antibiotic therapy in the critically ill surgical and trauma patient - monobactams carbapenems,...

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

28Nir Hus MD., PhD. Ryder Trauma Center Jackson

Memorial Hospital