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![•Penicillin-cephalosporin cross-reactivity studies that
confirmed penicillin allergy by skin testing are superior
in design compared with those that diagnosed
penicillin allergy by history alone.
•Another group of studies evaluated patients with
positive penicillin skin tests (to penicilloyl polylysine
[PPL], penicillin G, and/or the minor determinant
mixture [MDM]) who were challenged with
cephalosporins and found an overall reaction rate of
3.4 percent .](https://image.slidesharecdn.com/antibiotics2015inicu-150127100032-conversion-gate02/75/Antibiotics-2015-in-icu-53-2048.jpg)
Uploaded byDr. Mohamed Maged Kharabish
Antibiotics 2015 in icu
1) The document discusses various antibiotics used to treat gram positive and gram negative bacteria, including vancomycin, linezolid, daptomycin, aminoglycosides, aztreonam, cephalosporins, piperacillin-tazobactam, carbapenems, tigecycline, and atypical agents. 2) It provides information on the spectrum of activity, mechanisms of action, dosing, and clinical pearls for each antibiotic class. 3) Key points covered include time and concentration dependent antibiotic killing, monitoring of vancomycin and aminoglycoside levels, extended infusion of meropenem, and reserving tigecycline
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Antibiotics 2015 in icu
- 1. ANTIBIOTICS 2015 IN ICU SAMIREL ANSARY
- 2.
- 3. Definitions • Minimum InhibitoryConcentration – Antimicrobial concentration that inhibits visible microbial growth in artificial media • Gram Stain – Gram positive – Gram negative • Acid fast
- 4. • Problems withMIC: •Fixed drug concentration •All or none parameter. Growth vs. no growth •Does not provide information on the time course of antimicrobial activity •Drug concentrations change throughout the dosing interval •Does not capture interpatient pharmacokinetic variability •Does not provide info on post-antibiotic effects
- 5. Gram staining FOR differentiatingbacterialspecies into (gram- positive and gram-negative). The name comes from its inventor, Hans Christian Gram. Gram staining differentiates bacteria by the chemical and physical properties of their cell walls by detecting peptidoglycan, which is present in a thick layer in gram-positive bacteria.
- 6. Gram staining In aGram stain test, gram-positive bacteria retain the crystal violet dye, while a counterstain (commonly safranin or fuchsine) added after the crystal violet gives all gram-negative bacteria a red or pink coloring.
- 7. Acid-fastness A physical propertyof certain bacteria (and, less commonly, protozoa), specifically their resistance to decolorization by acids during staining procedures. The high mycolic acid content of certain Protozoa cell walls, and those of Mycobacteria, is responsible for the staining pattern of poor absorption followed by high retention. Usually used to identify mycobacteria.
- 8. Pharmacodynamics Time Dependent Killing •Beta-Lactams – Penicillin – Cephalosporins – Piperacillin-Tazobactam – Carbapenems • Meropenem • Ertapenem
- 9. • Pharmacokinetics versus pharmacodynamics •Pharmacokineticsmathematically describe the relationship of antibiotic concentration to time. • Aabsorption, distribution, metabolism, elimination, half-life, volume of distribution, and area under the concentration-time curve (AUC).
- 10. •Pharmacodynamics •Describe the relationshipof antibiotic concentration to pharmacologic effect or microorganism death. • The three main pharmacodynamic parameters that are used are the • peak to minimal inhibitory concentration ratio (peak/MIC), the AUC to MIC ratio (AUC/MIC)
- 11. •Pharmacodynamics • The timethe drug concentration remains above the MIC (T>MIC). • Concentration independent antimicrobials include: beta- lactams, vancomycin, macrolides, aztreonam, carbapenems, clindamycin, tetracyclines, quinupristin/dalfopristin, flucytosine, and azole antifungals.
- 12. Pharmacodynamics Concentration Dependent Killing •Fluoroquinolones – Levofloxacin – Ciprofloxacin – Moxifloxacin • Aminoglycosides – Amikacin – Tobramycin – Gentamicin
- 13. Pharmacodynamics AUC/MIC Dependent Killing •Vancomycin • Linezolid • Clindamycin • Macrolides – Azithromycin – Clarithromycin – Erythromycin
- 14. Keys to Success •Antibiotic covers potential infection/bacteria • Dose of antibiotic is appropriate for treatment of infection and adjusted for renal/hepatic impairment • Antibiotic penetrates site of infection • Antibiotic is being absorbed • Adequate treatment duration
- 15. Risk Factors forResistance • Antimicrobial therapy in the preceding 90 days • Current hospitalization of 5 days or more • High resistance rates in the unit • Residence in a nursing home or extended care facility • Immunocompromised • Home wound care • Chronic dialysis
- 16.
- 17. Gram Positive Bacteria •Cocci – Staphylococcus • S. aureus • S. epidermidis – Streptococcus • S. pyogenes (Group A) • S. viridians • S. pneumoniae – Enterococcus • E. faecalis • E. Faecium • Bacilli – Listeria monocytogenes – Bacillus anthracis – Corynebacterium species – Proprionibacterium acnes
- 18. Vancomycin • Spectrum ofactivity – Staph (MRSA, MSSA), strep, enterococcus, c. difficile colitis (oral) • Mechanism of action – Inhibits synthesis of peptidoglycan/bacterial cell wall formation • Dosing – Actual body weight – Loading dose = 25-30 mg/kg – Maintenance dose = 15-20 mg/kg – Usual Frequency = every 8-24h – Adjust dose for renal impairment
- 19. Vancomycin • Adverse effects –Redman syndrome – Thrombocytopenia – Possible nephrotoxicity ?? – Ototoxicity (rare) Ototoxicity is not associated with trough concentrations. • Monitoring – Goal Trough = 15-20 mcg/mL – Bacteremia, endocarditis, osteomyelitis, meningitis, pneumonia – Initial: trough before 4th or 5th dose – Maintenance: trough once weekly
- 20. Vancomycin with Dialysis •Continuous renal replacement therapy (CRRT) – 15mg/kg q24h – Hold dose if CRRT stopped > 8h – Trough before 4th or 5th dose • Intermittent hemodialysis (iHD) – Pulse dosing with iHD – iHD removes ~25% of vancomycin – Goal Pre-iHD level < 24 mcg/mL – Initial dose = 15mg/kg x1 dose – Maintenance dose based on pre-iHD levels
- 21. Linezolid • Spectrum ofactivity – Staph (MSSA, MRSA), strep, VRE • Mechanism of action – Binds to bacterial ribosomes to inhibit protein synthesis • Bacteristatic against staph, vre but cidal against strep pneumon • Time dependent killing
- 22. Linezolid • Adverse Effects –Myelosupression (pancytopenia, thrombocytopenia) – GI upset – Serotonin syndrome • Drug interactions – Monoamine oxidase inhibitors (MAOI’s) – Selective serotonin reuptake inhibitors (SSRI’s) • Dosing – 600mg IV/PO q12h
- 23. Linezolid • Clinical Pearls –May be used for vancomycin failure or intolerance – Oral & IV formulations – Bacteriostatic – No renal adjustment – May have prescribing restrictions – Expensive
- 24. Daptomycin • Spectrum ofactivity – Staph (MSSA, MRSA), strep, enterococcus (VRE) • Mechanism of action – Causes bacterial membranes to depolarize leading to inhibition of protein, DNA, and RNA synthesis • Typical Dosing – Adjust with renal impairment – 4-6 mg/kg (actual weight) q24-48h • Adverse Effects – Arthralgia – Myalgia – CPK elevations
- 25. Daptomycin • Clinical Pearls –Not for treatment of pneumonia – Can use doses of 8-10 mg/kg for severe infections – Monitor CPK at baseline and weekly – Can falsely elevate INR – May have prescribing restrictions – Takes 30-60 minutes to reconstitute – Expensive
- 26.
- 27. Gram Negative Bacteria Cocci •Neisseria gonorrhoeae • Neisseria meningitidis • Moraxella catarrhalis Bacilli • Pseudomonas aeruginosa • Acinetobacter species • Citrobacter species • Enterobacter species • Klebsiella pneumoniae • E. Coli • H. influenzae • Proteus mirabilis • S. maltophilia
- 28. Aminoglycosides • Spectrum ofactivity – Only gram negative, gram positive synergy • Mechanism of action – Bind bacterial ribosome and inhibit protein synthesis • Adverse effects – Nephrotoxicity – Ototoxicity – Prolonged neuromuscular blockade Medications Gentamicin Tobramycin Amkicacin
- 29. • Aminoglycoside antibioticspossess nondepolarizing neuromuscular blocking activity, which is additive or synergistic with the effects of the nondepolarizing neuromuscular blocking agents used in anesthesia . • Aminoglycosides cause presynaptic inhibition of acetylcholine release and postsynaptic reduction in sensitivity
- 30. Aminoglycosides • Clinical Pearls –Used for • Nosocomial infections • Double gram negative coverage • Endocarditis (synergy) – Two dosing schemes • Traditional dosing • Extended interval dosing/once daily dosing – Levels must be monitored • Traditional = peak & trough around 3rd dose • Extended interval = trough before 2nd dose – Monitor Scr daily
- 31. Aztreonam • Class – Monobactam •Spectrum of activity ‒ Gram positive: none ‒ Gram negative: most, except S. maltophilia • Mechanism of action – Inhibit cell wall synthesis • Dosing – Usual: 1-2g IV Q8h – Meningitis: 2g IV Q6-8h • Adverse effects (rare) – Transient eosinophilia – LFT elevations – Thrombocytopenia **Can be used with penicillin allergy**
- 32.
- 33. Spectrum of ActivityPrimary Use First Generation Cefazolin (Ancef) (IV) Cephalexin (Keflex) (PO) • Simple Gram (+) , simple gram (-) , no anaerobes. No ceph gets enterococci. • Simple SSTI, surgical prophylaxis Second Generation Cefotetan (Cefotan) (IV) Cefoxitin (Mefoxin) (IV) Cefuroxime (Ceftin) (IV) Cefaclor (Ceclor) (PO) Cefprozil (Cefzil) (PO) • Same spectrum as 1st Generation • Cefotetan and Cefoxitin cover anaerobes • Surgical prophylaxis if anaerobes, URTI, UTI Third Generation Ceftriaxone (Rocephin) (IV) Cefotaxime (Claforan) (IV) Ceftazadime (Fortaz) (IV) Cefpodoxime (Vantan) (PO) Cefdinir (Omnicef) (PO) Cefixime (Suprax) (PO) • Better gram (-) • Ceftazadime-pseudomonas • PNA, meningitis Fourth Generation Cefepime (Maxipime) (IV) • Good gram (+), nosocomial gram (-) including pseudomonas • No anaerobes • Sepsis, HAP, neutropenic fever Fifth Generation Ceftaroline (Teflaro) • MRSA, MSSA, E. faecalis, s.pneumoniae, • Some gram (-), NO pseudomonas • Pneumonia, SSTI Cephalosporins
- 34. • CABP pathogens,ceftaroline has activity against the Gram-positive organisms S. pneumoniae, S. aureus and Streptococcus pyogenes, and Gram-negative species (Haemophilus influenzae and CABP pathogens, ceftaroline has activity against the Gram-positive organisms S. pneumoniae, S. aureus and Streptococcus pyogenes, and Gram-negative species .
- 35. Cephalosporins • Clinical Pearls –Do not cover enterococcus (except ceftaroline) – ↑ gram negative coverage with higher generations – Used for surgical prophylaxis – Anaerobic coverage • Cefoxitin • Cefotetan – Pseudomonas coverage • Ceftazidime • Cefepime
- 36. Fluoroquinolines Medications Ciprofloxaci n Levofloxacin Moxifloxacin Gemifloxaci n Mechanism of Action InhibitDNA gyrase and topoisomerase IV inhibiting DNA synthesis Spectrum of Activity • Gram Negative: Enterobacteriaceae, Haemophilus spp, Neisseria spp and M. Catarrhalis • Atypicals Pseudomonas Pseudomonas S. pneumoniae Anaerobes S. pneumoniae - - - Clinical Use Gram (-) infections, Bone/Joint PNA, UTI PNA NOT: UTI PNA
- 37. Piperacillin-Tazobactam • Spectrum ofactivity – Gram negative: P. aeruginosa, Enterbacteriaceae – Gram positive: MSSA, Enterococci, Strep – Anaerobes • Mechanism of action – Inhibit cell wall synthesis • Adverse effects – Gastrointestinal intolerance – C. difficle colitis – Interstitial nephritis
- 38. • Mechanism ofAction: •Inhibit mucopeptide synthesis in the bacterial cell wall, thus results in formation of defective cell walls and osmotically unstable organisms susceptible to cell lysis •Tazobactam acts as a beta-lactamase inhibitor and inactivates both plasmid and chromosome mediated beta-lactamases
- 39. Carbapenems Meropenem (Merem®) Ertapenem (Invanz®) Imipenem - Cilastatin (Primaxin®) Doripenem (Doribax®) Mechanism of Action Inhibitcell wall synthesis Spectrum of Activity Broad Spectrum: Gram (+), Gram (-), ESBL, Anaerobes NOT: MRSA -- NOT: Pseudomonas, Enterococcus, Acinetobacter -- -- Adverse Effects ↓ Platelets Drug Fever Seizure ↓ Platelets Drug Fever Common Use Meningitis Intra-abdominal Nocardia NOT: Pneumonia
- 40. Carbapenems • Clinical Pearls –First line agent for extended spectrum beta-lactamase (ESBL) producing bacteria – Extended infusion meropenem • ↑ time above MIC – Reserved for severe infections – May have prescribing restrictions
- 41. Tigecycline • Spectrum ofactivity – Enterococcus (including VRE), MSSA, MRSA, MRSE, anaerobes – Not pseudomonas, proteus, providencia • Mechanism of action – Binds to bacterial ribosomes to inhibit protein synthesis • Dose – 100mg IV x 1 dose – 50mg IV q12h • Adverse effects – Nausea and vomiting – Hyperbiliruminemia
- 42. •Tigecycline has aspectrum of activity that includes anaerobes, many gram- positive cocci and gram-negative bacilli w/ the exception of Pseudomonas, Proteus, and Providencia. •N/V may occur in up to 2/3rds of patients
- 43. Tigecycline • Clinical Pearls –No renal adjustment – Hepatic dose adjustment (Child Pugh C) • 100mg IV x 1, then 25mg IV Q12h – Used for resistant infections – Do not use for • Ventilator associated pneumonia • Bacteremia – Can be used for • Intra-abdominal infections • Skin & soft tissue infections
- 44. •All-cause Mortality: •An increasein all-cause mortality has been observed •The cause of this mortality risk difference has not been established. •Tigecycline should be reserved for use in situations when alternative treatments are not suitable. •Death resulted from progression of infection •Especially in ventilator associated pneumonia •Reserve for use when other agents are not an option
- 45.
- 46. Atypical Bacteria Agents • Fluoroquinolones –Levofloxacin – Ciprofloxacin – Moxifloxacin – Gemifloxacin • Macrolides – Azithromycin – Erythromycin – Clarithromycin • Tetracyclines – Tetracycline – Doxycycline – Minocycline Bacteria • Mycoplasma • Legionella pneumoniae • Chlamydia pneumoniae • Richettsia • Actinomyces
- 47.
- 48. Clostridium Difficile Antimicrobials perIDSA Guidelines
- 49. Clostridium Difficile • IDSARecommendations – No probiotics - ↑ Bloodstream infections – Stop causative antimicrobials – Repeat testing during the same episode is discouraged – Vancomycin taper after second reoccurrence – Dual antimicrobials • Ileus = IV metronidazole + vancomycin enema **PO vancomycin is only used to treat c. diff infection**
- 50. • There isno evidence to support administration of combination therapy to patients with uncomplicated CDI. • Although hampered by its low statistical power, a recent trial did not show any trend toward better results when rifampin was added to a metronidazole regimen. • There is no evidence to support use of a combination of oral metronidazole and oral vancomycin.
- 51. Allergic Reactions • IgEreactions – Anaphylaxis – Bronchospasm – Angioedema – Pruritic rash – Uticaria – Hypotension
- 52. Penicillin Allergy Avoid Use Incidenceof Reaction May Use Cephalosporins • 1st/2nd generation cephalosporin 2% • Aztreonam • 3rd/4th generation cephalosporin Carbapenems • None? 0-11% • All carbapenems? • Aztreonam • Graded challenge or PCN skin test
- 53. •Penicillin-cephalosporin cross-reactivity studiesthat confirmed penicillin allergy by skin testing are superior in design compared with those that diagnosed penicillin allergy by history alone. •Another group of studies evaluated patients with positive penicillin skin tests (to penicilloyl polylysine [PPL], penicillin G, and/or the minor determinant mixture [MDM]) who were challenged with cephalosporins and found an overall reaction rate of 3.4 percent .
- 54. •If this analysisis limited to studies published after 1980 (when cephalosporins were no longer contaminated with penicillin), the reaction rate is reduced to 2 percent. •Thus, approximately 2 percent of patients with skin- test proven sensitivity to penicillin can be expected to react to cephalosporins. •Range for cephalosporin reaction was 0-12% reported in the literature.
- 55.
- 56. GOOD LUCK SAMIR ELANSARY ICU PROFESSOR AIN SHAMS CAIRO elansarysamir@yahoo.com
Editor's Notes
- #9 Pharmacokinetics versus pharmacodynamics Pharmacokinetics mathematically describe the relationship of antibiotic concentration to time. Terminology that is typically associated with pharmacokinetics includes: absorption, distribution, metabolism, elimination, half-life, volume of distribution, and area under the concentration-time curve (AUC). Pharmacodynamics describe the relationship of antibiotic concentration to pharmacologic effect or microorganism death. The three main pharmacodynamic parameters that are used are the peak to minimal inhibitory concentration ratio (peak/MIC), the AUC to MIC ratio (AUC/MIC), and the time the drug concentration remains above the MIC (T>MIC). concentration independent antimicrobials include: beta-lactams, vancomycin, macrolides, aztreonam, carbapenems, clindamycin, tetracyclines, quinupristin/dalfopristin, flucytosine, and azole antifungals.
- #47 Mycoplasma vs. mycobacteria Clinical Pearls Uses Community acquired pneumonia Opportunistic infections Tic born illness COPD exacerbations