Antimicrobial Pharmacology - NCLEX-PN

Acyclovir is converted to acyclovir-triphosphate and incorporated into the synthetic pathway for viral DNA as a guanosine molecule. The initial phosphorylation of acyclovir is carried out by viral thymidine kinase. Acyclovir has a higher affinity for viral thymidine kinase than mammalian thymidine kinase. Therefore, acyclovir is specifically effective in virally infected cells.

All of the drugs are antifungal agents but only flucytosine has been associated with bone marrow suppression and synergizes with other drugs which suppress bone marrow functions. Miconazole and ketoconazole may produce hepatotoxicity, gastro-intestinal upset and headaches. Amphotericin B may produce nephrotoxicity while itraconazole is associated with gastro-intestinal upset and rare liver dysfunction.

Amantadine only works after viral attachment to the cell, preventing viral uncoating. It is also believed to interfere with viral mRNA production. Amantadine is effective against influenza virus A.

All the listed agents are synthetic analogues, except interferon, which is a glycoprotein produced by many types of mammalian cells. It has been shown to be useful in treatment of hepatitis, papilloma viruses, hairy-cell leukemia and AIDS-related Kaposi's sarcoma. Idoxuridine, as its name implies, is a synthetic pyrimidine analog, which inhibits viral DNA polymerase. Zidovudine and zalcitabine are also synthetic pyrimidine analogs but they inhibit reverse transcriptase and act as chain terminators. Acyclovir is a synthetic purine analog which requires viral thymidine kinase to be converted to an active phosphorylated form, which then, inhibits viral DNA polymerase.

Loa loa is an extra-intestinal nematode, which may migrate to the CNS, causing encephalitis. Diethylcarbamazine is successful in treating Loa loa but will exacerbate the encephalitis unless steroids are used first to treat the symptoms of the encephalitis. Other side effects of diethylcarbamazine may be due to rapid death of nematodes and release of various toxic substances. Symptomatic treatment might be appropriate with a number of pharmacological classes, but most symptoms will resolve as the body is cleared of dead and dying nematodes.

Amantadine affects the central nervous system, producing mild, reversible disturbances. High dosages have been reported to induce seizures

Amoxicillin inhibits bacterial cell wall synthesis by interfering with the formation of cross-links between peptidoglycan polymer chains.

Macrolides, streptogramins, and clindamycin all work by inhibition of the 50S subunit of bacterial ribosomes. Tetracyclines have a similar mechanism of action, but instead affect the 30S unit of bacterial ribosomes.

Polymyxin antibiotics function by interfering with phospholipid function in bacterial cell membranes. After binding to lipopolysaccharide (LPS) in the outer membrane, polymyxins' hydrophobic tail causes damage to both the inner and outer membranes of Gram-negative bacteria.

Rifampin inhibits bacterial RNA synthesis by inhibiting RNA polymerase. This prevents the transcription of proteins within the bacterial cell, leading to cell death.

Hepatotoxicity and potential liver failure are the most serious potential adverse effects of rifampin use. Patients on this medication must establish baseline liver function tests and be monitored for liver damage. None of the other conditions listed are associated with rifampin use.

Aminoglycoside antibiotics are used to treat Gram negative bacteria. They have not been shown to be effective against Gram positive bacteria and are not antifungal. Recall the major difference between the Gram negative and positive bacteria are their cell wall composition; Gram negative have a small proportion of peptidoglycan and a high proportion of lipopolysaccharide, while Gram negative bacteria have a large proportion of peptidoglycan.

The only aminoglycoside antibiotic among those listed is streptomycin. Other examples of aminoglycosides include tobramycin and gentamicin. All aminoglycosides either end in -mycin or -micin. However, this suffix is not exclusive to aminoglycosides. It is also seen in the macrolides: erythromycin and azithromycin and both macrolides, and in lincosamides such as clindamycin.

Aminoglycoside antibiotics such as streptomycin and gentamicin have been associated with vestibular toxicity and hearing loss. Aminoglycosides remain in inner ear fluids longer than serum and can have a latent ototoxic effect, causing hearing loss even after the antibiotic has been discontinued. None of the other antibiotics listed are associated with ototoxicity.

Vancomycin is the correct answer. Antibiotics that inhibit bacterial cell wall synthesis include the beta-lactam antibiotics (penicillins and cephalosporins), vancomycin, and bacitracin. Synthesis of the bacterial cell wall takes place in 4 steps: 1) Precursors of the cell wall are synthesized within the bacterial cytoplasm. 2) The precursors are transported across the cell membrane. 3) Outside the cell membrane, the precursors are linked together to form chains called peptidoglycans. 4) The peptidoglycan chains are cross-linked to form a rigid, stable cell wall.

• Beta-lactam antibiotics act by inhibiting step 4, the cross-linking of peptidoglycans. They also activate hydrolytic enzymes, which degrade already-existing cell walls. This usually results in lysis and death of the bacteria. (Mutant bacterial strains, which lack the hydrolytic enzyme, are not killed by beta-lactams, but their growth is arrested)
• Vancomycin inhibits step 3, the elongation of the peptidoglycan chains
• Bacitracin interferes with step 2, the transport of precursors across the cell membrane

Aminoglycosides, tetracyclines, macrolides (erythromycin and its relatives), clindamycin, and chloramphenicol are inhibitors of bacterial protein synthesis. They act by binding to ribosomal subunits.

• Aminoglycosides bind to several sites on the bacterial ribosome. They interfere with the movement of ribosomes along the strand of mRNA. They also induce misreading of the mRNA so that incorrect amino acids are incorporated into the elongating peptide chain
• Tetracyclines bind to the 30S ribosomal subunit. Macrolides, clindamycin, and chloramphenicol bind to the 50S subunit. These antibiotics interfere with the attachment of tRNA to the ribosome, thus preventing the addition of amino acids to the peptide chain

Sulfonamides and trimethoprim act by inhibiting the synthesis of folic acid. Certain bacteria synthesize folic acid from precursors by a series of enzyme-catalyzed reactions. Sulfonamides and trimethoprim block different steps in this synthetic pathway by binding competitively to different enzymes. When used together, their actions are synergistic (mammals do not synthesize folic acid, but require it as a vitamin; therefore, these drugs do not interfere with metabolism in mammalian cells).

Quinolones (e.g. norfloxacin and ciprofloxacin) inhibit bacterial nucleic acid synthesis by interfering with DNA gyrase, a bacterial enzyme that catalyzes supercoiling of DNA.

Polymyxins have a detergent action that disrupts bacterial cell membranes. They can also have the same toxic effect on mammalian cells; for this reason, they are seldom used except in topical preparations.

Initial treatment for pulmonary or extrapulmonary tuberculosis is isoniazid (INH), rifampin (RMP), and pyrazinamide (PZA) as a short-course intensive daily regimen for 2 months, followed by INH and RMP for 4 more months. The most common side effects of rifampin are reddish urine and stool, saliva, sweat, tears, diarrhea, joint pain, back pain, swelling of feet and/or legs, and blood in urine. Hyperuricemia is a major toxic effect of pyrazinamide; other toxic effects include fever, indigestion, urticaria, photosensitivity, and joint pain. Isoniazid can cause polyneuropathy, jaundice, muscle pain, confusion, and unsteady walk.

The tetracycline antibiotics possess a wide range of antimicrobial activity against gram-positive and gram-negative bacteria, as well as Rickettsia, Mycoplasma, Chlamydia, Ureaplasma, some atypical mycobacteria, and amoebae. These drugs are primarily bacteriostatic and act by inhibiting microbial protein synthesis. The tetracyclines, after active transport into the cell, bind to the 30 S ribosomal subunit. This prevents the access of aminoacyl tRNA to the acceptor site on the mRNA-ribosome complex, inhibiting the addition of amino acids to the growing peptide chain. This effect is, for the most part, reversible and removal of the drug results in loss of action.

The other mechanisms listed are utilized by other antimicrobial agents. For example, all beta-lactam drugs are selective inhibitors of cell wall synthesis, and therefore active against growing bacteria. Sulfonamides are structural analogs of PABA that is necessary for folic acid synthesis. By competitive inhibition, the drug interferes with folic acid synthesis. Folic acid is an important precursor to the synthesis of nucleic acids. Quinolones are examples of antibiotics which inhibit bacterial DNA synthesis by blocking of the DNA gyrase. Antibiotics—polymyxin and colistin—and the antifungal agent amphotericin B act by inhibiting cell membrane function.

Tenofovir is categorized as a nucleoside analogue reverse transcriptase inhibitor (NRTIs). An NRTI’s mechanism of action is to block reverse transcriptase, an enzyme that enables the human immunodeficiency virus 1 (HIV-1) to flourish. This enzyme aids the HIV virus in making a copy of DNA from the viral RNA, and this DNA is incorporated into the host genome. The effectiveness has been found in a review conducted by the Centers for Disease Control and Prevention to be so effective that “pre-exposure prophylaxis can potentially be a vital option for HIV prevention in pearly at very high risk for infection, whether through sexual transmission or injecting drug use.”

In regards to Post-Exposure Prophylaxis (PEP), The United States Public Health Service recommend the use of tenofovir, emtricitabine, or a combination drug of these two medications—plus raltegravir for PEP in occupational exposure scenarios.

Transport antibiotics act as carriers of ions across membranes (e.g. valinomycin) or by forming channels in the membrane that allow ions to cross the membrane (example-gramicidin A). Gramicidin affects cell membrane permeability while polymyxin B interferes with bacterial cell wall production. These transport antibiotics, also called ionophores, are secreted by many microorganisms and disable other species by making their membranes permeable to ions. These antibiotics show high specificity for specific ions. Carriers bind ions on one side of the membrane and shuttle the ion across the membrane. The carrier antibiotics are donut shaped with a hydrophilic center where the ion binds and a hydrophobic periphery that allows the antibiotic to traverse the membrane.

The channel forming antibiotics form a β-helix that forms a "hole" in the membrane through which ions can move. These channels open and close and the accompanying ion movements can be detected by measuring the conductance across the membrane. The transport antibiotics have been a very useful tool for cell biologists and physiologists studying the movement of ions across biological membranes under a variety of conditions. Both types of antibiotics insert into the lipid bilayer but do not alter the composition of the membrane lipids. Penicillin is an antibiotic that acts by inhibiting cell wall synthesis by inhibiting the enzyme glycopeptide transpeptidase. Neomycin is an aminoglycoside antibiotic that binds to the 30S subunit of the ribosome inhibiting protein synthesis.