bug juice 101 deanna moore, msn, acnp-bc, ccrn, nremt-p
TRANSCRIPT
Bug Juice 101
Deanna Moore, MSN, ACNP-BC, CCRN, NREMT-P
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
Taxonomy - Bacterial
• Gram Stain• Acid-Fast Stain• Morphology• Oxygen use• Facultative• Toxins
Gram Stain
• Four step process –
Acid-Fast Stain
• Difficult to ID with normal gram staining
• Red stain does not wash off with acid alcohol– Mycobacterium
• 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
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)
Coagulase Test
– Differientiating between pathogenic strains of Staphylococcus
Catalase
Oxygen Use
• Obligate aerobes
• Facultative anaerobes
• Microaerophilic
• Obligate anaerobes
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
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
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
Gram Negative
• Nonenterics– Obligate aerobes
• Bordetella pertussis
• Legionella
– Facultative anaerobes• Haemophilus influenzae
• Coccobacilli– Acinetobacter - aerobic
Anaerobic Features
• Foul smelling discharge
• Proximity to mucosal membrane
• Necrotic tissue
• Gas formation in tissue or discharge
Anaerobes
• Gram positive bacilli– Clostridium
– Botulinum
– Tetani
– Perfringens
– Difficile
• Gram negative Bacilli– Spore forming rods
-Bacteroides fragilis
• peritonitis
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
Fungal Infections
• Candida albicans– Thrush, vaginitis, esophagitis
• Histoplasma capsulatum– Lung
• Cryptococcus neoformans– Lung, skin ulcers, HIV
• Aspergillus flavus– Lung
Brief Review - Match
• 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
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.
Antimicrobials by MOA
• 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
Some drugs can be either based on bacteria and drug concentration
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
• 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
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
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)
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
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
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
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
Vancomycin
• Gram positive cocci – all strains of S. aureus (coagulase +, -, MSSA, MRSA), aerobic and anaerobic streptococci
• Active against C. diff
• Enterococcal resistance 1-15%
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
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
Protein Synthesis Inhibitors
• Bind to or interfere with ribosomes of bacteria
• Tetracyclines
• Macrolides
• Clindamycin
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
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
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
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
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
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
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
Protein Synthesis InhibitorsGram Negative Spectrum
• Aminoglycosides
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
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
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
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
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
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
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
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
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
Dosing Considerations• Infusion related inflammatory response
– Fever, chills, nausea, vomiting, rigors – 70%– Cytokine release from activated monocytes– Most severe on initial infusion
• Pretreatment with acetaminophen 10-15mg/kg po and diphenhydramine 25 mg po/iv 30 min before. Give meperidine 25 mg iv for rigors
• If symptoms not relieved with pretreatment – add hydrocortisone 0.1 mg/ml to infusion
– Liposomal Amphotericin B• Lipid preparations – enhance binding to fungal cells over mammalian cells –
phospholipid vesicles• Less infusion related side effects, Less nephrotoxicity• Dose 5x higher• Very Costly (10x per mg + increased dose - $16 vs. $828)• Only approved for tx of documented fungal infections in pt intolerant of
standard AmB or empiric coverage in neutropenic with persistent fever
Adverse Effects• Phlebitis – need central access• Nephrotoxicity
– Binds to cholesterol on the surface of renal epithelial cells and produces an injury in the renal tubules – resembles RTA (distal) with increased urinary excretion of K, Mg
– Azotemia 30-40% with possible progression to ARF requiring dialysis– Stablilizes with continued infusions and improves with discontinuation of
therapy– Cr >3 – stop infusions – Aggravated with hypovolemia, concurrent drugs
• Hypokalemia, Hypomagnesemia – – Oral mg supplementation 300-600 daily– Stop with azotemia
Triazoles
• Candida septicemia in ICU - Fluconazole– Hemodynamically stable, Immunocompentent
• Voriconazole– Aspergillosis
– Emperic treatment of neutropenic with persistent fever
• Itraconazole– Invasive aspergillosis
– Doesn’t play well with others
Dosing• Fluconazole
– PO = IV– 400-800 daily dose, double 1st dose to decrease time to steady state (4-5d)– Adjust for renal impairment, Decrease by 50% for CrCl <50 ml/min– Interactions: inhibit cytochrome P450
• Phenytoin, statins, warfarin– No serious toxicity –
• Elevated liver enzymes in 10%• Voriconazole
– Loading 6 mg/kg q 12 for 24 h, then 4 mg/kg q 12h IV– 200 mg po BID – mx dosing– Long infusion – 1-2 h– Well tolerated with minor GI side effects– Elevated liver enzymes with combo with cyclosporin
Echinocandins
• New class – invasive candidiasis– Improved coverage for all Candida species– Less risk of drug interactions– No dose modifications
• Caspofungin– Comparable to AmB
• IV 70 mg initially, then 50 mg daily• Increased dose needed with some antivirals,
rifampin, dexamethasone, antiseizure meds
Duration of Therapy• Bacteremia
– Removable device 10-14 d• Cellulitis
– After acute inflammation 3 d• Kidney
– Cystitis 3d (single dose cipro ER)
– Pyelo 14 d (7 with cipro)
• Bone– Osteomyelitis 42 d
• GI– Cdiff 10-14 d– H pylori 10-14 d
• Lung– Pneumococcal 5 day (afebrile 3-5)– Enterobacter/pseudomonal 21 – 42 d– Staphylcoccal 21-28 d
What about pregnancy?
• Aminoglycosides• Erythomycin• Metronidazole• Nitrofuratoin• Sulfonamides/Trimethoprim• Tetracycle• Fluoroquinolines• Vancomycin• Azoles
Treatments - Match
• Cellulitis • UTI – uncomplicated• UTI - complicated• CAP – hospitalized• CAP – ICU• VAP• C. diff• Candida
• Metronidazole PO• Ancef, PCN• Ceftriazone + azithro• Bactrim• Diflucan• Carbepenem + Vanc• FQ• Amp + gent/zosyn
Questions?????????
References• www.cartoonstock.com• Gilbert, D.N., Moellering, R.C., Eliopoulos, G.M., and
Sande, M.A. The Sanford Guide to Antimicrobial Therapy 2007.
• Hull, M. Clostridium difficile - associated colitis, 2004• Marino, P.L. The ICU Book. 2007• Katzung, B. Basic and Clinical Pharmacology. 2004• Malvinder, P. Pneumocephalus associated with
Bacteroides fragilis meningitis. Journal of Post-graduate medicine, 2004.
• Talaro, A. and Talaro, K. Foundations in Microbiology.1996