Introduction to Antibacterial Therapy

1. Introduction to Antibacterial Therapy Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD July 22, 2010

2. Outline • Basic Clinical Bacteriology • Antibiotics • Categories • Pharmacology • Mechanisms of Resistance

3. Goodman’s Scheme for the Major Classes of Bacterial Pathogens • Gram Positive Cocci • Gram Negative Rods • Fastidious Gram Negative Organisms • Anaerobes

4. 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

5. Staphylococcus aureus • >95% produce penicillinase (beta lactamase) = penicillin resistant • At PHD ~60% of SA are hetero (methicillin) resistant = MRSA (less than national average) • Glycopeptide (vancomycin) intermediate (GISA) • MIC 8-16 • Eight nationwide • First VRSA reported July 5, 2002 MMWR • Seven isolates reported (5/7 from Michigan) • MICs 32 - >128 • No evidence of spread w/in families or hospital

6. 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

7. MSSA vs. MRSA Surgical Site Infections(1994 - 2000)

8. Coagulase Negative Staph • Many species – S. epidermidis most common • Mostly methicillin resistant (65-85%) • Often contaminants or colonizers – use specific criteria to distinguish • Major cause of overuse of vancomycin • S. lugdunensis is rarely a contaminant • Causes destructive endocarditis

9. 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

10. Streptococci • Beta hemolysis: Group A,B,C etc. • Invasive – mimic staph in virulence • S. pyogenes (Group A) • Pharyngitis, • Soft tissue • Invasive • TSS • Non suppurative sequellae: ARF, AGN

11. Other Beta hemolytic • S. agalactiae (Group B) • Peripartum/Neonatal • Diabetic foot • Bacteremia/endocarditis/metastatic foci • Group C/G Streptococcus • large colony variants: similar clinical illness as GAS plus bacteremia, endocarditis, septic arthritis • Small colony variants = Strept milleri

12. Viridans group Anginosus sp. Bovis sp.: Group D Mutans sp. Salivarius sp. Mitis sp.

13. Streptococcus anginosus Group Formerly ‘Streptococcus milleri’ or ‘Streptococcus intermedius’. S. intermedius; S. constellatus; S. anginosus Oral cavity, nasopharynx, GI and genitourinary tract.

14. S. anginosus Group Propensity for invasive pyogenic infections ie. abscesses. Grow well in acidic environment polysaccharide capsule resists phagocytosis produce hydrolytic enzymes: hyaluronidase, deoxyribonucleotidase, chondroitin sulfatase, sialidase

15. S. anginosus Group Oral and maxillofacial infections Brain, epidural and subdural abscesses intraabdominal abscesses empyema and lung abscesses bacteremias usually secondary to an underlying focus of infection. Look for the Abscess!

16. 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 (except ?Dapto) • Role in mixed flora intra-abdominal infection trivial- therapy for 2° peritonitis need not cover

17. Fermentors Oxidase negative Facultative anaerobes Enteric flora Numerous genera Escherischia Enterobacter Serratia, etc UTI, IAI, LRTI, 2°B Non-fermentors Pure aerobes Pseudomonas (oxidase +) and Acinetobacter (oxidase -) Nosocomial LRTI, bacteremia, UTI Opportunistic Inherently resistant Gram Negative Rods

18. Fastidious Gram Negatives • Neisseria, Hemophilus, Moraxella, HACEK • Require CO2 for growth • Culture for Neisseria must be plated at bedside • Chocolate agar with CO2 • Ligase chain reaction (like PCR) has reduced number of GU cultures for N. gonorrhea • Can’t do MIC without culture • Increasing resistance to FQ not detected w/o culture

19. Anaerobes • Gram negative rods • Bacteroides (gut/gu flora) • Fusobacteria (oral and gut) • Prevotella (mostly oral) • Gram positive rods • Clostridia (gut) • Proprionobacteria (skin) • Gram positive cocci • Peptostreptococci and peptococci (oral, gut, gu)

20. Anaerobic Gram Negative Rods • Fastidious • Produce beta lactamase • Endogenous flora • When to consider • Part of mixed infections • Confer foul odor • Heterogeneous morphology • Gram stain shows GNR but routine cults negative

21. Antibiotic Classificationaccording to Goodman • Narrow Spectrum • Active against only one of the four classes of bacteria • Broad Spectrum • Active against more than one of the classes • Boutique • Highly specialized use • Restricted to ID physicians

22. Narrow Spectrum • Active mostly against only one of the classes of bacteria • gram positive: glycopeptides, linezolid, daptomycin, telavancin • aerobic gram negative: aminoglycosides, aztreonam • anaerobes: metronidazole

23. Narrow Spectrum

24. Broad Spectrum • Active against more than one class • GPC (incl many MRSA) and anaerobes: clindamycin • GPC (not MRSA*) and GNR: cephalosporins, penicillins, sulfonamides, TMP/Sulfa (*include MRSA), FQ • GPC (not MRSA*), GNR and anaerobes: ureidopenicillins + BLI, carbapenems, tigecycline (*MRSA), tetracyclines (*MRSA), moxiflox • GPC and fastidious: macrolides

25. Penicillins/Carbapenems

26. Cephalosporins

27. 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

28. Pharmocodynamics: Dosing for Efficacy Peak Blood Level MIC Trough Time

29. Parameters of antibacterial efficacy • Time above MIC (non concentration killing) - beta lactams, macrolides, clindamycin, glycopeptides • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin • Peak/MIC (concentration dependent killing) - aminoglycosides, fluoroquinolones, daptomycin

30. Time over MIC • For beta lactams, 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) • For Vancomycin, evolving consensus that troughs should be >15 for most serious MRSA infections, especially pneumonia and bacteremia • If MRSA MIC is 1.5 - 2, should avoid vancomycin in favor of daptomycin, linezolid or tigecycline

31. 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 • Not always achieved for Streptococcus pneumoniae • Daptomycin • Dose on actual body weight

32. 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.

33. DNA gyrase DNA-directed RNA polymerase Quinolones Cell wall synthesis Rifampin ß-lactams & Glycopeptides (Vancomycin) DNA THFA mRNA Trimethoprim Protein synthesis inhibition Ribosomes Folic acid synthesis DHFA 50 50 50 Macrolides & Lincomycins 30 30 30 Sulfonamides PABA Protein synthesis inhibition Protein synthesis mistranslation Tetracyclines Aminoglycosides Cohen. Science 1992; 257:1064

34. Pathways of Common Resistance Mechanisms • Impede access of drug to target • Beta lactamases: multiple classes • Aminoglycoside altering enzymes • Chloramphenicol altering enzymes • Altered porin channels – carbapenems • Efflux pumps - macrolides • Alterations in target • Altered binding proteins: MRSA, DRSP • Methylation of ribosomes: macrolides • Bypass metabolic pathways: TMP/Sulfa • Alteration in gyrases

35. Some Background onEnterobacteriaceae β-lactam antibiotics (derivatives of penicillin) have long been the mainstay of treating infections caused by Enterobacteriaceae. However, resistance to β-lactams emerged several years ago and has continued to rise. Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs) Plasmid-mediated AmpC-type enzymes

36. Extended Spectrum Beta Lactamases (ESBL) • Hyper production derived from TEM beta lactamases • Predominantly in Klebsiella and E coli • Confer resistance to penicillins, cephalosporins, monobactams • Plasmids also confers R to FQ/AG • Indications for carbapenems*

37. Amp C Beta Lactamases • Chromosomal cephalosporinases active against • 1st - 3rd generation cephalosporins, penicillins even with BLI • Constituent or Inducible • Reside in periplasmic space • Not easily detected when in low numbers • SPICE organisms possess Amp C • Serratia • Pseudomonas • Indole + Proteii • Citrobacter • Enterobacter • Indication for carbapenems* (imipenem, meropenem, ertapenem, doripenem)

38. The Last Line of Defense Fortunately, our most potent β-lactam class, carbapenems, remained effective against almost all Enterobacteriaceae. Doripenem, Ertapenem, Imipenem, Meropenem Unfortunately, “Antimicrobial resistance follows antimicrobial use as surely as night follows day”

39. Klebsiella Pneumoniae Carbapenemase KPC is a class A b-lactamase Confers resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems Occurs in Enterobacteriaceae Most commonly in Klebsiella pneumoniae Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp., Also reported in Pseudomonas aeruginosa (South America)

40. Susceptibility Profile of KPC-Producing K. pneumoniae

41. Carbapenem resistance in K. pneumoniaeNHSN Jan 2006- Sept 2007 Hidron, A et al Infect Control Hospital Epidemiol. 2008;29:996

42. Geographical Distribution of KPC-Producers Frequent Occurrence Sporadic Isolate(s)

43. 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

44. 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 – 2000’s: Take this new antibiotic, it is a bigger miracle! • ?2011: Eat this root!

45. 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

46. Thanks to • Shahbaz Hasan, MD for allowing me to use slides from his 6/6/07 Clinical Grand Rounds on Streptococci • Eliane S Haron, MD for allowing me to use the “Eat this root” slide • Jean B. Patel, PhD and CDR Arjun Srinivasan, MD, Division of Healthcare Quality Promotion at CDC for Kpc slides