Antimetabolites and Fluoroquinolones Flashcards
List key members of anti-folate antimicrobial drugs
- Sulfamethoxazole/Trimethoprim
- Sulfadiazine/Pyrimethamine
- Sulfadoxine/Pyrimethamine
List key members of fluoroquinolones
- Ciprofloxacin (2nd)
- Levofloxacin (3rd)
- Norfloxacin (2nd)
- Moxifloxacin (4th)
What is the miscellaneous drug mentioned in the antimetabolites/fluoroquinolones lecture?
Nitrofurantoin
What are the recommendations for antimicrobial prophylaxis for Anthrax?
Indication: suspected exposure
Drug: ciprofloxacin
What are the recommendations for antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia
Indication: immunocompromised patient
Drug: trimethoprim/sulfamethoxazole
List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfamethoxazole/trimethoprim
- Uncomplicated UTI**
Ear, sinus, respiratory infections, nocardiosis
S. typhus carrier eradication
*Opportunistic infections - toxoplasmosis , pneumocystis jirovecii - Oral, IV
Renal clearance
t1/2 8-10 hours - Rash (Steven Johnson), fever, leukopenia, acute hemolysis in pts with G6PD deficiency, hyperkalemia, **higher incidence of adverse effects in AIDS pts (higher doses)
List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfasalazine (pro-drug)
- Ulcerative colitis, Chron’s disease - ANTI-INFLAMMATORY, NOT ANTIBIOTIC
- Metabolism: via colonic intestinal flora to sulfapyridine and 5-ASA. 5-ASA undergoes hepatic N-acetylation
- Hypersensitivity, Stevens-Johnson syndrome
List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfacetamide
- Ocular infections, trachoma
- Topical eye drops, ointment
- Attention: hypersensitivity, steven-johnson syndrome
List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfisoxazole/erythromycin
- Otitis media
- Powder for suspension (pediatric)
- Superinfection**; c. difficile diarrhea/pseudomembranous colitis
What is the MOA of sulfonamides?
Competitive inhibitors of dihydropteroate synthase = essential enzyme in folic acid (folate) biosynthesis pathway of many bacteria; by inhibiting the enzyme, it inhibits bacteria from converting PABA into dihydrofolate
What is the MOA of trimethoprim (TMP)?
Inhibits dihydrofolate reductase (DHFR) –> inhibit production of tetrahydrofolate –> inhibit production of purines & pyrimidines
Is TMP/SMX bacteriostatic or bactericidal?
When given alone, TMP/SMX = bacteriostatic BUT when in combo = bactericidal
List the antimicrobial spectrum of TMP-SMX (name, site of infection, condition)
Gram(-) Rods:
(SOME) Haemophilus influenzae
Site of infection: respiratory tract
Condition: sinusitis
OTHER: (Condition = Opportunistic infection)
Pneumocystis jirovecii (carinii)
Site of infection: lung (prevention or tx)
Condition: pneumonia
Describe the specificity for prokaryotes for TMP vs other DHFR inhibitors
Methotrexate - Potent for Mammal targets; used for cancer bc cancer cells are multiplying rapidly and have a high demand for folate to conduct gene duplication
Trimethoprim - potent for E.Coli - aka good for bacterial targets
Pyrimethamine - potent against Plasmodium aka good for that and other weird things like Toxoplasmosis
What are the resistance mechanisms for SMX/TMP
SMX: (1) mutation of dihydropteroate synthase, (2) enhanced acquisition of PABA
TMP: (1) mutation of DHFR (2) over expression of DHFR
Many pathogens are resistant to TMP-SMX. List the two important points to note about resistance
(1) Folic acid auxotrophs are naturally resistant = E. faecalis
(2) Methicillin-resistant Staphylococcus (MRSA) is variably susceptible to TMP/SMX (tx MRSA with Vancomycin)
What are the main therapeutic uses for SMX-TMP?
(1) Uncomplicated UTI
(2) Treatment & prevention of pneumocystis jirovecii pneumonia in HIV pts
(3) Toxoplasmosis in immunocompromised pts (HIV, transplant, etc.)
What are the main adverse effects of sulfonamides?
(1) Hypersensitivity (Stevens-Johnson)
(2) Kernicterus
(3) Hemolytic anemia (attention: pts with X-linked inherited G6PD deficiency)
Describe the kernicterus that can be caused by tx with SMX-TMP
Neonatal encephalopathy due to sulfa drugs displacing bilirubin from albumin & poor bilirubin clearance PLUS developmentally inadequate glucuronidation in neonates (ability to glucuronidate occurs ~day 60)
Why is SMX contraindicated near term pregnancy; in breast fed neonate
Because of liver immaturity. SMX displaces bilirubin from albumin. Excess bilirubin in blood = jaundice. Excess bilirubin in brain = kernicterus
Explain how SMX can cause hemolytic anemia in pts
“Sulfonamides can cause oxidative stress on erythrocytes. Individuals with G6PD deficiency generate insufficient NADPH, and excess GSSG and H2O2. These oxidants cause hemoglobin denaturation, acute hemolysis, and red cell loss.”
Sulfa drugs cause oxidation rxns. When oxidation occurs, body’s defense is with reduced glutathione (GSH). Erythrocytes have lots of GSH. Pt given sulfonamides –> oxidation rxn in erythrocytes –> GSH turns into oxidized form = glutathione disulfide = GSSG. In response, erythrocytes pump out GSSG as well as convert it back into GSH. Conversion of GSSG –> GSH requires run of NADP –> NADPH. NADP –> NADPH requires G6PD. Pts who are deficient in G6PD are more vulnerable to oxidative stresses (more common in pts of Mediterranean descent)
What is the AE for trimethoprim? What should be given to prevent this?
(1) Birth defects due to folate deficiency - trimethoprim interferes with folate “acquisition” bc its competing for the active transport of folate into the body (use same transporter)
Give folinic acid - rectifies anti-folate toxicity of TMP-SMX w/o impairing its antimicrobial activity
List the 3 main properties regarding fluoroquinolones
(1) Enter gram(-) bacteria through porins
(2) Bactericidal - esp. if serum concentration of fluoroquinolone >30-fold MIC
(3) Concentration-dependent killing
MIC = minimum inhibitory concentration
What is the MOA of fluoroquinolones?
Fluoquinolones inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase inhibition –> gram(-)
Topoisomerase IV inhibition –> gram(+)
Resulting disruption of DNA has a lasting, “post-antibiotic” effect
= FQ bind to DNA-enzyme complex (= replication fork)
What are the mechanisms of resistance towards FQs?
(1) Mutation of DNA gyrase/topoisomerase
(2) Cellular membrane efflux mechanisms
(3) Decreased number of porins - MDR
List the names for 1st, 2nd, 3rd, and 4th generation FQs
1st - Nalidixic acid (limited spectrum of activity)
2nd - Ciprofloxacin, Norfloxacin, Ofloxacin
3rd - Levofloxacin (L-isomer of ofloxacin)
4th - Moxifloxacin*, Gemifloxacin
In general, describe the spectrum of activity of FQs
Gen 2,3,4 FQs are effective against range of gram(-) rods - enterobacteria, pseudomonas spp, HEMOPHILUS INFLUENZAE, MORAXELLA CATARRHALIS
For tx of OSTEOMYELITIS d/t gram(-) bc FQs have high bone penetration, even with oral admin
FQs also active against several atypical organisms that cause pneumonia
List the atypical and gram(+) organisms covered by 2nd generation FQ
= Ciprofloxain
Atypical: Mycoplasma, Chlamydia, Mycobacteria, Legionella
Gram(+): Bacillus anthracis (anthrax), otherwise minimal
List the atypical and gram(+) organisms covered by 3rd generation FQ
= Levofloxacin
Atypical: MORE ACTIVE against Mycoplasma, Chlamydia, Legionella
Gram(+): some gram(+) cocci - S. Pneumoniae
List the atypical and gram(+) organisms covered by 4th generation FQ
= Moxifloxacin
Atypical: MORE ACTIVE against Mycoplasma, Chlamydia, Legionella
Gram(+): enhanced gram(+) cocci and bacilli; and anaerobes
**Moxifloxacin has NO activity against pseudomonas aeruginosa
What are the indications for use of Ciprofloxacin?
Community acquired pneumonia (CAP) (including multi drug resistance strep. pneumoniae = MDRSP) Acute bacterial rhino sinusitis Skin and skin structure infections Nosocomial pneumonia **UTI
What are the indications for use of Levofloxacin?
CAP (including MDRSP) Acute exacerbation of chronic bronchitis Acute bacterial rhinosinusitis Skin and skin structure infections Nosocomial pneumonia
What are the indications for use of Moxifloxacin?
CAP (including MDRSP)
Acute exacerbation of chronic bronchitis
Acute bacterial rhino sinusitis
Skin and skin structure infections
What are the indications for use of Gemifloxacin?
CAP (including MDRSP)
Acute exacerbation of chronic bronchitis
List the distinctive uses of Ciprofloxacin
ANTHRAX Osteomyelitis Febrile neutropenia Typhoid Fever Abdominal infections + Metronidazole
List the distinctive uses of Levofloxacin
Septic & pneumonic plague
Pyelonephritis
List the distinctive uses of Moxifloxacin
Complicated intra-abdominal infections (Anaerobic)
What impairs the oral absorption and lowers the bioavailability of all FQs?
Antacids with Mg++ or aluminum
Dietary products with Ca++ (milk, yogurt)
Vitamin mineral supplements with iron or zinc
Take separately - NOT together!
What is unique about the distribution and elimination of Levofloxacin?
~85% urinary excretion
<5% hepatic
Describe the CT problems associated with FQs
AE of FQs
Peds: cartilage erosion, arthropy = CI in pts <18 YO [exception = anthrax]
USE TOPICAL ADMINISTRATION - ear/eye drops –> no AE effect
Geriatrics: tendon rupture, tendonitis = CI in geriatric pts >60 YO & adults with stress on tendons (gymnasts, climbers**)
Also - phototoxicity
What cardiac AE is associated with FQ?
Prolonged QTc interval - via block of rapidly inactivated delayed rectifier K+ current, Ik (hERG) - block slows depolarization
Channel block and resultant QT prolongation are dose-dependent & reversible
Effect: moxafloxacin > gemifloxacin > levofloxacin
What is the updated Boxed Warning for FQs
“Advising that serious side effects associated with FQs generally outweigh the benefits for patients with acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis and uncomplicated UTI who have other tx options”
