Antimetabolites and Fluoroquinolones

Question 1

List key members of anti-folate antimicrobial drugs

Answer 1

1. Sulfamethoxazole/Trimethoprim
2. Sulfadiazine/Pyrimethamine
3. Sulfadoxine/Pyrimethamine

Question 2

List key members of fluoroquinolones

Answer 2

1. Ciprofloxacin (2nd)
2. Levofloxacin (3rd)
3. Norfloxacin (2nd)
4. Moxifloxacin (4th)

Question 3

What is the miscellaneous drug mentioned in the antimetabolites/fluoroquinolones lecture?

Answer 3

Nitrofurantoin

Question 4

What are the recommendations for antimicrobial prophylaxis for Anthrax?

Answer 4

Indication: suspected exposure
Drug: ciprofloxacin

Question 5

What are the recommendations for antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia

Answer 5

Indication: immunocompromised patient
Drug: trimethoprim/sulfamethoxazole

Question 6

List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfamethoxazole/trimethoprim

Answer 6

1. Uncomplicated UTI**
   Ear, sinus, respiratory infections, nocardiosis
   S. typhus carrier eradication
   *Opportunistic infections - toxoplasmosis , pneumocystis jirovecii
2. Oral, IV
   Renal clearance
   t1/2 8-10 hours
3. Rash (Steven Johnson), fever, leukopenia, acute hemolysis in pts with G6PD deficiency, hyperkalemia, **higher incidence of adverse effects in AIDS pts (higher doses)

Question 7

List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfasalazine (pro-drug)

Answer 7

1. Ulcerative colitis, Chron’s disease - ANTI-INFLAMMATORY, NOT ANTIBIOTIC
2. Metabolism: via colonic intestinal flora to sulfapyridine and 5-ASA. 5-ASA undergoes hepatic N-acetylation
3. Hypersensitivity, Stevens-Johnson syndrome

Question 8

List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfacetamide

Answer 8

1. Ocular infections, trachoma
2. Topical eye drops, ointment
3. Attention: hypersensitivity, steven-johnson syndrome

Question 9

List the activity/clinical use, pharmacokinetics/drug interactions, and adverse events/toxicities for: sulfisoxazole/erythromycin

Answer 9

1. Otitis media
2. Powder for suspension (pediatric)
3. Superinfection**; c. difficile diarrhea/pseudomembranous colitis

Question 10

What is the MOA of sulfonamides?

Answer 10

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

Question 11

What is the MOA of trimethoprim (TMP)?

Answer 11

Inhibits dihydrofolate reductase (DHFR) –> inhibit production of tetrahydrofolate –> inhibit production of purines & pyrimidines

Question 12

Is TMP/SMX bacteriostatic or bactericidal?

Answer 12

When given alone, TMP/SMX = bacteriostatic BUT when in combo = bactericidal

Question 13

List the antimicrobial spectrum of TMP-SMX (name, site of infection, condition)

Answer 13

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

Question 14

Describe the specificity for prokaryotes for TMP vs other DHFR inhibitors

Answer 14

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

Question 15

What are the resistance mechanisms for SMX/TMP

Answer 15

SMX: (1) mutation of dihydropteroate synthase, (2) enhanced acquisition of PABA
TMP: (1) mutation of DHFR (2) over expression of DHFR

Question 16

Many pathogens are resistant to TMP-SMX. List the two important points to note about resistance

Answer 16

(1) Folic acid auxotrophs are naturally resistant = E. faecalis
(2) Methicillin-resistant Staphylococcus (MRSA) is variably susceptible to TMP/SMX (tx MRSA with Vancomycin)

Question 17

What are the main therapeutic uses for SMX-TMP?

Answer 17

(1) Uncomplicated UTI
(2) Treatment & prevention of pneumocystis jirovecii pneumonia in HIV pts
(3) Toxoplasmosis in immunocompromised pts (HIV, transplant, etc.)

Question 18

What are the main adverse effects of sulfonamides?

Answer 18

(1) Hypersensitivity (Stevens-Johnson)
(2) Kernicterus
(3) Hemolytic anemia (attention: pts with X-linked inherited G6PD deficiency)

Question 19

Describe the kernicterus that can be caused by tx with SMX-TMP

Answer 19

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)

Question 20

Why is SMX contraindicated near term pregnancy; in breast fed neonate

Answer 20

Because of liver immaturity. SMX displaces bilirubin from albumin. Excess bilirubin in blood = jaundice. Excess bilirubin in brain = kernicterus

Question 21

Explain how SMX can cause hemolytic anemia in pts

Answer 21

“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)

Question 22

What is the AE for trimethoprim? What should be given to prevent this?

Answer 22

(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

Question 23

List the 3 main properties regarding fluoroquinolones

Answer 23

(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

Question 24

What is the MOA of fluoroquinolones?

Answer 24

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)

Question 25

What are the mechanisms of resistance towards FQs?

Answer 25

(1) Mutation of DNA gyrase/topoisomerase (2) Cellular membrane efflux mechanisms (3) Decreased number of porins - MDR

Question 26

List the names for 1st, 2nd, 3rd, and 4th generation FQs

Answer 26

1st - Nalidixic acid (limited spectrum of activity) 2nd - Ciprofloxacin*, Norfloxacin, Ofloxacin 3rd - Levofloxacin* (L-isomer of ofloxacin) 4th - Moxifloxacin*, Gemifloxacin

Question 27

In general, describe the spectrum of activity of FQs

Answer 27

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

Question 28

List the atypical and gram(+) organisms covered by 2nd generation FQ

Answer 28

= Ciprofloxain Atypical: Mycoplasma, Chlamydia, Mycobacteria, Legionella Gram(+): Bacillus anthracis (anthrax), otherwise minimal

Question 29

List the atypical and gram(+) organisms covered by 3rd generation FQ

Answer 29

= Levofloxacin Atypical: MORE ACTIVE against Mycoplasma, Chlamydia, Legionella Gram(+): some gram(+) cocci - S. Pneumoniae

Question 30

List the atypical and gram(+) organisms covered by 4th generation FQ

Answer 30

= Moxifloxacin Atypical: MORE ACTIVE against Mycoplasma, Chlamydia, Legionella Gram(+): enhanced gram(+) cocci and bacilli; and anaerobes **Moxifloxacin has NO activity against pseudomonas aeruginosa

Question 31

What are the indications for use of Ciprofloxacin?

Answer 31

``` Community acquired pneumonia (CAP) (including multi drug resistance strep. pneumoniae = MDRSP) Acute bacterial rhino sinusitis Skin and skin structure infections Nosocomial pneumonia **UTI ```

Question 32

What are the indications for use of Levofloxacin?

Answer 32

``` CAP (including MDRSP) Acute exacerbation of chronic bronchitis Acute bacterial rhinosinusitis Skin and skin structure infections Nosocomial pneumonia ```

Question 33

What are the indications for use of Moxifloxacin?

Answer 33

CAP (including MDRSP) Acute exacerbation of chronic bronchitis Acute bacterial rhino sinusitis Skin and skin structure infections

Question 34

What are the indications for use of Gemifloxacin?

Answer 34

CAP (including MDRSP) | Acute exacerbation of chronic bronchitis

Question 35

List the distinctive uses of Ciprofloxacin

Answer 35

``` ANTHRAX Osteomyelitis Febrile neutropenia Typhoid Fever Abdominal infections + Metronidazole ```

Question 36

List the distinctive uses of Levofloxacin

Answer 36

Septic & pneumonic plague | Pyelonephritis

Question 37

List the distinctive uses of Moxifloxacin

Answer 37

Complicated intra-abdominal infections (Anaerobic)

Question 38

What impairs the oral absorption and lowers the bioavailability of all FQs?

Answer 38

Antacids with Mg++ or aluminum Dietary products with Ca++ (milk, yogurt) Vitamin mineral supplements with iron or zinc Take separately - NOT together!

Question 39

What is unique about the distribution and elimination of Levofloxacin?

Answer 39

~85% urinary excretion | <5% hepatic

Question 40

Describe the CT problems associated with FQs

Answer 40

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

Question 41

What cardiac AE is associated with FQ?

Answer 41

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

Question 42

What is the updated Boxed Warning for FQs

Answer 42

"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"