Bug Juice 101

1. Bug Juice 101 Deanna Moore, MSN, ACNP-BC, CCRN, NREMT-P

2. Objectives • Review taxonomy of microorganisms • Describe lab tests used for speciation • Review antibiotic classes, mechanism of action, spectrum of activity, and dosing considerations • Review common infections encountered in the hospital setting and appropriate treatment

3. Taxonomy - Bacterial • Gram Stain • Acid-Fast Stain • Morphology • Oxygen use • Facultative • Toxins

4. Gram Stain • Four step process –

5. Acid-Fast Stain • Difficult to ID with normal gram staining • Red stain does not wash off with acid alcohol • Mycobacterium

6. Gram Positive Two protective layers Phospholipid bilayer Protects bacteria Peptidoglycan cell wall Allows passage of antimicrobials Gram Negative Three layers LPS – protein, Lipid A Endotoxin More difficult to tx

7. Lab Biomedical Tests • Catalase – defense against h2o2 and superoxide • Citrate – utilize citrate as only carbon source • Coagulase – determine if pathogenic • Indole – ability to break down tryptophan • Optichin – Id Streptococcus pneumo • Oxidase – Presence of cytochrome oxidase • Urease – enzyme that breaks C-N bond (proteus)

8. Coagulase Test • Differientiating between pathogenic strains of Staphylococcus

9. Catalase

10. Oxygen Use • Obligate aerobes • Facultative anaerobes • Microaerophilic • Obligate anaerobes

11. Gram Positive Cocci • Streptococci – catalase negative, microaerophilic • Group A beta hemolytic • “strep” throat, Skin infections – necrotizing fascitis • Group D alpha hemolytic • Enterococcus faecalis, faecium – UTI, bacteremia • Pneumoniae – pneumococcus • Pneumonia, meningitis, endocarditis • Staphylocci – catalase positive, facultative anaerobes • Coagulase Positive • S. aureus – skin flora – pna, sepsis, uti • Coagulase Negative • S. epidermidis –skin flora - prosthetics

12. Gram Positive Rods • Endospore Forming • Bacillus – anthracis, cereus (food poisoning) • Regular, Non-endospore forming • Lactobacillus • Irregular, Non-Endospore forming • Cornyebacterium (diptheria in children) – fac anaerobes, cat + • Listeria – only gp to produce endotoxin – fac an, cat + • Pna immunosuppressed • Mycobacteria • Weakly gram positive • Tuberculosis – obligate aerobes

13. Gram Negative • Aerobic Cocci • Neisseria – facultative anaerobes, encapsulated (resistant to host organism) • Meningitidis – meningococcus • Gonorrhea • Bacilli (rods) - enterics • Facultative anaerobes • Ecoli • Klebsiella • Serratia • Proteus • Helicobacter pylori • Enterobacter • Obligate aerobe • Pseudomonas

14. Gram Negative • Nonenterics • Obligate aerobes • Bordetella pertussis • Legionella • Facultative anaerobes • Haemophilus influenzae • Coccobacilli • Acinetobacter - aerobic

15. Anaerobic Features • Foul smelling discharge • Proximity to mucosal membrane • Necrotic tissue • Gas formation in tissue or discharge

16. Gram positive bacilli Clostridium Botulinum Tetani Perfringens Difficile Gram negative Bacilli Spore forming rods -Bacteroides fragilis peritonitis Anaerobes

17. Fungi • Cell Membrane • Major steroid is ergosterol – object of antifungals • Cell Wall • Potent antigens for immune system • Capsule • Polysaccharide coating in some fungi – very antiphagocytic for human immune cells

18. Fungal Infections • Candida albicans • Thrush, vaginitis, esophagitis • Histoplasma capsulatum • Lung • Cryptococcus neoformans • Lung, skin ulcers, HIV • Aspergillus flavus • Lung

19. Enterococcus? Coag positive staph? Gram positive rod? Gram negative enteric? Gram negative nonenteric Gram negative coccibacillus Gram positive rod - anaerobe Acinetobacter H. flu Klebsiella Streptococcus MRSA Lactobacillus C diff Brief Review - Match

20. As said by J.B.S. Haldane….. • The danger with germ-killing drugs is that they may kill the patient as well as the germ.

21. BACTERIOSTATIC Control Inhibit protein synthesis Intact immune system Tetracyclines Doxycycline Macrolides Sulfonamides BACTERIOCIDAL Kill Cell wall inhibitors PCN Vanc Cephalosporins Carbapenems Aminoglycosides Monobactams Fluoroquinolones Metronidazole Isoniazid, Rifampin Antimicrobials by MOA Some drugs can be either based on bacteria and drug concentration

22. Beta-Lactams/Cell Wall Inhibitors • PCN • Specific step in cell wall synthesis • Only bactericidal if cells are actively synthesizing cell wall • Resistance • Inactivation by Beta lactamase – most common • More than 300 • S.aureus, H. flu, Ecoli – still sensative to cephalosporins • Pseudomonas – both PCN and CPN • Modification of target PCN binding proteins • Impaired penetration of drug • Presence of efflux pump

23. PCN G – 1929 – Alexander Fleming • Streptococci, meningococci, enterococci, PCN susceptible pneumococci, non Betalactamase producing staphylococci • Lots of resistance – limited use now • PCN resistant to staphlococcal beta lactamase • Methicillin, Nafcillin • Systemic staphylococcal – • oxacillin, nafcillin 8-12 g/d (1-2 q 6h) • Methicillin - nephrotoxicity

24. Extended Spectrum PCNs • Spectrum of PCN G + Gram Negative • Penetrate outer membrane • Inactivated by beta lactamases • Aminopenicillins – ampicillin and amoxicillin • PO/IV, UTIS, Respiratory, OM, sinusitis • Not effective against klebsiella, pseudomonas, enterobacter, citrobacter, serratia • Carboxypenicillins – carbenicillin and ticarcillin • Amp spectrum + pseudomonas, enterobacter (ticarcillin) • Ureidopenicillins – azlocillin, mezlocillin and pipericillin • Above + klebsiella • Combo drugs: + betalactamase inhibitors – clavulanic acid, sulbactam, tazobactom – increases spectrum Betalactamase prod S. aureus, Gram neg • Most common – pipercillin-tazobactam –– synergistic activity (8:1) • 3.375 g q 6h • 2.25 g q 8h (renal insufficiency) • Empiric for UTI and intraabdominal sepsis, empiric tx of neutropenic patients with fever

25. Cephalosporins • First generation: • Aerobic GPC • Not MRSA, Staph Epi • i.e. cefazolin (Ancef) • Second generation: • Increased act against aerobic and anaerobic GNR - enteric • cefoxitin • Third generation: • Greater activity against GNR, including P. aeruginosa and H. Flu, less active against aerobic GPC than 1st generation • Ceftriaxone (Rocephin) – severe CAP • Ceftazidime (Fortez) – antipseudomonal – no serious adverse effects • Fourth generation: • Broad spectrum • Cefepime – (Pseudomonas, streptococci, MRSA)

26. Cephalosporin Dosing Considerations • Adjust dose in renal failure – extend interval rather than deceasing amount • Preserve concentration-dependent bacterial killing • Ceftriaxone requires no dose adjustment in renal failure • Toxicity – adverse reactions uncommon and nonspecific (rash, N/D) • Risk for superinfection with 2/3 generation • MRSA, enterococcus + fungi • 5-15% cross reaction with PCN – avoid with previous anaphylactic reaction to PCN

27. Carbepenems • Imipenem – effective against all but MRSA, C. diff, Enterococcus • Inactivated by enzymes on luminal surface of proximal renal tubules • Impossible to achieve high levels in urine • Cilastatin – enzyme inhibitor • Meropenem – broadest spectrum • Slightly superior to imipenem secondary to side effect profile but clinical experience is limited

28. Dosing Considerations • Imipenem dosing • 500 mg q 6h • 1000 mg q 6h – pseudomonas • Renal failure – reduced by 50-75% • Generalized seizures in 1-3% • Most often in those with seizure disorder, mass, renal failure • Max daily dose 2g or 25 mg/kg • Meropenem dosing • 1 g q 8h • Dose reduction of 50% in renal failure • Ertapenem • 1 g q 24 • Standard dosing inadequate in obesity • ? Allergy if PCN allergy

29. Other Beta Lactams • Monobactams • Resistant to beta lactamases • Active GNR inc pseudomonas, serratia • No activity against GP or anerobes • Aztreonam • Resembles aminoglycosides, q8h dosing • Tolerated by PCN allergic

30. Vancomycin • Gram positive cocci – all strains of S. aureus (coagulase +, -, MSSA, MRSA), aerobic and anaerobic streptococci • Active against C. diff • Enterococcal resistance 1-15%

31. Dosing Considerations • 1 g q 12 h • Infused slowly – 10mg/min • Continous infusions can achieve bactericidal drug levels in blood • Dose reduction in renal insufficiency – increase dose interval • Trough 5-15, need 20 for CNS, lung

32. Toxicity • Red Man Syndrome • Rapid administration – vasodilation, flushing, hypotension – secondary to histamine release • Ototoxicity • Reversible hearing loss for high freq at high levels (>40) • Permanent deafness at 80 • Nephrotoxicity • 5% - no apparent relationship with dose • Higher when used with aminoglycosides • Usually returns to normal after cessation of tx

33. Protein Synthesis Inhibitors • Bind to or interfere with ribosomes of bacteria • Tetracyclines • Macrolides • Clindamycin

34. Tetracyclines • Broad spectrum bacteriostatic • Inhibit protein synthesis • Gram positive + gram negative + anaerobes • Resistance: • decreased IC accumulation, ribosone protection, enzymatic inactivations • Short acting (tetra), intermediate acting, Long acting (doxy, mino) • Mycoplasma pneumoniae, chlamydiae, rickettsiae, H pylori • Adverse effects • Superinfection – pseudomonas, proteus, staphylococci, clostridia, candida • Hepatotoxicity, nephrotoxicity, venous thrombosis, photosensitivity, vestibular sx, calcium chelation • Doxycycline • No renal adjustment required • Antiseizure meds, barbituates, etoh – decrease half life

35. Macrolides • May be used for strep/staph in patients allergic to PCN, Cephalosporins • PO/IV • Erythromycin, clarithromycin, azithromycin • Few side effects – majority with e-mycin • Gut motility, hepatotoxicity – acute cholestatic hepatitis • Inhibit P450 (except azithromycin) – theophylline, warfarin, cyclosporine, methylprednisone, digoxin

36. Clindamycin • Inhibits protein synthesis • Anaerobes from penetrating wounds of abdomen • Dental prophylaxis • Female genital tract • PO/IV • Adverse effects: GI upset, impaired liver function, neutropenia, C DIFF

37. Antifolate, DNA Gyrase Inhibitors • Antifolate • Inhibit growth by reversibly blocking folic acid synthesis • Sulfonamides • Trimethoprim • DNA Gyrase Inhibitors • Block bacterial DNA synthesis • Fluorinated allow for better systemic levels • Fluoroquinolones

38. Sulfonamides/Trimethoprim • Sulfamethoxazole/Trimethoprim (TMP-SMX) • Synergy for wide gram +/gram – coverage • S. pneumo, H. Flu, Enteric UTIs • PO/IV • Side effects: n/v/d, hemolytic or aplastic anemia, thrombocytopenia, skin rash – can be SJS

39. Fluoroquinolones • -1987/1996 • Two generations – differ in pharmacokinetics and spectrum • Early – Ciprofloxaxin – staphylocci (MRSA), most aerobic gram negative bacilli (pseudomonas) • Less active against streptococci • Newer – Levofloxacin, gatifloxacin, moxifloxacin • Same spectrum as early except against pseudomonas • Increased coverage streptococci, pneumococci, Myco, Hflu • Lung and UTI • Limited value in ICU secondary to limited action on pseudomonas and MRSA – used as part of multiple drug tx

40. Dosing Guidelines • Cipro q 8h secondary to shorter half life • Newer q 24 • Dose adjustments required for all except moxifloxacin (liver metabolism) • Considerations: • Cipro interferes with theophylline and warfarin • Relatively safe • QT prolongation • Torsades • Cipro less effective in ICU secondary to resistance of GN • Newer agents not a choice for VAP except in early onset

41. Protein Synthesis InhibitorsGram Negative Spectrum • Aminoglycosides

42. Aminoglycosides • Derived from cultures of Streptomyces • First - streptomycin • Eight drugs • Three clinically relevant: gentamicin (66), tobramycin (75) and amikacin (81) • Most active against gram negative bacilli including pseudomonas • Bactericidal – concentration dependent + postantibiotic effect • Usually reserved for immunocompromised or unstable gram negative sepsis

43. Dosing Considerations • Based on body weight and renal function • Compare the ideal vs actual body weight and use the lower of the two for dosing • Small fraction in adipose tissue when considering body distribution • Once daily dosing except in endocarditis • Gentamycin: 4-7 mg/kg/d, P 5-10, T<2 (serratia) • Tobramycin: 3-5 mg/kg/d, P 5-10, T <2 (pseudomonas) • Amikacin: 15 mg/kg/d, P 20-30, T<5 • Cleared by kidneys – dosing is adjusted secondary to creatinine clearance

44. Nephrotoxicity • Obligate nephrotoxins • Renal impairment will eventually develop if treatment continues • Oxidative injury in cells lining the proximal tubules • Early signs – cylindrical casts in the urine, proteinuria, inability to concentrate • Urine changes occur during the first week • Cr rises 5-7 days after initiation of therapy • Renal impairment enhanced by hypovolemia, age, preexisting renal impairment, hypokalemia, hypomagnesemia, concurrent tx with other “kidney” offenders (loops, cyclosporin, cisplatin, vanc) • Can progress to ARF but usually reversible

45. Other adverse effects • Ototoxicity • Irreversible hearing loss and vestibular damage • Usually not apparent to patient • Can block Ach release from presynaptic nerve terminals – usually not apparent with therapeutic dosing • Small risk with MG and NDMA

46. Metronidazole • Anaerobes • C. diff, Bacteroides • Side effects: No alcohol – disulfiram reaction, GI upset, neutropenia, paresthesias, caution in CNS disease • Drug interactions • Coumadin – increased INR • Antiseizure meds – increase elimination of metronidazole • Do not use in pregnancy

47. Linezolid - • Newest abx – 2000 – synthetic • Bacteriostatic except bactericidal to streptococci • Inhibits protein synthesis by prevent ribosome complex formation • Resistant gram positive organisms • Initially only recommended when vancomycin not effective or tolerated • May be replacement for vancomycin • MRSA pneumonia due to penetration into respiratory secretions

48. Dosing Considerations • 600 mg BID • IV = PO • Safe in short courses • Longer courses (>1 month) • Thrombocytopenia • Peripheral and optic neuropathy • Peripheral is irreversible, optic partially resolves

49. Antifungals • Amphotericin B • Naturally occuring – fungicidal for most pathogenic fungi in humans • Most effective yet most toxic • Triazoles • Synthetic antifungals • Less toxic • Fluconazole, itraconazole, voriconazole • Echinocandins • New class for invasive candidiasis • Improved spectrum, less drug interactions, no dose modifications • Capsofungin

50. Amphotericin B - AmB • IV use only – vehicle to enhance solubility in plasma • Once daily dosing – 0.5-1mg/kg • Delivered over 4 hours (may be reduced to 1 if tolerated) • Daily infusions until cumulative dose is achieved – total dose is determined by type and severity of infection – 500 mg – 4 g