The Beta-Lactam Antibiotics Cell wall active agents ï‚ Prevent the final step in the...

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Transcript of The Beta-Lactam Antibiotics Cell wall active agents ï‚ Prevent the final step in the...

  • Slide 1
  • The Beta-Lactam Antibiotics Cell wall active agents Prevent the final step in the synthesis of the bacterial cell wall Range from very narrow spectrum to very broad spectrum
  • Slide 2
  • -Lactams -lactam ring
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  • How do they work? 1.The -lactam binds to Penicillin Binding Protein (PBP) 2.PBP is unable to crosslink peptidoglycan chains 3.The bacteria is unable to synthesize a stable cell wall 4.The bacteria is lysed
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  • Penicillin binding protein Peptidoglycan Synthesis
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  • PK/PD The -lactams are time-dependent killers The effect is directly proportional to the amount of TIME the concentration of the antibiotic at the site of infection is ABOVE the MIC of the organism. The -lactams are BACTERIOCIDAL (at therapeutically attainable levels)
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  • Time Dependant H Derendorf
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  • Time Dependant WA Craig
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  • So many choices which one to pick? What is the likely organism? Whats its major mode of resistance? Wheres the infection? Whats my local environment? the UNC Hospital antibiogram What does the micro lab say? in vitro sensitivity testing
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  • Classification Penicillins Natural penicillins PenG, PenVK, Benzathine Pen, Procaine Pen Aminopenicillins Ampicillin, Amoxicillin Anti-Staph penicillins Oxacillin, Dicloxacillin Anti-Pseudomonal [Carboxy] Ticarcillin [Ureido] Piperacillin
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  • Classification Cephalosporins 1 st Generation Cephalexin, Cefazolin 2 nd Generation Cefoxitin, Cefuroxime, Cefotetan 3 rd Generation Cefotaxime, Ceftriaxone, Ceftazidime 4 th Generation Cefepime
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  • Penicillin G Available PO, IM, IV (dosed in units) Drug of Choice (DoC) [2-4 MU IV q4h] T. pallidum, N. meningitidis, Group A Strep, and Actinomycosis Long-acting forms Procaine PenG (12 hrs) Benzathine Pen (5 days) [2.4 MU IM for syphilis] Adverse Reactions other than skin rash Penicillin serum sickness/drug fever Jarisch-Herxheimer reaction (1 and 2 syphilis) Hemolytic anemia, pancytopenia, neutropenia
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  • Ampicillin/Amoxicillin Amp (IV, PO)Amox (PO) Spectrum: PenG + H. flu and some E. coli DoC: Listeria monocytogenes and Enterococcus [Amp 2g IV q4h] Dental Prophylaxis Amox 1 gram PO x 1 prior to appt. Integral in H. pylori regimens ADRs Non-allergic rashes (9%) esp. when associated with a viral illness (mononucleosis - EBV) Amox better tolerated PO and better absorbed (Amp must be taken on empty stomach)
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  • Oxacillin IV DoC MSSA, MSSE [2g IV q4h] Actually less active against Pen susceptible isolates than Pen More active than Vanc vs. MSSA Significant hepatic metabolism No need to dose adjust for renal impairment ADRs Hepatotoxicity (cholestatic hepatitis) Neutropenia Kernicterus in neonates
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  • Dicloxicillin Oral NOT equivalent to IV Ox (therapeutically) Poor oral absorption ~50% (better on empty stomach) Dose: 250-500mg po QID
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  • Piperacillin IV DoC: Pseudomonas Spectrum: most Enterobacteriaceae (E. coli, Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Shigella) Most active penicillin vs. Pseudomonas Often used in combination with Aminoglycoside or Cipro/Levofloxacin ADRs Bleeding (platelet dysfunction) Neutropenia/Thrombocytopenia
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  • -Lactamase Inhibitors How do you evade a -lactamase? 1.Use a non--lactam agent 2.Steric Inhibition Penicillins with large side chains Cephalosporins 3.-lactam + -lactamase inhibitors Not all -lactamases are inhibitable (!)
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  • Clavulanic Acid Augmentin (Amox/Clav) PO Spectrum: MSSA and upper respiratory infections (S. pneumo, H. flu, M. catarrhalis) and most anaerobes Clav is responsible for most of the GI side- effects seen with Amox/Clav Variable ratios of Amox/Clav in liquids/tabs/chewtabs
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  • Sulbactam Unasyn (Amp/Sulbactam) Spectrum: Amp + most anaerobes + many enteric Gm (-) rods, OSSA DoC: for GNR mixed infection E.coli, Proteus, anaerobes when Pseudomonas is not implicated Diabetic foot (once Pseudomonas ruled out) Wound infections Sulbactam alone is very active against Acinetobacter spp.
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  • Tazobactam Zosyn (Pip/Tazo) THE most broad-spectrum penicillin Tazobactam may improve the activity of piperacillin vs. gram-negative rods, including anaerobes 4.5g IV q8h = 3.375g IV q6h 4.5g IV q6h for Pseudomonas
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  • The Cephalosporins (generalized) 1 st GenerationGram (+) 2 nd Generation Decreasing Gram (+) and Increasing Gram (-) 3 rd Generation Gram (-), but also some GPC 4 th GenerationGram (+) and Gram (-) *Not effective vs. Enterococcus or Listeria
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  • Cephalexin/Cefazolin PO/IV Stable vs Staph penicillinase Spectrum: MSSA, PSSP, most E. coli, and some Klebs Can be dose thrice weekly in HD pts [1.5 grams IV TIW] DoC: surgical prophylaxis, bacterial peritonitis in CAPD pts [1 gm in the dwell bag] ADRs Positive Coombs test (though, hemolytic anemia is rare)
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  • Cefuroxime IV/PO Extensive use in pediatrics Spectrum: Strep pneumo, Viridans Strep, most H. flu, N. meningitidis DoC: uncomplicated CAP (esp. H. flu), UTI/pyelo
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  • Cefotaxime IV Spectrum: Strep pneumo, Neisseria spp., most Gram (-) enterics, M. catarrhalis and H. flu (including -lactamase +) DoC: bact meningitis (esp. in peds + amp if < 4 weeks), CAP, complicated UTI/pyelonephritis, Bacterial Peritonitis
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  • Ceftriaxone IV Once daily dosing (95% protein bound = long half-life) Spectrum: Strep. pneumoniae, most Enterbacteriaceae, Excretion: 50% urine, 50% bile = no need to adjust for renal insufficiency CSF penetration: 5-15% in meningitis, 1.5% with out inflammation DoC: bacterial meningitis, CAP, Strep. viridans endocarditis (+ gent) ADRs Cholestasis Elevated bilirubin (displacement) Diarrhea
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  • Ceftazidime IV Spectrum: Enteric GNR (including Pseudomonas; some Acinetobacter) No anaerobic activity (same for cefotaxime and ceftriaxone) DoC: Pseudomonas infx
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  • Third Generation Cephs: Issues -lactamase induction? ESBLs De-repression of chromosomal -lactamases Selective pressure for VRE?
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  • Cefepime IV NON-Spectrum: MRSA, C. diff, Burkholderia, Stenotrophomonas, gram- negative anaerobes Stable vs. de-repressed chromosomal - lactamases, but not ESBL Less -lactamase induction than 3 rd Cephs DoC: HAP, febrile neutropenia
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  • Carbapenems Imipenem, Meropenem, Ertapenem Broad-spectrum coverage: Gram positive: PSSP, MSSA, VSE Gram negative: most gram-negative organisms (Acinetobacter sp., Pseudomonas sp.) Lack of coverage: Ertapenem: Pseudomonas sp., Acinetobacter sp. All: Stenotrophomonas, Legionella sp., MRSA, VRE
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  • Carbapenems Distribution: similar to penicillins Excretion: renal clearance Adverse reactions: Hypersensitivity: rash, urticaria, cross-reactivity Imipenem: seizures (rare) High doses Renal dysfunction Most likely can occur with all carbapenems at high doses
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  • Carbapenems Resistance: Gram negative: usually combination of mechanisms (Carbapenemase production + decreased entry) Imipenem Decreased production of OprD (outer membrane protein for carbapenems) Imipenem utilizes OprD > meropenem, ertapenem Pseudomonas, Enterobacter Susceptible to efflux system in Enterobacter Meropenem: substrate for multi-drug efflux systems May have increased MIC for meropenem but not imipenem All: low affinity PBPs
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  • Monobactams Monobactams: Aztreonam Spectrum: ONLY Gram negative aerobic bacteria Lack of Coverage: Some resistant P. aeruginosa, E. cloacae, and C. freundii Acinetobacter sp., Stenotrophomonas sp. Pharmacokinetics: Well distributed into tissues, esp. inflamed tissues Excretion: renal clearance Adverse reactions: Skin rash No cross-reactivity with Beta-Lactam class
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  • What about penicillin allergies? Literature reports a ceph/pen cross-reactivity of 1 10% The cross-reactivity of aztreonam/pen or ceph is essentially 0% The cross-reactivity of carbapenems/penicillins is also around 10% (similar to that of ceph/pen) Decision making: Severity of reaction Eos