Inhibitors of DNA Synthesis or Integrity
Cell wall inhibitors cannot kill all bacteria because some bacteria lack a cell wall. Other bacteria have unique structures that inherently resist the accumulation or action of cell wall inhibitors. However, bacteria, in preparation for cell division, must replicate their double stranded DNA. To facilitate replication, topoisomerase type II, a bacterial DNA gyrase, must first unwind and separate, and then reassemble the original DNA during the process.53
In the replication process, bacteria must synthesize folate. Its synthesis begins with the formation of dihydropteroic acid from pteridine and para-aminobenzoic acid (PAPA), a reaction catalyzed by dihydropteroate synthase (Figure 7).32 Dihydropteroic acid and glutamate condense to form dihydrofolate (DHF).32 Dihydrofolate reductase (DHFR) reduces DHF to tetrahydrofolate (THF). THF is an essential cofactor in the synthesis of DNA, RNA, and proteins (Figure 7).32
Figure 7. Folate Synthesis.
Modified from Harbison H, Rose HS, Coen DM, Golan DE. Principles of antibacterial and antineoplastic pharmacology. In Golan DE, Tashjian, Jr. AH, Armstrong EJ, Armstrong AW. Ed. Principles of pharmacology. The pathophysiologic basis of drug therapy. 2nd ed. 2008. Wolters Kluwer/Lippincott Williams & Wilkins. Baltimore, MD.32
Fluoroquinolones block topoisomerase type II activity and disrupt the integrity of bacterial DNA.53-57 They are bactericidal in susceptible organisms and are primarily active against aerobic gram-positive and gram-negative cocci and bacilli.53-57 The newer agents (e.g., moxifloxacin) have some anaerobic activity.11,58,59 Fluoroquinolones are indicated for the treatment of infections with designated, susceptible bacteria and are not empirical options in treating odontogenic infections.54-56
Metronidazole is a pro-drug. One of its metabolite directly binds to bacterial DNA, causes loss of its helical structure, and effects strand breakage.45,60,61 It is bactericidal in susceptible organisms and is active against most obligate anaerobes. However, it lacks clinically relevant activity against obligate aerobes and facultative anaerobes.61,62 Metronidazole, in combination with an agent active against aerobic/facultative organisms (e.g., a penicillin), is an empirical option in treating odontogenic infections.61,62"
Metronidazole is well absorbed after oral administration and reaches peak plasma concentrations in 1 to 2 hours.61 It is distributed to most body fluids and tissues, including bone; crosses the placenta, and reaches concentrations in saliva and human milk similar to those found in plasma.61 The drug is metabolized by hepatic oxidation and glucuronic conjugation.61 The major route of elimination of metronidazole and its metabolites is via the kidneys.61
Sulfamethoxazole (SMX) and trimethoprim (TMP), block succeeding steps in folate synthesis (see Figure 7).32,63 SMX-TMP formulations are bacteriostatic in susceptible organisms. It has activity against a broad spectrum of aerobic gram-positive and gram-negative organisms, but it is not active against anaerobes.63 SMX-TMP does not have the requisite spectrum to be considered an empirical option in treating odontogenic infections.