β-lactams
ß-lactams Sub-families Penicillins Cephalosporins Monobactams Carbapenems
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
ß-lactams General PK A variable D wide M insignificant E mostly renal
General ADEs ß-lactams Allergic reactions (hypersensitivity) 0.005-0.01% % overall: 10%
ß-lactams General ADEs Penicillin-cephalosporin cross-sensitivity 1970s reports: ~10% beta-lactam ring
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
ß-lactams General ADEs GI - ~5% (ampicillin, cefuroxime) Interstitial nephritis - 1-2% Impaired liver function - 1-4%
daily freq. adult g/day admin. route leading brand generic sub-class 6 12-24mU INJ Penicillin penicillin G Natural Penicillins 2/4 2 PO Rafapen penicillin V 4 4 4-8 2 INJ PO Penibrin ampicillin Aminopenicillins 3 2.5-3 PO Moxypen amoxycillin -- -- -- -- -- -- -- -- methicillin oxacillin Penicillinaseresistant Penicillins 4 4 4-8 1-2 INJ PO Orbenil cloxacillin 3-4 12 INJ Baypen mezlocillin Extendedspectrum Ureidopenicillins 3-4 12 INJ Pipril piperacillin 1. Penicillins
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)
1.2. Aminopenicillins vs. Gram-negative PO bioavailability: ampi~40%, amoxi~90% amoxi - RTIs - H. pylori eradication protocols ampi (IV) Enterococci
1.3. Penicillinase-resistant Penicillins penicillin-resistant Staphylococci methicillin/oxacillin - resistance markers (MRSA/ORSA) cloxacillin MSSA (phlebitis)
1.4. Extended-spectrum Penicillins vs. Gram-negative and anaerobic piperacillin (anti-pseudomonal)
1.5. Penicillin + β-lactamase inhibitor amoxycillin + clavulanate (Augmentin ) ampicillin + sulbactam (Unasyn ) piperacillin + tazobactam (Tazocin ) ticarcillin + clavulanate (Timentin )
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
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
1 2. Cephalosporins 2.1 First generation generic leading brand admin. route adult g/day daily freq. cephalexin Ceforal PO 2-4 3-4 cefazolin Cefamezin INJ 3-6 3
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
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?
2 2. Cephalosporins 2.2 Second generation generic leading brand admin. route adult g/day daily freq. cefaclor Ceclor PO 0.75-1.5 3 cefuroxime Zinnat PO* INJ 0.5-1 2.25-4.5 2 3 cefonicid Monocef INJ 0.5-2 1 * - cefuroxime axetil = prodrug (hydrolyzed post-absorption)
2. Cephalosporins 2 2.2 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
2. Cephalosporins 2 2.2 Second generation - clinical uses Empiric Tx of CA-RTIs - Streptococcus pneumonia - Haemophilus influenza - Moraxella catarrhalis Uncomplicated UTIs (narrower: cotrimoxazole) SSSIs (narrower: cephalexin)
2. Cephalosporins 3 2.3 Third generation generic leading brand admin. route adult g/day daily freq. ceftriaxone Rocephin INJ 2-4 1-2 ceftazidime Fortum INJ 2-6 3 cefotaxime Claforan INJ 3-8 3-4 cefixime Supran PO 0.4 1-2
2. Cephalosporins 3 2.3 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
2. Cephalosporins 3 2.3 Third generation ceftazidime: Potent anti-pseudomonal Stable vs. many ß-Lactamases (not ESBL ) X Inactive vs. Staph, less active vs. Strep.
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
2. Cephalosporins 3 2.3 Third generation - clinical uses Empiric/specific Tx of various nosocomial infections Important role in: Spontaneous Bacterial Peritonitis Meningitis - Pseudomonal - Meningococcal - Pneumococcal
2. Cephalosporins 4 2.4 Fourth generation Generic cefepime leading brand Maxcef admin. route INJ adult g/day 4-6 daily freq. 2-3
2. Cephalosporins 4 2.4 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
2. Cephalosporins 4 2.4 Fourth generation - clinical use Empiric/specific Tx of nosocomial infections
3. Monobactam generic leading brand admin. route adult g/day daily freq. aztreonam Azactam INJ 3 3
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
4. Carbapenems generic leading brand admin. route adult g/day daily freq. imipenem Tienam INJ 2-4 3-4 meropenem Meronem INJ 3 3 ertapenem Invanz INJ 1 1 Stable vs. most ß-lactamases, including ESBL PAE vs. Gram-positive AND Gram-negative
4. Carbapenems Spectrum Gram-positive (X MRSA) Gram-negative Anaerobes Clinical uses ESBL; other MDR Empiric/specific Tx of various nosocomial infections
imipenem 4. Carbapenems + cilastatin (DHP-1 inhibitor) GI disturbances Impaired renal function Seizures ~ 0.5% higher??
4. Carbapenems meropenem Not liable to DHP degradation Seizures ~ 0.7% valproate levels Vs. imipenem: - minor microbiological variance - CNS penetration - nephrotoxicity
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?