dellit TH, et al Clin Infec Dis : Scope of the problem Estimates suggest that up to 50% of antimicrobial use is inappropriate Inappropriate/unnecessary use leads to increased costs, resistant pathogens and superinfections Resistant pathogens impact morbidity, mortality and healthcare costs 19

20 Impact of Antimicrobial Resistance Indirect cost benefit from decreasing or preventing resistance and hospital-acquired infections MRSA bacteremia and surgical site infections are associated with higher mortality and attributable cost compared to MSSA VRE incremental cost over VSE: $27,190 C. difficile: $1.1 billion additional costs annually in the U.S ($3,669 per case) Antimicrobial-resistant infections Attributable cost $18,588-$29,069 per patient Increased length of stay days Attributable mortality 6.5% Stosor V, et al. Arch Intern Med 1998;158:522-7 Muto C, et al. Clin Infec Dis 2007;45: Dellit TH, et al. Clin Infec Dis 2007;44: MRSA = methicillin-resistant Staph. aureus MSSA = methicillin-susceptible Staph. aureus VRE = vancomycin-resistant enterococci Consequences of Indiscriminate Antibiotic Use Increased antibiotic use Prolonged hospitalization Increase in Increased resistant consumption of strains resources More resistance Increase in resistant strains More potent antibiotics Suboptimal therapy morbidity & mortality, adverse effects Bad Bugs, No Drugs! One of the top 3 16 greatest threats to 14 worldwide health 12 (World Health 10 Org.) 8 Drug development pipeline is barely trickling IDSA has called for a new focus on drug development Adapted from Spellberg, et al Clin Infec Dis 2008;46: (modified) IDSA Clin Infec Dis 2010;50: Boucher HW, et al. Clin Inf Dis 48:

21 Resistance Types Inherent Genetic, structural or physiologic characteristics of the pathogen Acquired Spontaneous mutation or horizontal transfer of resistant genes Rybak MJ Pharmacotherapy 2004;24:203S-215S Acquired Resistance Resistant Bacteria Susceptible Bacteria Resistance Gene Transfer New Resistant Bacteria Mechanisms of Resistance 21

22 Mechanisms of Resistance Enzymes Degrading enzymes (β-lactamases) Modifying enzymes Target site changes (ribosome, e.g.) Reduced access to target site Decreased expression of porins Efflux pumps Drug is pumped out of the bacteria Metabolic bypass Organism finds a different way to make the needed product Emergence and Spread of Resistance Selective pressure Antibiotic use Proliferation of multiple-drug resistant clones Difficulty in detecting new phenotypes Selection Pressure Use of antibiotics puts pressure on bacterial populations (squeezes the balloon) Example: ciprofloxacin is used to treat a Pseudomonas urinary tract t infection After 7 days of treatment, a urine culture is repeated. Pseudomonas is no longer present, it is now positive for Enterococcus faecium & yeast Ciprofloxacin is not active against enterococci or yeast what s left behind flourishes 22

23 Selection Pressure Subtherapeutic concentrations of antibiotics can leave resistant populations to proliferate Altered flora Agents that are active against enteric flora (3 rd generation cephalosporins, fluoroquinolones, e.g.) select for enterococcus Selection Pressure Antimicrobial Exposure Resistant strains rare Resistant strains predominant As the antibiotic kills the susceptible strains, the resistant strains are left to thrive with no competition for nutrients. How We Acquire Resistant Organisms in Hospitals Transfer of a patient with resistant organism from another facility Adapted from Peterson DL. Clin Inf Dis 2006;42:S90-5 Antibiotic Resistance in Hospitals Transfer of resistance genes between organisms Antibiotic use leads to in vivo selection Patient-topatient transfer of organisms via contaminat ed environme nt Patient-to-patient transmission facilitated by antibiotic use 23

24 Antimicrobial Resistance- What can we do to decrease it? Minimize the spread of resistant organisms by strictly observing contact and other precautions Treat infection NOT colonization Use narrow spectrum agents when possible Shorten duration of therapy when possible Reducing Resistance- Strategies to Consider Formulary management Work with the microbiology lab Provide guidance on duration of therapy Order sets Empiric therapy recommendations Duration of Therapy Information on duration is not abundant Prolonged antibiotic therapy can result in: Colonization with resistant organisms Since many infections are associated with normal flora, this can lead to infection with drug resistant organisms Superinfections such as Clostridium difficile colitis The need for antibiotic therapy should be reassessed daily in most cases 24

25 Infection Site Lower respiratory tract Community-acquired pneumonia 1,2 Ventilator-associated pneumonia 3,4 Intra-abdominal infections 5 Bacteremia 6 Removable source Non-removable source Urinary Tract 7 Uncomplicated/complicated Acute pyelonephritis Meningitis 8 Clostridium difficile colitis 9 1. Eur Respir J 2005; 26: CID 2007;44(suppl 2): S Am J Respir Crit Care Med 1996; 153: JAMA 2003; 290: Recommended Antibiotic Duration 5-10 days 8-15 days 5-14 days 14 days Up to 28 days 3-7 days 14 days 5-21 days days 5. CID 2010; 50: ICHE 2010; 31: CID 2009;49: CID 1999; 29: CID 2004; 39: Summary Treating infections is a delicate balance of patient, organism and drug characteristics Normal flora varies by body site and often plays a role in infection Antimicrobial agents vary widely in mechanism of action, spectrum of activity and uses MIC s are unique to each medication and should not be compared to one another Bacterial resistance is increasing & results in poorer patient outcomes, but you can have an impact Questions? 25