BETA-LACTAMANTIMICROBIAL AGENTS

Alan M. Stamm, M.D.

astamm@uabmc.edu

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 3rd 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 3.375 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 30-60 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.