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Introduction to Antibacterial Therapy. Clinically Relevant Microbiology and Pharmacology Edward L. Goodman, MD July 21, 2003. Rationale. Antibiotic use (appropriate or not) leads to microbial resistance Resistance results in increased morbidity, mortality, and cost of healthcare
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Introduction to Antibacterial Therapy Clinically Relevant Microbiology and Pharmacology Edward L. Goodman, MD July 21, 2003
Rationale • Antibiotic use (appropriate or not) leads to microbial resistance • Resistance results in increased morbidity, mortality, and cost of healthcare • Appropriate antimicrobial stewardship will prevent or slow the emergence of resistance among organisms (Clinical Infectious Diseases 1997; 25:584-99.) • Antibiotics are used as “drugs of fear” • (Kunin CM Annals 1973;79:555)
Antibiotic Misuse • Surveys reveal that: • 25 - 33% of hospitalized patients receive antibiotics (Arch Intern Med 1997;157:1689-1694) • 22 - 65% of antibiotic use in hospitalized patients is inappropriate (Infection Control 1985;6:226-230)
Consequences of Misuse of Antibiotics • Contagious RESISTANCE • No equivalent downside to overuse of endoscopy, calcium channel blockers, etc. • Morbidity - drug toxicity • Mortality • Cost
Outline • Basic Clinical Bacteriology • Categories of Antibiotics • Pharmacology of Antibiotics
Goodman’s Scheme for the Major Classes of Bacterial Pathogens • Gram Positive Cocci • Gram Negative Rods • Fastidious GNR • Anaerobes
Gram stain: clusters Catalase pos = Staph Coag pos = S aureus Coag neg = variety of species Chains and pairs Catalase neg = streptococci Classify by hemolysis Type by specific CHO Gram Positive Cocci
Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin resistant • At PHD ~50% of SA are hetero (methicillin) resistant = MRSA • Glycopeptide (vancomycin) intermediate (GISA) • MIC 8-16 • Eight nationwide (one at PHD) • VRSA reported July 5, 2002 MMWR • MIC >128
Methicillin Methicillin-resistant S. aureus (MRSA) [1970s] Vancomycin [1997] [1990s] [ 2002 ] Vancomycin Vancomycin-resistant Vancomycin- resistant S. aureus intermediate- enterococci (VRE) resistant S. aureus (VISA) Evolution of Drug Resistance in S. aureus Penicillin Penicillin-resistant S. aureus [1950s] S. aureus
Coagulase Negative Staph • Many species – S. epidermidis most common • Mostly methicillin resistant (65%) • Often contaminants or colonizers – use specific criteria to distinguish • Major cause of overuse of vancomycin
Nosocomial Bloodstream Isolates All gram-negative (21%) Other (11%) SCOPE Project Viridans streptococci (1%) Coagulase-negative staphylococci (32%) Candida (8%) Staphylococci aureus (16%) Enterococci (11%) Clin Infect Dis 1999;29:239-244
Streptococci • Beta hemolysis: Group A,B,C etc. • Invasive – mimic staph in virulence • S. pyogenes (Group A) • Pharyngitis, • Soft tissue • Non suppurative sequellae: ARF, AGN
Beta strept - continued • S. agalactiae (Group B) • Peripartum/Neonatal • Diabetic foot • Bacteremia/endocarditis/metastatic foci • Group D (non enterococcal) = S. bovis • Associated with carcinoma of colon
Viridans Streptococci • Many species • Streptococcus intermedius group • Liver abscess • Endocarditis • GI or pharyngeal flora • Most other are mouth flora – cause IE
Enterococci • Formerly considered Group D Streptococci now a separate genus • Bacteremia/Endocarditis • Bacteriuria • Part of mixed abdominal/pelvic infections • Intrinsically resistant to cephalosporins • No bactericidal single agent
Fermentors Oxidase negative Facultative anaerobes Enteric flora Numerous genera Escherischia Enterobacter Serratia, etc Non-fermentors Oxidase positive Pure aerobes Pseudomonas and Acinetobacter Nosocomial Opportunistic Inherently resistant Gram Negative Rods
Fastidious Gram Negative Rods • Neisseria, Hemophilus, Moraxella, HACEK • Require CO2 for growth • Neisseria must be plated at bedside • Chocolate agar with CO2 • Ligase chain reaction has reduced number of cultures for N. gonorrhea
Anaerobes • Gram negative rods • Bacteroides • Fusobacteria • Gram positive rods • Clostridia • Proprionobacteria • Gram positive cocci • Peptostreptococci and peptococci
Anaerobic Gram Negative Rods • Produce beta lactamase • Endogenous flora • Part of mixed infections • Confer foul odor • Heterogeneous morphology • Fastidious
Antibiotic Classificationaccording to Goodman • Narrow Spectrum • Active against only one of the four classes • Broad Spectrum • Active against more than one of the classes • Boutique • Active against a select number within a class
Narrow Spectrum • Active mostly against only one of the classes of bacteria • gram positive: glycopeptides, linezolid • aerobic gram negative: aminoglycosides, aztreonam • anaerobes: metronidazole
Broad Spectrum • Active against more than one class • GPC and anaerobes: clindamycin • GPC and GNR: cephalosporins, penicillins, T/S, newer FQ • GPC, GNR and anaerobes: ureidopenicillins ± BLI, carbapenems • GPC and fastidious: macrolides
Boutique Antibiotics • Just like the Mall • specialty stores • specialty drugs • Often like the Mall – stores in search of business; drugs in search of diseases • Synercid – for VRE faecium, not faecalis, MRSA • Linezolid – VRE, MRSA • ID consult needed
Pharmacodynamics • MIC=lowest concentration to inhibit growth • MBC=the lowest concentration to kill • Peak=highest serum level after a dose • AUC=area under the concentration time curve • PAE=persistent suppression of growth following exposure to antimicrobial
Parameters of antibacterial efficacy • Time above MIC - beta lactams, macrolides, clindamycin, glycopeptides • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin • Peak/MIC - aminoglycosides, fluoroquinolones
Time over MIC • Should exceed MIC for at least 50% of dose interval • Higher doses may allow adequate time over MIC • For most beta lactams, optimal time over MIC can be achieved by continuous infusion (except unstable drugs such as imipenem, ampicillin)
Higher Serum/tissue levels are associated with faster killing • Aminoglycosides • Peak/MIC ratio of >10-12 optimal • Achieved by “Once Daily Dosing” • PAE helps • Fluoroquinolones • 10-12 ratio achieved for enteric GNR • PAE helps • not achieved forPseudomonas nor Streptococcus pneumoniae
AUC/MIC = AUIC • For Streptococcus pneumoniae, FQ should have AUIC >= 30 • For gram negative rods where Peak/MIC ratio of 10-12 not possible, then AUIC should >= 125.
Antibiotic Use and Resistance • -Strong epidemiological evidence that antibiotic use in humans and animals associated with increasing resistance • -Subtherapeutic dosing encourages resistant mutants to emerge; conversely, rapid bactericidal activity discourages • -Hospital antibiotic control programs have been demonstrated to reduce resistance
Further Activities of CAMP • Decrease inappropriate fluoroquinolone use • Staff education • Restricted reporting • Decrease inappropriate sputum cultures • Staff education • Laboratory disclaimer • Decrease inappropriate vancomycin levels • Education about unnecessary peak levels
Further Activities of CAMP • Monitor surgical site infections and intervene as necessary • Improved timing and administration of pre-op antibiotics • clipping not shaving • nasal decolonization • changing pathogens (MRSA, gram- rods) • Automated protocol-driven antibiotic prescribing • Computerized physician order entry
Antibiotic Armageddon “There is only a thin red line of ID practitioners who have dedicated themselves to rational therapy and control of hospital infections” Kunin CID 1997;25:240
Historic overview on treatment of infections • 2000 BC: Eat this root • 1000 AD: Say this prayer • 1800’s: Take this potion • 1940’s: Take penicillin, it is a miracle drug • 1980’s: Take this new antibiotic, it is better • ?2003 AD: Eat this root