Antibiotic Therapy in the Critically Ill Antibiotic Therapy in the Critically Ill
Surgical and Trauma Patient - Surgical and Trauma Patient -
Monobactams Carbapenems, QuinolonesMonobactams Carbapenems, Quinolones
Nir Hus MD., PhD.Nir Hus MD., PhD.
01/12/201101/12/2011
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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CARBAPENEMSCARBAPENEMSImipenem/Cilastatin (Primaxin)Imipenem/Cilastatin (Primaxin)
MeropenemMeropenem
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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CARBAPENEMS β-lactams that contain a fused β-lactam ring and a 5-
membered ring system that differs from the penicillins in being unsaturated (double bond between C-2 and C-3) and containing a carbon atom instead of the sulfar atom.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Imipenem / Cilastatin, i.v Mechanism of action
Imipenem like other β-lactam antibiotics binds to penicillin- binding proteins, disrupts bacterial cell wall synthesis and cause death of susceptible micro-organisms.
Antibacterial spectrum Aerobic & anaerobic G+ (S. aureus, Enterococci and
Streptococci) & G- including pseudomonas and most enterobacter.
MRSA is less susceptible
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Imipenem / Cilastatin, i.v Pharmacokinetics
Not absorbed orally ( i.v infusion )
Poor distribution in CSF (not used in meningitis)
Partly broken down by dehydropeptidase in the proximal tubule- given with cilastatin ( dihydropeptidase inhibitor )
Excreted primarily by the kidney
Doses must be reduced in renal failure
Half- life about 1 hrNir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Imipenem / Cilastatin, i.v Clinical uses:
Infections require multiple antibiotics ( useful in nosocomial infections )
Not used alone for resistant pseudomonas infections
Not used for MRSA infections
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Imipenem / Cilastatin, i.v Side effects
Similar to those seen with B- lactams
Nausea & vomiting are frequent
Excessive levels with renal failure may lead to seizures
Pts allergic to penicillins may be allergic to imipenem
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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MEROPENEM Meropenem is a second generation carbapenem.
Meropenem is not hydrolyzed by DHP-I and is resistant to most β-lactamases, including a few carbapenemases that hydrolyze carbapenem.
The lower incidence of nephrotoxicity of meropenem (compared with imipenem) has been correlated with its greater stability to DHP-I.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Imipenem / cilastatin vs Meropenem
Higher reported incidence of seizures.
A 1g of imip./cilas require 200 ml saline to dissolve, whereas 1g of meropenem dissolves in only 20 ml saline.
Meropenem can be given either by i.v bolus or i.v infusion
Lower incidence of nephrotoxicity of meropenem (compared with imipenem)
Imip./cilas should be given only by i.v infusion. Less suitable for fluid restricted pts Not suitable for outpatients- need hospitalization
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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MONOBACTAMSMONOBACTAMSAZTREONAMAZTREONAM
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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MONOBACTAMS Monobactams have a monocyclic β-lactam ring and
are resistant to β-lactamases
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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AZTREONAM Mechanism of action
Aztreonam was isolated from Chromobacterium violaceum.
Similar to other B- lactams. Aztreonam is the first clinically useful monobactam. The antimicrobial activity of Aztreonam differs from
those of other β-lactam antibiotics and more closely resembles that of an aminoglycosides in activity without the nephrotoxicity of aminoglycosides.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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AZTREONAM
Antibacterial spectrum Active only against G- aerobic bacteria (pseudomonas,
N. gonorrhea, N. meningitidis, H. influenzae and enterobacteriaceae )
Inactive against G+ and anaerobic bacteria. The combination of Aztreonam and piperacillin is
synergistic against some strains of P. aeruginosa and Enterobacter spp.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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AZTREONAM Pharmacokinetics
Poorly absorbed orally( i.v / 8 hr ) Limited penetration into the CSF Excreted primarily by the kidney Half- life 2 hr
Side effects Similar to other B- lactams. Pts allergic to penicillins and cephalosporins can
receive aztreonam
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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AZTREONAM Clinical uses of aztreonam
Active against G- aerobes only Alternative for penicillins and cephalosporins. Safe alternative to aminoglycosides, esp. in elderly and
pts with renal impairments.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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TIGEMONAM It is an investigational monobactam that is orally
active.
It is highly resistant to β-lactamases.
The antibacterial spectrum of activity of tigemonam resembles that of aztreonam.
It is very active against the Enterobacteriaceae, including: E. coli, Klebsiella, Proteus, Enterobacter species.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONESQUINOLONESNorfloxacinNorfloxacin
Ciprofloxacin, Ciprofloxacin, Ofloxacin, Ofloxacin,
Levofloxacin, Levofloxacin, MoxifloxacinMoxifloxacin
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONES Mechanism of action:
Inhibit bacterial DNA synthesis by inhibiting DNA gyrase and topoisomerase IV resulting in rapid cell death.
Mechanism of resistance: Chromosomal:
Alter target enzymes: DNA gyrase and topoisomerase IV
Decreased drug penetration: Pseudomonas, E. coli Plasmid: seen in some K. pneumoniae and E. coli Mutations in both target enzymes are needed to produce
significant resistance.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONES Quinolones (1st generation)
Highly protein bound Mostly used in UTIs
Fluoroquinolones (2nd, 3rd and 4th generation) Modified 1st generation quinolones Not highly protein bound Wide distribution to urine and other tissues; limited CSF
penetration.
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONES
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[Conc] < serum: Prostatic tissue fluidBoneCSF
QUINOLONES [Conc] > serum:
Prostate tissue
Stool
Bile
Lung
Neutrophils
Macrophages
KidneysNir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONES Drug interactions:
↓ absorption: Al3+, Mg2+, and Ca2+ antacids CYP450 inhibition potential drug interactions for ciprofloxacin.
Example: Can increase warfarin exposure (real changes in INR are rare, but monitor)
Adverse effects: GI: Nausea, vomiting CNS: HA, dizziness, confusion, insomnia, delerium,
hallucinations, seizure (rare) Cardiovascular: Torsades de pointes (rare) Musculoskeletal: Rupture of tendon (rare) Neurologic: Polyneuropathy (rare)
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Ciprofloxacin Administration [Usual Dosage]: IV, PO [500 – 750 mg q 8-12h]
Spectrum: Gram- aerobic rods, and Legionella, and other atypicals. Poor activity against Strep. pneumoniae.
Indications: Nosocomial pneumonia Intra-abdominal infections Uncomplicated/complicated UTI Anthrax exposure and prophylaxis
Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases absorption Increased effects of warfarin
ADRs QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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Levaquin
Administration [Usual Dosage]: IV, PO and ophthalmic [500-750 mg q24h]
Spectrum: Gram-, Gram+ (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens, Mycobacterium tuberculosis.
Indications: Chronic bronchitis and Community acquired Pneumonia. Nosocomial pneumonia Skin & Soft Tissue infections Intra-abdominal infections
Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases its absorption
ADRs Blood glucose disturbances in DM patients QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis
Nir Hus MD., PhD. Ryder Trauma Center Jackson
Memorial Hospital
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QUINOLONES
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Memorial Hospital