Antibiotics that Inhibit Intermediary and Nucleic Acid Metabolism
I. Sulfonamides- Inhibitors of Folic Acid Metabolism
A. Structures- all single or double ring structures.
B. Mechanism- Bacteriostatic. Inhibits folic acid metabolism, depleting Tetrahydrofolate which is necessary for biosynthesis of purines (A & G), thymidine, and methionine. Mammals can get the folate they need from their diet; microbes can’t.
C. Pharmacology- Variable intestinal absorption among compounds. Many are absorbed well, while others are designed to stay in gut for intra-GI effects. Extensive binding to plasma proteins. Penetration of tissues is variable. CSF levels of the short-acting drugs vary from 30-80% of serum levels. Metabolism and inactivation occurs by acetylation on the N4 position by liver enzymes. Excreted in glomerulus, but partially reabsorbed in tubule. High concentration is achieved in the urine.
D. Adverse reactions-
1. allergic reactions- Rashes, drug fever, and vasculitis are common. Stevens-Johnson syndrome is a more severe blistering rash of the skin and mucous membranes. Can be fatal.
2. insoluble crystals- form in urinary tract. Try to drink more water & keep urine alkaline.
3. bone marrow suppression- anemia, neutropenia, and thrombocytopenia. These are often mild and well tolerated by normal Pts, but dangerous in AIDS Pts.
4. kernicterus- bilirubin-mediated damage to the basal ganglia due to bilirubin being kicked off of its albumin carrier. This only happens in those with inadequate hepatic conjugation systems (immature liver) and incompletely formed BBB, so don’t use it late in pregnancy or in newborns. You can use it in the first 2 trimesters if there isn’t a good alternative (ex. Toxoplasma gondii infection).
E. Resistance to Sulfa drugs- mechanisms include cellular impermeability, overproduction of dihydrofolate reductase, or production of mutant DHFR enzyme.
F. Individual Sulfonamides-
1. Short-acting- orally absorbable- both used for UTIs because of good uptake, rapid excretion, and high urine levels achieved.
a. sulfisoxazole- for UTIs, ear infections, and URIs. This + erythromycin = Pediazole. Good tissue penetration.
b. sulfamethazole- used as combo with trimethoprim (TMP) because their long half-lives match. Used for UTIs.
2. Poorly absorbed-
a. sulfasalazine- rarely used. Intra-GI tract agent. Broken down by gut flora to 5-aminosalicylate (good for ulcerative colitis) and sulfapyridine (gives adverse effects). Now there is an enteric coated 5-aminosalicylate called mesalamine that avoids the sulfa side effects.
3. Topical-
a. sulfacetamide- eye drops for conjunctivitis.
b. Silver sulfadiazine (Silvadene) for burns.
4. Long-acting-
a. sulfadoxine- used in combo with pyrimethamine for chloroquine-resistant malaria.
5. Combo-
a. Trimethoprim- Sulfamethoxazole (TMP-SMX) (Bactrim, Septra, co-trimoxazole)- synergistic combo Tx due to sequential blockade. Spectrum includes G(-), G (+), and some parasites (P. carinii). This drug reaches high concentrations in prostatic and vaginal fluid, so its good for Tx of infections in these areas.
II. Quinolones-
A. Structure- all two or three ring structures.
B. Mechanism- Inhibit DNA gyrase (topoisomerase II & IV) which is needed to unwind supercoiled DNA for gene expression. DNA gyrase has two subunits, A & B. Subunit A is the one with the quinolone binding site, but resistance mutations have been found on both subunits. Quinolones are bactericidal to G(-)bugs, even quiescent ones. Quiescent G(+) bugs aren’t as sensitive. -lactams aren’t like this, so if you’re treating an indolent G(-) bacillary osteomyelitis, use quinolones.
C. Pharmacology- GI absorption ranges from good to fair, but can be inhibited by divalent cations (antacids, Tums, mineral supplements). There is a modest first-pass effect, but ~50% of the drug is excreted unchanged in the urine. Good penetration to most body fluids, including prostate, but excluding CSF(~10% of serum levels).
D. Adverse effects-
1. CNS- tiredness, confusion, decreased memory and concentration (GABA-R interaction?)
2. Photosensitivity
3. Rash, anaphylaxis- occasional
4. Neutropenia- rare and reversible with cessation.
5. GI upset- usually mild
6. Drug interactions- Ciprofloxacin and enoxacin interfere with caffeine and theophylline metabolism, leading to toxicity (seizures).
7. Cartilaginous erosions in young animals- so don’t give it to kids, although the parent drug, nalidixic acid, has been safely used in kids for 40 yrs.
E. Resistance to Quinolones- Anaerobes are resistant, although the reason is unclear, since they do have a DNA gyrase. And recent resistance has emerged among Staph. aureus, Pseudomonas, and Campylobacter. MRSA are highly resistant to quinolones for unknown reasons 50-80% of the time. There is complete cross resistance between quinolones.
F. Therapeutic Niches-
1. bacterial diarrhea (except C. difficile) and typhoid fever in adults.
2. prostatitis
3. bacillary osteomyelitis
4. complicated UTIs resistant to other agents- (too expensive to be 1st line, so use TMP-SMX instead.)
5. outpatient follow-up of or suppressive Tx of Pseudomonas infection (ex. CF Pts)
6. multi drug resistant TB
7. M. avium infections
8. Do Not use these drugs for: routine URIs, cellulitis, skin boils, impetigo, meningitis, CNS infections, infections in children or during pregnancy, FUO.
G. Quinolone classes-
1. 1st generation- norfloxacin- least active agent
2. 2nd generation- ciprofloxacin, levofloxacin, ofloxacin- have good G(-) and some G(+) activity.
3. 3rd generation- gatifloxacin, sparfloxacin- increased activity against G(+) organisms.
4. 4th generation- moxifloxacin- increased activity against G(+) and anaerobic organisms.
III. RNA Polymerase Inhibitor- Rifampin
A. Structure- big, with multiple rings
B. Mechanism- Inhibits bacterial polymerase.
C. Pharmacology- Administered orally or IV. Good tissue levels, including CNS.
D. Spectrum- good activity against G(+), Neisseria and Mycobacteria.
E. Resistance- develops rapidly, so this is usually given in a combo, unless it is used as prophylaxis for Neisseria meningitidis or INH- resistant TB. There is no cross resistance with other antimicrobial classes.
F. Adverse effects-
1. red feces, urine, tears and sweat
2. hepatitis, additive with isonazid (INH).
3. fever and flu-like symptoms when given intermittently for TB.
4. Erythema Multiforme.
IV. Antibiotics for Urinary Tract Infections (UTIs)-
A. DNA gyrase inhibitors- don’t reach high levels in serum, but are concentrated in the urine to achieve bactericidal action against G(-) organisms. Resistance develops quickly elsewhere.
1. nalidixic acid
2. cinoxacin
B. Nitrofurantoin (Macrodantin)- mechanism unknown. Active against G(-) and G(+) organisms. Side effect is pneumonitis, requiring cessation of Tx and addition of steroids. May also cause N & V, anorexia, neuropathies, and hemolytic anemia.
V. Metronidazole-
A. Mechanism- the nitro group is reduced to toxic products by ferredoxin in anaerobic bacteria and parasites, so it is bactericidal against anaerobic organisms.
B. Pharmacology- good oral absorption and distribution to tissues, including brain. Hepatic metabolism and excretion via urine.
C. Adverse effects- Common ones are nausea, metallic taste, disulfiram-like effects with alcohol, dark urine, tingling, numbness, dizziness, and vertigo. May rarely cause seizures and ataxia. Interacts with coumadin to potentiate anticoagulant effects. May be mutagenic, so don’t use in pregnancy, during nursing, or for long in kids.
D. Therapeutic Niches- anaerobic infections(including brain abscess), Giardia infection, invasive amebiasis, vaginal Trichomonas, or vaginal bacteriosis.
VI. Inhibitors of Cell Membrane Transport- Polymixins
A. Mechanism- These drugs bind to the lipid A portion of the lipopolysaccharide (LPS) of G(-) outer membrane. They can also bind to membranes that have a lot of PE. Either way, they disrupt membrane transport. Bactericidal. Action is inhibited by cations.
B. Clinical Uses-
1. topical- wounds, burns, and pseudomonas infection, or inhaled for bronchial infections.
2. Intrathecal or intraocular injection for serious pseudomonas infection.(rare)
3. Can be given IV, rarely.
C. Adverse effects- none topically, but if given IV, severe reactions can occur, including dizziness, flushing, hypoTN, and nephrotoxicity.
Tags: anemia, Bacteriostatic, bone marrow suppression, conjunctivitis, drug fever, insoluble crystals, Kernicterus, Neutropenia, Quinolones, Rashes, sulfamethazole, sulfisoxazole, Sulfonamides, thrombocytopenia
