Antimicrobials Flashcards
Imipenem
- Imipenem (a carbapenem)- Same MOA as other penicillins; very resistant to β-lactamases including the chromosomal extended spectrum β-lactamases, very broad antibacterial spectrum.
- It is always administered with cilastatin, an inhibitor of dehydropeptidase in proximal tubule brush border.
- Not many species are resistant to imipenem except for some new strains of Pseudomonas aeruginosa.
Aztreonam
Aztreonam- Same MOA as other penicillins; structurally resistant to β-lactamases.
-Effective against Enterobacteriaceae and Pseudomonas aeruginosa plus many gram-negative bacteria in penicillin-allergic patients.
Aminoglycosides-Gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin
- MOA-Aminoglycosides binds to the 30S ribosomal subunit and interfere with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA. Aminoglycoside binding to the 30S subunit also causes misreading of mRNA, leading to premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein or incorporation of incorrect amino acids (indicated by the X). This ultimately results in the production of abnormal or nonfunctional proteins.
- Tox-Nephrotoxicity and ototoxicity are the major side effects of the aminoglycosides. Ototoxicity results from progressive damage to vestibular and cochlear sensory cells, which is usually irreversible. Toxicities are dose-dependent. Severe acute tubular necrosis (ATN) may occur rarely. This impairment in renal function is almost always reversible because the proximal tubular cells have the capacity to regenerate. Toxicity correlates with the total amount of drug administered. ATN is more likely to be encountered with longer courses of therapy. The most important result of renal toxicity may be reduced excretion of the drug, which, in turn, predisposes to irreversible ototoxicity.
Aminoglycosides produce neuromuscular blockade by inhibiting acetylcholine release from the preganglionic terminal (through competition with Ca2+) and to a lesser extent by noncompetitively blocking the receptor.
Tetrocyclines/Macrolides-doxycycline, azithromycin, tigecycline, minocycline
- Many tetracyclines are nephrotoxic and are rarely used to treat UTIs.
- Tox-Tetracyclines can produce renal tubular acidosis, azotemia and Fanconi’s syndrome (from outdated preps). All are excreted as nephrotoxic metabolites by the kidney except doxycycline.
- Doxycycline is excreted unchanged via bile in feces and is also excreted unchanged in the urine but without the nephrotoxic metabolites of the older tetracyclines.
- Women with an apparent UTI at risk for STDs are often treated with doxycycline or azithromycin (first choice for chlamydia urethritis) unless the UTI organism is identified as E. coli (resistant to doxycycline).
- Tigecycline is a glycylcycline, which is a derivative of the tetracycline, minocycline. It is not absorbed orally like minocycline. Parenteral use only with rapid and wide distribution into tissues. Effective against tetracycline-resistant bacteria due to less affinity for efflux pumps and ribosomal protection proteins. Little nephrotoxicity for tigecycline or minocycline.
Trimethoprim-Sulfamethoxazole
- Sulfamethoxazole and Trimethoprim act sequentially and synergistically to inhibit tetrahydrofolate production in bacteria.
- Sulfonamides (like sulfamethoxazole) are potent inhibitors of the utilization of PABA by dihydropteroate synthase in the synthesis of dihydrofolic acid, which humans do not perform.
- Trimethoprim is a selective inhibitor of dihydrofolate reductase in bacteria but not in humans. Thus, the synthesis of tetrahydrofolate is dramatically reduced, which inhibits DNA synthesis in bacteria.
- Although mutations in the two bacterial enzymes have increased resistance, TMP/SMX is widely used because it is effective against a broad spectrum of gram-positive and gram negative bacteria.
- As for all sulfonamides, the most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria (hives), nausea, vomiting, diarrhea in the hypersensitive.
- TMP-SMX (Bactrim) is used prophylactically as systemic agents in women who are prone to UTIs.
Quinolones-Nalidixic Acid, Cinoxacin, levofloxacin, ciprofloxacin
-Quinolones and fluoroquinolones are DNA gyrase inhibitors in gram-negative bacteria and topoisomerase IV inhibitors in gram-positive bacteria.
-Nalidixic acid and cinoxacin (quinolones) have limited usefulness because of their narrow antibacterial spectrum (gram-negative only), the high doses required and the widespread resistance to them due to mutations in the DNA gyrase protein.
-In contrast, fluoroquinolones have a broad antimicrobial spectrum and few bacterial resistant strains have developed until very recently.
-Levofloxacin and Ciprofloxacin are the second most commonly prescribed treatments for lower urinary tract infections behind TMP-SMX.
-DNA gyrase relieves the strain of supercoiling during bacterial DNA replication just as topoisomerase acts in humans. At therapeutic doses, the quinolones do not inhibit the topoisomerase I or II of the human host.
-Resistance is increasing: mutations in DNA gyrase and Topo IV; active transport from cell.
-Tox: well tolerated, mild nausea, vomiting, GI distress, arthropy in children. Fluoroquinolones markedly alter normal GI flora.
Methenamine
Methenamine has been used for prophylaxis of chronic UTI. It is metabolized to formaldehyde, spontaneously at low urine pH but not in plasma at pH 7.4.
Nitrofurantoin
- Nitrofurantoin has a narrow antibacterial spectrum (gram-positive enterococci; E coli) but Proteus, Pseudomonas, Enterobacter and Klebsiella are resistant.
- Nitrofurantoin is used for uncomplicated lower (nonsystemic) UTIs like cystitis.
- 40% of the drug is excreted into the urine unchanged where bacteria reduce nitrofurantoin to form highly reactive intermediates that damage DNA. The antibacterial activity is higher in acidic urine.
- Nitrofurantoin is used as a prophylactic antiseptic treatment of chronic UTI. It turns the urine brown.
- Tox: nausea, vomiting, and diarrhea; the macrocrystalline preparation is absorbed and excreted more slowly and is better tolerated.
Praziquantel
- Praziquantel has broad antihelminthic activity against trematodes and cestodes but not nematodes. It causes muscular contraction and paralysis and at higher drug levels- tegumental damage by an influx of Ca.
- Tox: abdominal distress.
Metrifonate
- Metrifonate is an organophosphorus compound and must be activated to dichlorovos which inhibits acetylcholinesterase in the worm and is only effective against S. hematobium.
- Organophosphates are used in pesticides (as well as sarin and VX nerve agents) irreversibly inactivate acetylcholinesterase,
Oxamniquine
- Oxamniquine is ineffective against Schistosoma hematobium but is effective against Schistosoma masoni and other trematodes.
- Oxamniquine is activated by a single step, in which a schistosome enzyme converts oxamniquine into an ester (probably acetate, phosphate, or sulfate). Subsequently, the ester spontaneously dissociates, the resulting electrophilic reactant is capable of alkylation of schistosomal DNA. Mild side effects.
