Antibiotics III

Fluoroquinolones

Ciprofloxacin, Norflaxacin, Ofloxacin, Sparfloxacin, Moxifloxacin, Gatifloxacin, Enoxacin; Nalidixic acid (a quinolone)

Mechanism: Inhibit DNA Gyrase (Topoisomerase II). Bactericidal.

Pharm: Don't take with divalent cations -- impairs absorption (similar to tetracyclines). Well absorbed, long half-lives, enter CSF (Cipro the most), eye, prostate.

Clinical use: UTI and GI infections with gram negative rods (including Pseudomonas), Neisseria, some gram positive organisms. Moxifloxacin is best for pneumococcus. All fluoroquinolones work for atypical pneumonias (Chlamydia, Legionella, Mycoplasma). Prophylaxis for neutropenic patients.

Side effects: Can cause GI upset, superinfections, skin rashes (certain substitutions); headache, dizziness (CNS effects). Can also prolong QTc interval. Cipro interferes with theophylline and warfarin metabolism (P450), increasing blood levels. Gatifloxacin is a insulin secretagogue -- can cause diabetes. Unique side effect: FluroquinoLONES hurt attachment to your BONES. Tendonitis and tendon rupture in adults; leg cramps and myalgias in kids; contraindicated in pregnancy due to damage to cartilage growth in animal studies.

Most fluoroquinolones are renally excreted (including Cipro). Moxifloxacin is hepatically excreted, so don't need to adjust dose in renal failure, but OTOH cannot use it to treat UTI.

Resistance can develop in variety of ways: changing target, drug efflux pumps, acetylation of enzyme, competitive inhibition of enzyme. Concept of MPC (maximum protective concentration), which is the amount that protects against mutations.

Metronidazole

Completely absorbed, no interaction with food. Reaches all tissues.

Mechanism: Form toxic metabolites in bacterial cell that damage the DNA. Bactericidal. Also anti-protozoan.

Clinical use: Drug of choice for anaerobic bacteria, below the diaphragm (contrast clindamycin, above the diaphragm).

GET GAP on the Metro!

Giardia
Entamoeba
Trichomonas

Gardnerella vaginalis
Anaerobes (Bacteroides and Clostridium)

H. Pylori (triple therapy with bismuth, amoxicillin/tetracycline, and metronidazole).

Notably absent from this list: acne (Propionibacteria -- use Tetracycline), actinomycosis, some anaerobic cocci.

Side effects: Metallic taste in mouth. Disulfiram-like reaction. Headache.

Trimethoprim-Sulfamethoxazole

This combination blocks synthesis of tetrahydrofolate at two sequential steps, inhibiting bacterial DNA synthesis. Sulfamethoxazole as well as other sulfonamides (sulfisoxazole, sulfadiazine) block synthesis of dihydropteroic acid from pteridine and PABA by dihydropteroate synthethase by generating PABA antimetabolites. This step is not performed in human cells, so is specific for bacteria. Trimethoprim blocks the synthesis of tetrahydrofolic acid from dihydrofolic acid. Trimethoprim has 100x affinity for the bacterial version of dihydrofolate reductase.

Sulfonamides are used clinically as a wide-spectrum antibiotic: gram +, gram -, Nocardia, Chlamydia. They are often used for simple UTIs. Toxicities: Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis as sulfa drugs can crystallize in kidneys), photosensitivity, kernicterus in infants, displace other drugs (e.g., warfarin) from albumin.

Trimethoprim, like sulfonamides, is bacteriostatic. The main use is in combination with sulfonamides for recurrent UTIs, Shigella, Salmonella, and Pneumocystis jiroveci pneumonia. Trimethoprim = TMP. "Treats Marrow Poorly." Toxicity includes megaloblastic anemia, leukopenia, and granulocytopenia.

Rifampin

Four R's:

RNA polymerase inhibitor
Revs up P450
Red/Orange secretion
Rapid Resistance if used alone

Used for mycobacterium tuberculosis, but can't use alone since rapidly selects for resistance. Delays resistance to dapsone in leprosy. Prophylaxis for meningitis, Hib.

P450 (CYP3A) effects: women get pregnant if on oral contraceptives, need triple dose of warfarin, methadone takers will withdraw.

Other drugs in same class called rifamycins. Different properties in P450 activation, half-life, absorption, not too important.

Pharm: Goes everywhere, well-absorbed.

Daptomycin

Treats gram positive skin infections (e.g., MSSA, MRSA, VRE). An alternative to vancomycin. Activity is calcium-dependent. Not effective with pneumonia since interacts with surfactant.

A lipopeptide. Large molecule, small volume of distribution.

Major toxicity: muscle damage.