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Antibiotic Therapy in the Critically Ill Surgical and Trauma Patient - Monobactams Carbapenems, Quinolones Nir Hus MD., PhD. 01/12/2011.

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Presentation on theme: "Antibiotic Therapy in the Critically Ill Surgical and Trauma Patient - Monobactams Carbapenems, Quinolones Nir Hus MD., PhD. 01/12/2011."— Presentation transcript:

1 Antibiotic Therapy in the Critically Ill Surgical and Trauma Patient - Monobactams Carbapenems, Quinolones Nir Hus MD., PhD. 01/12/2011

2 Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

3 3 CARBAPENEMS Imipenem/Cilastatin (Primaxin) Meropenem Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

4 4 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

5 5 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

6 6 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 hr Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

7 7 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

8 8 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

9 9 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

10 10 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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12 12 MONOBACTAMS AZTREONAM Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

13 13 MONOBACTAMS Monobactams have a monocyclic β-lactam ring and are resistant to β-lactamases Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

14 14 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

15 15 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

16 16 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

17 17 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

18 18 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

19 19 QUINOLONES NorfloxacinCiprofloxacin,Ofloxacin,Levofloxacin,Moxifloxacin Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

20 20 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

21 21 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

22 22 QUINOLONES

23 23 [Conc] < serum: Prostatic tissue fluidBoneCSF QUINOLONES [Conc] > serum: Prostate tissue Stool Bile Lung Neutrophils Macrophages Kidneys Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

24 24 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

25 25 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

26 26 Levaquin Administration [Usual Dosage]: IV, PO and ophthalmic [ 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

27 27 QUINOLONES

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


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