Medical Pharmacology Topics   

Antibiotics: Batericidal Agents

The beta-lactams and quinolones are bactericidal agents. The beta-lactams interfere with cell wall homeostasis, while quinolones are topoisomerase inhibitors. These drug classes are named by theier reactive chemical groups. The beta-lactams contain four rings in which steric constrains or chemical substituents activate the beta-lactam bond, making the compound reactive. The newer quinolone antibiotics like crproflaxin and levoflaxin contain a fluorine atom attached t the reactive quinolone ring.

Beta-Lactams Mechanism of Action

Beta-lactams act mainly by blocking the synthesis of peptidoglycan, a component of the cell wall formed of parallel glycase strands cross-linked by peptides. Peptidoglycan synthesis includes cytoplasmic rections to form precursors, catalyzed transglycolase, and cross-linking of peptide components catalyzed by transpeptidase. The transpeptidase step is specifically and irrevrsibly inhibited by beta-lactams. They attack multiple targets called penicillin binding proteins (PBPs), of which transpeptidase is the main example.

Mechanisms of resistance against the beta lactams include altered PBPs and production of beta-lactamases. PBPs in Streptococcus pneumoniae, methicillin-resistant Staph. aureus, Enterococcus faecium and E. hirae often bind pooly to beta-lactamase (50% of the strains may be resistant). Production of beta-lactamases in the primary mechanism of resistant in S. aureus, Moraxella catarrhalis and Neisseria goonorrhea.

The beta-lactams have many drug interactions. Bacteriostatic antibiotics (chloramphenicol, macrolides and tetracyclines) interfere with the action of beta-lactams. The aminoglycoside antibiotics have synergistic antibacterial action byt are chemically incompatible with the beta-lactams. Low pH and destroxe solution inactivates beta lactams. Probenecid bloks their excretion thus prolonging effective blood levels of most beta-lactams (excepts a few cephalosporins).

Beta-lactams are potent haptens and may cause skin rashes (common) or anaphilaxis (rare) in allergic patients. Up to 10% of patients receiving 3rd generation cephalosporins (i.e. ceftazidine, ceftriaxone) or imipenem may suffer secondary infections.

Renal levels of beta-lactams are generally high (may route of excretion) but CNS levels are low since organic acids are actively transported from the CNS. Still, tyhey are GABA antagonists and will cause irritability, tremors or seizures at high concentrations. GI irritation, oral candidiasis, and inflamation at the site of injection may also occur.

Beta-Lactam Agents

The beta-lactams are classified according to their chemical structures as either penicillins or cephalosporins. The penicillins include penicillin G, penicillin V, nafcillin, amoxicillin and ampicillin. Parenteral nafcillin is indicated to treat penicillinase-producing S. aureus. It is primarily excreted by the liver, contrary to the primary renal excretion of most beta-latams.

Parenteral penicillin G is indicated to tret S. pneumoniae, non-penicillinase strains of S. aureus, oral anaerobes, Neisseria meningitidis, and Treponema pallidum. It may cause hypernatremia or hyperkalemia if administered as the sodium or potassium salt. At hign doses, electrolyte impalance may cause heart failure or fatal arrhythmias.

Oral penicillin V is indicated to treat S. pneumoniae, non-penicillinase strains of S. aureus, and Enterococci. It may block estrogen, thus antagonizing oral contraceptives.

Parenteral or oral ampicillin is indicated to treat S. pneumoniae, Bacteriorides fragilis (in combination with sulbactam), Hemophilus influenzae (alone or in combination with sulbactam), Proteus mirabilis and Enterococci. Sulbactam is a beta-lactamase inhibitor that potentiates the action of ampicillin against beta-lactamase producing strains. Ampicillin interferes with the action of oral contraceptives and may cause antibiotic-associated colitis.

Oral amoxicillin is indicated to treat B. fragilis (in combination wit clavulanic acid), H. influenzae (alone or in combination with clavulanic acid), and P. mirabilis (in combination with clavulanic acid. Clavulanic acid is a beta-lactamase inhibitor that potentiates the action of amoxicillin against beta-lactamase producing strains. GI irritation is common with the amoxicillin/clavulanic acid combination. Amoxicillin is also an estrogen blocker.

The cephalosporins include cefazolin, ceftazidine, ceftriaxone and imipenem. These agents interfere with several laboratory tests. Large doses may provoke a false positive Coomd's test (antiglobulin) or glucose urinary test (copper sulfate based). Prothrombin time may be prolonged due to inhibition of gut flora that produces vitamin K.

Parenteral cefazolin is indicated to treat Escherichia coli, Klebsiella pneumoniae and P. mirabilis. Parenteral ceftazidine is indicated to treat E. coli, K. pneumoniae, P. mirabilis and P aeruginosa.

Parenteral ceftriaxone is indicated to treat S. pneumoniae, N. meningitidis, N. gonorrhea, H. influenzae, E. coli, K. pneiumoniae, Enterobacter, and P. mirabilis. It may cause biliary sludging (pain, nausea, vomoting), and is primarily eliminated by the liver.

Quinolones

The quinolone antibiotics are bactericidals of rapid effectys that inhibit baterial topoisomerases II and IV. Topoisomerase II is the primary target, promoting double-strand breaks in bacterial DNA. By inhibitin topoisomerase IV, ecadenation of daughter bacterial cells is blocked. The quinolones will also inhibit mammalian topoisomerases I and II, but at much higher concentration than needed to inhibit baterial topoisomerases.

The representative quionolone agents are nalidixic acid, ciproflaxin and levoflaxin. Nalixilic acid is an older agent that does not differentiate much between bacterial and hosts targets, and is useful only to treat urinary infections (where it accumulates).

Ciproflaxin and levoflaxin are indicated for urinary track infections, pneumonia and bronchitis caused by gram-negative aerobes. Ciproflaxin is also indicated in N. gonorrhea and Pseudomonas. Levoflaxin is indicated for community-aquired pneuminia.

The quinolones are widely distributed to most tissues, and ciproflaxin distributes to the CNS. Tissue levels may exceed plasma levels. They are eliminated mostly in urine, and renal impairment requires dose adjustments.The main adverse reactions are due to CNS stimulation: headache, dizziness, insomnia and nervousness. Seizures are rare but may occur in sensitive patients or those usig alcohol or theophilline. Pain, nausea, vomiting, tendonitis and tendon rupture are also common. Unpredictable acute liver failure is associated with certain quinolones.

Drugs containing metals decrease the absorption of quinolones. Cyproflaxin and others compete for P450, thus slowing theophilline metabolism. Warfarinm may havee greater anticoaguant effects with fluoroquinolones. Quinolones are contraindicated in patients taking antiarrythmics, antidepresants or other drugs that prolong the QT interval.

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