Medical Pharmacology Topics
All clinically used beta-lactams contain a four-member ring in which steric constrains or chemical substituets activate the beta-lactam bond which blocks peptidoglycan synthesis. Peptidoglycan is formed of parallel glycan strands external to bacterial cells, and cross linked by peptides to form a highly rigid structure. Precursors are attached to an existing glycan strand in a reaction catalyzed by transglycolase, then the peptide components are cross-linked in a reaction catalyzed by transpeptidase. The beta lactams irreversibly inhibit transpeptidase.
Beta-lactams may release autolysin activity (?), resulting in lysis of bacteria (i.e. bactericidal effect). They also attack multiple targets called penicillin binding proteins (PBPs). Some PBPs are transpeptidases, others are D-alanine carboxypeptidases, thought to be involved in cell wall remodeling. Some beta-lactams have higher affinity for particular PBPs, with the most critical targets usually being PBP-1 (transpeptidase), PBP-2 (maintains rod shape) and PBP-3 (required for septum formation).
Beta-lactams can be classified into penicillins, cephalosporins, cephamycins, carbapenems, carbacephems, and monobactams.
There are two mechanisms of resistance to beta-lactams: altered PBPs and beta-lactamase. PBPs from Streptococcus pneumoniae, MRSA, Enterococcus faecium, Enterococcus faecium and Enterococcus hirae bind poorly to all members of the beta lactam family.
The
primary resistance in S. aureus, Moraxella catarrhalis, Neisseria
gonorrhea is their production of beta-lactamase These enzymes destroys both
narrow and broad spectrum penicillins, although nafcillin and related drugs
resist the action of S. aureus penicillinase. Periplastic beta-lactamases
of gram-negative bacteria destroy many beta-lactam antibiotics, but certain
drugs are relatively resistant: imipenem, cefoxitin, 3rd generation cephalosporins
and 4th generation cefepime.
Bacteriostatic antibiotics (chloramphenicol, macrolides, tetracyclines) interfere with the actions of beta-lactams, while they are inactivated by low pH, dextrose and aminoglycosides. Oral contraceptives (estrogens) are inactivated by beta-lactams.
Although the aminoglycosides are chemically incompatible with the beta-lactams, they have synergistic antibacterial action. Probenecid blocks the excretion and prolongs effective blood levels of beta-lactams, except for the cephalosporins. Some penicillins inhibit platelet aggregation, thus potentiating anticoagulants, thrombolytics and platelet inhibitors. Beta-lactamase inhibitors like clavulanic acid, sulbactam and tazobactam block the destruction of the beta-lactam antibiotic. Clear synergy or additivity may be produced by these combinations:
Some beta-lactams cause interference with laboratory tests. Large doses of cephalosporins often provoke a positive Coomb's test (antiglobulin). False positives or false elevated values of the urinary glucose test based on copper sulfate may be caused by many cephalosporins. Prothrombin time (PT) may be prolonged because all cephalosporins inhibit gut flora that produce vitamin K. Beta-lactam containing an N-methylthiotetrazole side chain directly cause hypoprothrombinemia.
Beta-lactams present many side effects: allergic, GI, CNS, hematological, renal, superinfections and others. They are potent haptens, capable of provoking strong allergic reaction after covalent linkage to protein. Neutropenia, producing sore throat and fever, may occur at high doses of beta-lactams. Agents with the N-methylthiotetrazole side chain may lead to platelet dysfunction and bleeding. Beta-lactams are GABA antagonists and may produces irritability, tremors or seizures at high CNS concentrations. Imipenem commonly causes dizziness or headache, but seizures are rare.
Gastrointestinal irritation producing mild diarrhea, nausea and vomiting may occur with any oral and some parenteral beta-lactams, but is more common with the amoxicillin/clavulanic acid combination. Ceftriaxone may cause biliary slugging producing pain, nausea and vomiting. Oral candidiasis is common with prolonged therapy, especially with broad spectrum drugs. Ampicillin and other broad spectrum oral penicillins can cause antibiotic-associated colitis due to superinfection with Clostridium difficile (metronidazole or vancomycin are use to control it). Up to 10% of patients receiving 3rd generation cephalosporins or imipenem may suffer secondary infections with resistant bacteria or yeast.
Interstitial nephritis is uncommon with current drugs but dosage of cephalosporins and others must be adjusted based on creatinine clearance. Exceptions include cefoperazone, cefriaxome, penicillin V, penicillin G, ampicillin and amoxicillin. Electrolyte imbalance is uncommon but may occur with certain salt forms of penicillins. Hypernatremia may occur with penicillin G and others administered as a sodium salt, leading to congestive heart failure. Hyperkalemia may occur if the potassium salt is used, leading to fatal arrhythmias.
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