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• 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
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