BETA-LACTAM ANTIMICROBIAL AGENTS

1. BETA-LACTAMANTIMICROBIAL AGENTS Alan M. Stamm, M.D. astamm@uabmc.edu October 23, 2002

2. Beta-lactams • Each agent has this 4-member ring which is essential for antibacterial activity.

3. Outline • Mechanism of action. • Mechanisms of resistance. • Pharmacology. • Adverse effects. • Classes of beta-lactams. • Clinical uses.

4. Mechanism of Action - 1 • Interference with cell wall synthesis: prevention of cross-linking of linear peptidoglycan strands by inhibition of transpeptidase, carboxypeptidase, or endopeptidase. • Inhibition occurs by competitive binding to enzyme located beneath cell wall on inner surface of cell membrane.

5. Mechanism of Action - 2 • Structural weakening leads to cell death. • Effect is bactericidal or lethal, not bacteriostatic or inhibitory. • However, the effect depends on: • active multiplication/division of bacteria • beta-lactam penetration of cell wall • affinity of beta-lactam for enzyme, a.k.a. penicillin binding protein (PBP) • activation of autolytic system of bacteria

6. Mechanisms of Resistance - 1 • Production of beta-lactamase: bacterial enzyme catalyzing hydrolysis of beta-lactam ring. • chromosomal vs. plasmid DNA • one vs. multiple in a single bacterium • dozens exist with varying spectrums • e.g., Staphylococcus aureus - penicillinase

7. Mechanisms of Resistance - 2 • Decreased access of drug to target penicillin binding protein. • exclusion by outer membrane protein channels = porins • augmented efflux mechanisms • e.g., Enterobacter species • e.g., Pseudomonas aeruginosa

8. Mechanisms of Resistance - 3 • Alteration of penicillin binding protein: decreased affinity, less effective competitive inhibition. • clinical isolates are often broadly resistant to antibacterial agents • e.g., drug resistant Streptococcus pneumoniae • e.g., methicillin resistant Staph. aureus (MRSA) • e.g., vancomycin resistant Enterococci (VRE)

9. Pharmacology - 1 • Absorption: some are acid stable and absorbed in the duodenum - peak serum level in 1-2 hours; many are administered only intravenously. • Half-life: most are short, ~1 hour; with serious disease, these must be administered 4-6 times per day or as a continuous infusion.

10. Pharmacology - 2 • Elimination: primarily by glomerular filtration and tubular secretion; decreased in patients with renal impairment; reduce dose if creatinine clearance <40-50 ml/min. • Biliary excretion is predominant for nafcillin and significant for ureidopenicillins.

11. Efficacy • A principal determinant is T>MIC = the proportion of time for which beta-lactam level at the site of infection exceeds the minimal inhibitory concentration of the bacterium.

12. Adverse Effects - 1 • IgM-mediated erythematous, maculopapular, trunkal rash. • Diarrhea, Clostridium difficile colitis. • Hemolytic anemia, neutropenia, thrombocytopenia, bleeding. • Fever. • Interstitial nephritis. • Anicteric hepatitis, cholestatic jaundice. • Seizures.

13. Adverse Effects - 2 • Comparatively safe. • Safe in pregnancy. • Phlebitis from IV administration. • Superinfection from alteration of normal flora. • e.g., thrush (oral candidiasis) • Selection of resistant bacteria. • particularly 3rd generation cephalosporins

14. Allergy • IgE-mediated urticaria, anaphylaxis. • From 1-10% report allergy to penicillin; 10-30% of these have a positive skin test. • Cross-reactivity occurs with other beta-lactams: 10% with cephalosporins. • Detection: history, skin testing - penicilloyl-polylysine and penicillin G. • Management: avoidance, substitution, desensitization - PO or IV.

15. Penicillins - 1 • Natural penicillins: • for streptococci, normal oral flora, meningococci, anaerobes • benzylpenicillin = penicillin G • aqueous Na+ or K+ crystalline IV • procaine IM • benzathine (Bicillin) IM • phenoxymethylpenicillin = penicillin V PO

16. Penicillins - 2 • Penicillinase resistant penicillins: • for methicillin susceptible Staphylococcus aureus (MSSA) • nafcillin IV • cloxacillin PO • dicloxacillin PO

17. Penicillins - 3 • Extended spectrum penicillins: • more broadly active against gram-negatives • aminopenicillins • ampicillin IV • amoxicillin PO • ureidopenicillins (acylaminopenicillins) • piperacillin IV

18. Penicillins - 4 • Penicillin + beta-lactamase inhibitor combinations: • even more active against gram-negatives • ampicillin + sulbactam (Unasyn) IV • piperacillin + tazobactam (Zosyn) IV • amoxicillin + clavulanate (Augmentin) PO

19. Cephalosporins - 1 • 1st generation: • active against streptococci, methicillin susceptible staphylococci, some gram-negatives • cephapirin (Cefadyl) IV • cefazolin (Ancef, Kefzol) IM, IV • cephalexin (Keflex) PO

20. 2nd generation: more broadly active against gram-negatives cefuroxime (Kefurox, Zinacef) IV, (Ceftin) PO 2nd generation: added activity against anaerobes cefotetan (Cefotan) IV Cephalosporins - 2

21. Cephalosporins - 3 • 3rd generation: • much broader and better activity against gram-negatives (but less vs. staphylococci) • ceftriaxone (Rocephin) IV • cefotaxime (Claforan) IV • few have added activity against Pseudomonas aeruginosa, e.g., ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime) IV

22. Cephalosporins - 4 • 4th generation: • activity against a broader range of gram-negative bacilli; better penetration of outer membrane and less affinity for beta-lactamases • cefepime (Maxipime) IV

23. Cephalosporins - 5 • Cephalosporins are not useful in the treatment of infections due to methicillin resistant Staphylococcus aureus (MRSA), Enterococci, or Listeria monocytogenes.

24. Carbapenems • The most broadly active of antibacterial agents - streptococci, MSSA, gram-negatives, anaerobes: • imipenem/cilastatin (Primaxin) IV • meropenem (Merrem) IV • Induce production of beta-lactamases by gram-negative bacilli. • Hold in reserve – do not use routinely.

25. Carbacephems • Greater chemical stability in solution. • Activity similar to 2nd generation cephalosporin cefuroxime: • lorcarbef (Lorabid) PO • No need to use this class.

26. Monobactams • Active against aerobic gram-negative bacilli; resistant to hydrolysis: • aztreonam (Azactam) IV • An alternative to an aminoglycoside. • Do not induce production of beta-lactamases. • Minimal risk of reaction in those allergic to penicillins.

27. Selection of Antibiotics - 1 • Patient factors: • history of antibiotic allergy • pharmacogenomic profile • recent antibiotic exposure • age and organ dysfunction • status of host defenses • disposable income

28. Selection of Antibiotics - 2 • Infectious disease factors: • source of acquisition - community, travel, occupation, nosocomial • site of infection - likely pathogens and their usual susceptibility patterns • severity of infection

29. Selection of Antibiotics - 3 • Antibiotic factors: • cidal vs. static • route of administration & schedule of dosing • tissue penetration • spectrum of antimicrobial activity • local pattern of antimicrobial resistance or proven susceptibility • potential adverse effects & drug interactions

30. Selection of Antibiotics - 4 • Public health considerations: • prevention of transmission • induction of resistance • cost

31. Respiratory Infections • Pharyngitis due to Streptococcus pyogenes (Group A streptococci): • penicillin V or amoxicillin 250 mg PO tid x 10 days • Community acquired pneumonia: • ceftriaxone 2 g IV qd (often with a macrolide) initially if hospitalized

32. Urinary Tract Infections • Pyelonephritis: • ceftriaxone 2 g IV qd initially if hospitalized

33. Sexually Transmitted Diseases • Gonorrhea: • ceftriaxone 125 mg IM once • Syphilis: • early stages - benzathine penicillin G 2.4 million units IM once • neurosyphilis - aqueous penicillin G 3 million units IV q 4 hours x 10 days

34. Skin / Soft Tissue Infections • Cellulitis: • nafcillin 1 g IV q 4 hours initially if hospitalized or cephalexin 500 mg PO qid • Diabetic foot infection: • cefotetan 2 g IV q 12 hours or piperacillin/tazobactam 3.375 g IV q 6 hours

35. Central Nervous System Infections • Meningitis: • ampicillin 2 g IV q 4 hours + ceftriaxone 2 g IV q 12 hours + vancomycin initially pending results of cultures and susceptibility tests

36. Endocarditis • Due to viridans Streptococci: • ceftriaxone 2 g IV qd + gentamicin x 2 weeks • Due to Enterococcus fecalis: • ampicillin 2 g IV q 4 hours + gentamicin x 4-6 weeks

37. Surgery - Prophylaxis • Cardiovascular: • cefazolin 1 g IV once 30-60 minutes prior to procedure

38. Summary • Beta-lactam antibiotics are often the treatment of choice because of their efficacy and safety. • Learn how to use one agent from each of the classes. • Adjust your practice in accordance with changes in susceptibility.