Antibiotics- Antimetabolites and DNA Synthesis Inhibitors

Question 1

Sulfamethoxazole

Answer 1

*Sulfomanide – topically oral, IV – well distributed (especially CNS and CSF, crosses placenta) – widespread resistance
*False substrate – competitively inhibit binding of PABA to DHPS enzyme (high PABA levels inhibit sulfa activity)
*Dose reduction in renal failure
GI distress, rash, bone marrow and liver toxicity, hemolytic anemia, kernicterus. Steven’s Johnson Syndrome
*Bacteriostatic (NOT used alone) – BROAD spectrum – many gram+ and gram-, some parasites (plasmodium malaria and CNS toxoplasma), NOT Rickettsia – UTI’s!

Question 2

Trimethoprim

Answer 2

• DHFR inhibitor
• Blocks later step in folic acid synthesis pathway than sulfas, inhibits bacterial DHFR 100,000x better than human DHFR
• Bacteriostatic

Question 3

Tmp-sulfa

Answer 3

• DHFR inhibitor – oral, wide distribution
• Tmp acts synergistically with sulfa
• GI distress, rash, bone marrow and liver toxicity, hemolytic anemia, kernicterus. Steven’s Johnson Syndrome, bone marrow suppression with neutropenia, anti-folate effect (caution in pregnancy/alcoholics)
• Bactericidal – broad spectrum (Not pseudomonas, anaerobes, or atypical bacteria) – UTIs (decreased efficacy with increased E. coli resistance), Pneumocystis pneumonia, sinusitis, otitis media, community acquired MRSA

Question 4

Ciprofloxacin
Levofloxacin
Moxifloxacin

Answer 4

• Fluoroquinolone – concentration dependent killing (AUC/MIC – 25 in normal, 100 if compromised) – oral and IV – wide distribution (bone, prostate, low CSF0
• Rapid inhibitors of DNA synthesis – inhibit bacterial DNA gyrase and topoisomerase, blocks DNA unwinding, induces irreversible DNA damage/degradation
• Reduced dosing with liver or kidney failure

GI issues common, arthropathy in kids, Achilles tendon rupture (no athletes), hepatotoxicity, MRSA and C. diff colonization

NO for pregnancy (birth defects, spontaneous abortions)

*Bactericidal – Gram- including pseudomonas (cipro>levo>moxi), gram+ including strep (moxi>levo>cipro), poor anaerobic, good against nosocomial infections and atypical bacteria – use for complicated UTIs, community acquired UTIs, acute bacterial prostatitis, pneumonia, STDs, osteomyelitis