ß-lactams. Sub-families. Penicillins. Cephalosporins. Monobactams. Carbapenems

Transcription

1 β-lactams

2 ß-lactams Sub-families Penicillins Cephalosporins Monobactams Carbapenems

3 ß-lactams Mode of action PBPs = Trans/Carboxy/Endo- peptidases PBP binding (Penicillin-Binding Proteins) activation of autolytic membranal enzymes inhibition of peptidoglycan synthesizing enzymes

4 ß-lactams General PK A variable D wide M insignificant E mostly renal

5 General ADEs ß-lactams Allergic reactions (hypersensitivity) % % overall: 10%

6 ß-lactams General ADEs Penicillin-cephalosporin cross-sensitivity 1970s reports: ~10% beta-lactam ring

7 General ADEs current concept: side-chain similarity ß-lactams Penicillin-cephalosporin cross-sensitivity true penicillin allergy associated with 3-fold increase in allergies to non-related drugs

8 ß-lactams General ADEs GI - ~5% (ampicillin, cefuroxime) Interstitial nephritis - 1-2% Impaired liver function - 1-4%

9 daily freq. adult g/day admin. route leading brand generic sub-class mU INJ Penicillin penicillin G Natural Penicillins 2/4 2 PO Rafapen penicillin V INJ PO Penibrin ampicillin Aminopenicillins PO Moxypen amoxycillin methicillin oxacillin Penicillinaseresistant Penicillins INJ PO Orbenil cloxacillin INJ Baypen mezlocillin Extendedspectrum Ureidopenicillins INJ Pipril piperacillin 1. Penicillins

10 1.1. Natural Penicillins penicillin G penicillin V acid stable? No Yes admin. route IV, IM PO penicillin: Streptococcal pharyngitis Pneumococcal pneumonia Syphilis (Treponema pallidum)

11 1.2. Aminopenicillins vs. Gram-negative PO bioavailability: ampi~40%, amoxi~90% amoxi - RTIs - H. pylori eradication protocols ampi (IV) Enterococci

12 1.3. Penicillinase-resistant Penicillins penicillin-resistant Staphylococci methicillin/oxacillin - resistance markers (MRSA/ORSA) cloxacillin MSSA (phlebitis)

13 1.4. Extended-spectrum Penicillins vs. Gram-negative and anaerobic piperacillin (anti-pseudomonal)

14 1.5. Penicillin + β-lactamase inhibitor amoxycillin + clavulanate (Augmentin ) ampicillin + sulbactam (Unasyn ) piperacillin + tazobactam (Tazocin ) ticarcillin + clavulanate (Timentin )

15 1.5. Penicillin + β-lactamase inhibitor β-lactamase inhibitors: penicillin role: activity β-lactamase inhibitor role: resistance reversal NOT ALL β-lactamases inhibited! combination compared to the penicillin alone: MSSA, more Gram-negatives and anaerobes

16 1.5. Penicillin + β-lactamase inhibitor distinguishing features: amox/clav - IV/PO (GI ADEs, LFT) pip/taz - broadest spectrum ticar/clav - amp/sul - MDR Acinetobacter baumannii

17 1 2. Cephalosporins 2.1 First generation generic leading brand admin. route adult g/day daily freq. cephalexin Ceforal PO cefazolin Cefamezin INJ 3-6 3

18 1 2. Cephalosporins 2.1 First generation - spectrum Gram-positive > Gram-negative MSSA, most Strep. few Gram-negatives (E. coli) X inactive vs. Enterococci, MRSA, anaerobes

19 1 2. Cephalosporins 2.1 First generation - clinical uses Skin and Skin Structure Infections (SSSIs) Surgical prophylaxis (cefazolin) Not 1 st choice for RTIs, UTIs, CNS infections why?

20 2 2. Cephalosporins 2.2 Second generation generic leading brand admin. route adult g/day daily freq. cefaclor Ceclor PO cefuroxime Zinnat PO* INJ cefonicid Monocef INJ * - cefuroxime axetil = prodrug (hydrolyzed post-absorption)

21 2. Cephalosporins Second generation - spectrum ~ Gram-positive + ~ Gram-negative Compared to 1 st generation: Broader vs. Gram-negative H. influenza, Moraxella catarrhalis,, Neisseria spp. Nearly equivalent vs. Gram-positive MSSA, some Strep. X Inactive vs. clinically-significant anaerobes

22 2. Cephalosporins Second generation - clinical uses Empiric Tx of CA-RTIs - Streptococcus pneumonia - Haemophilus influenza - Moraxella catarrhalis Uncomplicated UTIs (narrower: cotrimoxazole) SSSIs (narrower: cephalexin)

23 2. Cephalosporins Third generation generic leading brand admin. route adult g/day daily freq. ceftriaxone Rocephin INJ ceftazidime Fortum INJ cefotaxime Claforan INJ cefixime Supran PO

24 2. Cephalosporins Third generation - spectrum Gram-negative > Gram-positive Many ß-Lactamases (not ESBL) Gram-negative rods Strep. pneumoniae X Inactive vs. Enterococci, MRSA (MSSA - partial), X Inactive vs. clinically-significant anaerobes

25 2. Cephalosporins Third generation ceftazidime: Potent anti-pseudomonal Stable vs. many ß-Lactamases (not ESBL ) X Inactive vs. Staph, less active vs. Strep.

26 2. Cephalosporins 32.3 Third generation ceftriaxone: t1/2~8hr ( 1-2/d) Renal + hepatic elimination Bilirubin in age<1mo ceftriaxone, cefotaxime: - significant biliary penetration - peritonitis

27 2. Cephalosporins Third generation - clinical uses Empiric/specific Tx of various nosocomial infections Important role in: Spontaneous Bacterial Peritonitis Meningitis - Pseudomonal - Meningococcal - Pneumococcal

28 2. Cephalosporins Fourth generation Generic cefepime leading brand Maxcef admin. route INJ adult g/day 4-6 daily freq. 2-3

29 2. Cephalosporins Fourth generation - spectrum Extended Gram-positive and Gram-negative: zwitterionic affinity to PBPs stability vs. most β-lactamases (ESBL?) X Moderately active vs. Pseudomonas X Inactive vs. Enterococci, MRSA, anaerobes

30 2. Cephalosporins Fourth generation - clinical use Empiric/specific Tx of nosocomial infections

31 3. Monobactam generic leading brand admin. route adult g/day daily freq. aztreonam Azactam INJ 3 3

32 3. Monobactam Spectrum Aerobic Gram-negatives X Moderately anti-pseudomonal Stable vs. most β-lactamases (not ESBL) Clinical uses Empiric Alternative to aminoglycosides Alternative in penicillin/cephalosporin allergy

33 4. Carbapenems generic leading brand admin. route adult g/day daily freq. imipenem Tienam INJ meropenem Meronem INJ 3 3 ertapenem Invanz INJ 1 1 Stable vs. most ß-lactamases, including ESBL PAE vs. Gram-positive AND Gram-negative

34 4. Carbapenems Spectrum Gram-positive (X MRSA) Gram-negative Anaerobes Clinical uses ESBL; other MDR Empiric/specific Tx of various nosocomial infections

35 imipenem 4. Carbapenems + cilastatin (DHP-1 inhibitor) GI disturbances Impaired renal function Seizures ~ 0.5% higher??

36 4. Carbapenems meropenem Not liable to DHP degradation Seizures ~ 0.7% valproate levels Vs. imipenem: - minor microbiological variance - CNS penetration - nephrotoxicity

37 4. Carbapenems ertapenem Not liable to DHP degradation Seizures ~ 0.5% Once-daily (t1/2~4hr) (3mo-12yr: BID) Pseudomonas aeruginosa: inherent resistance Less suitable for empiric Tx Resistance-inducing?