Transcript Antimicrobials

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
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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
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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
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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
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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
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Clostridium
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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
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Enterococcus?
Coag positive staph?
Gram positive rod?
Gram negative enteric?
Gram negative nonenteric
Gram negative
coccibacillus
• Gram positive rod anaerobe
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Acinetobacter
H. flu
Klebsiella
Streptococcus
MRSA
Lactobacillus
C diff
As said by J.B.S. Haldane…..
• The danger
with germkilling drugs
is that they
may kill the
patient as
well as the
germ.
Antimicrobials by MOA
• BACTERIOSTATIC
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Control
Inhibit protein synthesis
Intact immune system
Tetracyclines
Doxycycline
Macrolides
Sulfonamides
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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
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Spectrum of PCN G + Gram Negative
– Penetrate outer membrane
– Inactivated by beta lactamases
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Aminopenicillins – ampicillin and amoxicillin
– PO/IV, UTIS, Respiratory, OM, sinusitis
• Not effective against klebsiella, pseudomonas, enterobacter, citrobacter, serratia
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Carboxypenicillins – carbenicillin and ticarcillin
– Amp spectrum + pseudomonas, enterobacter (ticarcillin)
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Ureidopenicillins – azlocillin, mezlocillin and pipericillin
– Above + klebsiella
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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
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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
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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 (TMPSMX)
• 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
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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 Inhibitors
Gram 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
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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
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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
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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
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Bacteremia
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After acute inflammation
Cystitis
– Pyelo
14 d (7 with cipro)
42 d
GI
– Cdiff
– H pylori
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3d (single dose cipro ER)
Bone
– Osteomyelitis
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3d
Kidney
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10-14 d
Cellulitis
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Removable device
10-14 d
10-14 d
Lung
– Pneumococcal
– Enterobacter/pseudomonal
– Staphylcoccal
5 day (afebrile 3-5)
21 – 42 d
21-28 d
What about pregnancy?
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Aminoglycosides
Erythomycin
Metronidazole
Nitrofuratoin
Sulfonamides/Trimethoprim
Tetracycle
Fluoroquinolines
Vancomycin
Azoles
Treatments - Match
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Cellulitis
UTI – uncomplicated
UTI - complicated
CAP – hospitalized
CAP – ICU
VAP
C. diff
Candida
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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 Postgraduate medicine, 2004.
• Talaro, A. and Talaro, K. Foundations in
Microbiology.1996