Lecture 30 - Intro Anti-Microbials

Question 1

Folic Acid Anti-Metabolites

Answer 1

• Sulfonamides (Sulfa Drugs)
• Trimethoprim

Question 2

Sulfonamides

Answer 2

• 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)

Question 3

Trimethoprim

Answer 3

• 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)

Question 4

Trimethoprim + Sulfonamide (TMP-SMX)

Answer 4

• 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

Question 5

Uses of TMP-SMX (co-tramoxazol, trimethoprim-sulfa)

Answer 5

• 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

Question 6

TMP-SMX Side Effects

Answer 6

• 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)

Question 7

DNA Inhibitors

Answer 7

• quinolones
• fluoroquinolones
• nitrofurantoin

Question 8

-DNA Inibitors (mechanism of action)

Answer 8

• 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

Question 9

-General Properties of Quinolones

Answer 9

• 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)

Question 10

Ciprofloxacin

Answer 10

• in the quinolone, fluroquinolone familty
• primary target DNA gyrase (Topo II)
• making them great for gram-negative
• poor activity against Streptococcus

Question 11

Moxifloxacin

Answer 11

• gram positive and anerobic activity
• poor penetration into urinary tract

Question 12

Fluoroquinolone Resistance

Answer 12

• 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)

Question 13

Fuoroquinolone Adverse Effects

Answer 13

• 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)

Question 14

Nitrofurantoin

Answer 14

• 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)

Question 15

RNA inhibitors

Answer 15

• Rifamycins
• Fidaxomicin

Question 16

Rifamycin Mechanism

Answer 16

• 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

Question 17

Rifamycin Metabolism

Answer 17

• 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)

Question 18

Rifamycins Uses

Answer 18

• 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

Question 19

Rifamycin Adverse Effects

Answer 19

• 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)

Question 20

Fidaxomicin

Answer 20

• 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)