Lecture 30 - Intro Anti-Microbials Flashcards
Folic Acid Anti-Metabolites
- Sulfonamides (Sulfa Drugs)
- Trimethoprim
Sulfonamides
- folic acid anti-metabolite
- also called sulfa drugs
- blocks Dihydropteroate Synthetase (involved in folic acid metabolism)
- higher upstream than Trimethoprim
- humans dont have this enzyme so it doesnt matter -also work on parasites (will get this later)
Trimethoprim
- folic acid anti-metabolite
- blocks dihydrofolate reductase (involved in folic acid synthesis)
- humans have this enzyme but trimethoprim binds the bacterial enzyme 50,000 fold stronger than the human one
- also work on parasites (will get this later)
Trimethoprim + Sulfonamide (TMP-SMX)
- sulfonamides rarely used alone
- trimethoprim used in conjunction (synergy)
- 5:1 = SMX:TMP -shut down two different parts of the pathway
- enhances activity
- bactericidal against microbes & decreases the emergence of resistance
- bacterocidal against MOST microbes
Uses of TMP-SMX (co-tramoxazol, trimethoprim-sulfa)
- gram negatives (respiratory & urinary tract)
- staph. aureus (bc MRSA)
- some protozoa and fungi
- [pseudomonas and enterococci are resistant]
- excellent bioavailibility
- excellent tiss penetration (unchanged in urine, penetrates prostate & CSF)
- cheap (50 cents/pill)
- resistance if gains new dihydrofolate reductase (TMX) or chromosomal mutation (SMX))
- 2/3 E.coli are sensitive
- 95% of staph aureus are sensitive
TMP-SMX Side Effects
- side effects (rash, stomach, hyperkalemia, hepatitis, pancreatitis, Stevens-Johnson syndrome)
- teratogenic (cannot use during early pregnancy)
- late in pregnancy (sulfonamide can displace billirubin, can lead to kernicterus, hyper-billirubinemia) -also displaces warfarin and phenytoin among others from albumin (can have hemorrhage)
DNA Inhibitors
- quinolones
- fluoroquinolones
- nitrofurantoin
-DNA Inibitors (mechanism of action)
- Relax DNA coiling or enhance DNA coiling
- Topo II (DNA gyrase) - makes coils
- Topo IV - de-concatenates intertwined chromosomes
**these two enzymes form transient covalent bonds to DNA via phospho-tyrosine on the protein to have their action
**fluoroquinolones stabilize this complex, thus keeping the Topo on the DNA, either cutting it, winding it so much that it breaks
-General Properties of Quinolones
- all work on gram-negative
- some work on gram-positive (depend on ability to bind Topo IV)
- active against “atypicals” (mycobacteria (TB), chylmydia)
- great oral bioavailibility (unless takin di-valent metal = Zinc, antacids Ca, Fe, etc)
Ciprofloxacin
- in the quinolone, fluroquinolone familty
- primary target DNA gyrase (Topo II)
- making them great for gram-negative
- poor activity against Streptococcus
Moxifloxacin
- gram positive and anerobic activity
- poor penetration into urinary tract
Fluoroquinolone Resistance
- across class, can develop during therapy
- mutations in target enzymes (gyrA or parC)
- single mutation (staph aureus), double mut (e.coli), global mut (Fq’E.coli clone = most E.coli infections in hospitals)
- efflux pumps (depression of multi-drug resistance transporters)
- plasmid mediated resistance (rare)
Fuoroquinolone Adverse Effects
- considered quite safe
- common problems (dessimates commensals, nausea, vomiting, abdominal pain, headache, dizzy)
- serious (prolong QT interval in combo with other meds, tendon rupture, potential for arthropathy in children)
Nitrofurantoin
- old drug, resurgence due to resistance to other agents
- mechanism of action unclear (many effects)
- reacts covalently with DNA
- active against common gram-positive and negative uropathogens, not against more resistant microbes
- administered only by mouth, poor serum levels, only works in urine
- FIRST LINE AGENT = UTI
- adverse effects (nausea, pulmonary fibrosis - rare with extended use)
RNA inhibitors
- Rifamycins
- Fidaxomicin
Rifamycin Mechanism
- bind to beta-subunit of RNA polymerase and block transcription
- resistance due to mutations in binding pocket occurs at rate of 10^-8 (chromosomal enzyme)
- bacteriostatic
Rifamycin Metabolism
- all metabolized by CYP P450 3A4
- rifampin (most widely used drug in this class) potent inducer (can increase metabolism of many drugs; problem in HIV protease inhibitor concentrations)
- rifabutin much less so (increased levels can result from concomitant use of P450 3A4 inhibitors)
- rifaximin not absorbed at all (only in the GI tract)
Rifamycins Uses
- for prophylaxis (eradicate carriage of Neisseria Meningitidis, staph aureus; used in place where someone has been infected with N.meningitides = dorm)
- in combo with other antimicrobials (FIRST LINE for TB, mycobacterial infection)
- for syngery in serious bacterial infections (little evidence of benefit)
- for GI infections (rifaximin only) = traveler’s diarrhea
Rifamycin Adverse Effects
- Rifampin turns secretions orange (tears for example)
- GI (pain, nausea, vomiting, diarrhea)
- hematological (usually mild thrombocytopenia, leukopenia, anemia)
- hepatitis (more likley with co-administration of other agents, preexisting liver disease)
Fidaxomicin
- non-absorbable oral antimicrobial approved in 2011; different class that others here
- blocks RNA polymerase by preventing formation of open DNA complex
- poor activity againt Gram (-) enteric flora including Gram (-) anaerobes
- no serious side effects reported (leaving intestinal microbes intact)
- approved only for C.difficile infections
- fewer relapses that with vancomycin
- >$100/pill (10 day treatment >$2000)