BETA-LACTAM ANTIMICROBIAL AGENTS Alan M. Stamm, M.D. October 23, 2002

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

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

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.

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

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

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

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)

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.

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.

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.

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.

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 3 rd generation cephalosporins

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.

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

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

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

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

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

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

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

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

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

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.

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

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.

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

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

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

Selection of Antibiotics - 4 Public health considerations: –prevention of transmission –induction of resistance –cost

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

Urinary Tract Infections Pyelonephritis: –ceftriaxone 2 g IV qd initially if hospitalized

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

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 g IV q 6 hours

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

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

Surgery - Prophylaxis Cardiovascular: –cefazolin 1 g IV once minutes prior to procedure

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.