Sulfonamides, Antifolates, Fluoroquinolones - Fitzy lecture Flashcards by Autumn Brubaker

Sulfamethoxazole

Trimethoprim

Oral, IV
Renal clearance
T1/2 8-10 h

USE:

uncomplicated UTI, ear, sinus, respiratory infections, nocardiosis
s. typhus carrier eradication
toxoplasmosis, pneumocystis jiroveci

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Adverse effects/toxicities Sulfamethoxazole -Trimethoprimin, Sulfadoxine -Pyrimethamine, Sulfadiazine - Pyrimethamine

Rash
Steven-Johnson
Fever
leukopenia
acute hemolysis in G6PD deficiency
Hyperkalemia

higher incidence of adverse effects in AIDS patients (higher doses)

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Sulfadoxine

Pyrimethamine

T1/2 4-8 days
Hepatic and renal clearance
Sulfa can displace albumin bound warfarin, bilirubin

USE:
malaria tx and prevention

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Sulfadiazine - Pyrimethamine

Sulfa about 10 hrs
Pyrimethamine about 4 days

USE: toxoplasmosis

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Sulfasalazine (Pro-drug)

Metabolism: colonic intestinal flora to sulfapyridine and 5-aminosalicylic acid (5-ASA)

5-ASA undergoes hepatic N-acetylation

USE:
ulcerative colitis, Crohns disease

Anti-inflammatory NOT abx

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Sulfacetamide

topical eye drops, ointment

USE: ocular infections, trachoma

Adverse effects: hypersensitivity, Stevens-Johnson syndrome

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Silver sulfadiazine

Topical cream

USE: dressing - prevent and treat 2nd and 3rd degree burn infection

Adverse effects: hypersensitivity, Stevens-Johnson syndrome

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Sulfisoxazole/erythromycin

Powder for suspension - pediatric

USE: OM

Adverse events: superinfection - C. diff diarrhea, pseudomembranous colitis

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Anthrax infection

suspected exposure

drug: ciprofloxacin

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Pneumocystis jirovecii pneumonia

Indication: immunocompromised patient

Drug: trimethoprim-sulfamethoxazole

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Toxoplasmosis infection

HIV infected with CD4 less than 100/uL

Drug: trimethoprim-sulfamethoxazole

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MOA of sulfonamides

competitive inhibitors of dihydropteroate synthase (enzyme in folic acid biosynthesis of bacteria)

1- PABA substrate for bacterial folic acid synthesis
2- Sulfonamides resemble PABA
3- sulfonamides inhibit dihydropteroate synthesis

Gram + and - bacteria filling dihydrofolate pools by de novo biosynthesis of folic acid sensitive to sulfonamides
(Humans from diet, not affected)

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Sulfamethoxazole -Trimethoprim (TMP-SMX) synergistic effect

Sulfamethoxazole inhibits dihydropteroate synthase

Trimethoprim inhibits dihydrofolate reductase

Individually bacteriostatic agents, combined bactericidal against many susceptible bacteria

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Anti-microbial spectrum of TMP-SMX

Gram - rods:
E coli, Proteus mirabilis - cystitis, prostatitis

Salmonella typhi, Shigella spp. - diarrhea

H. influenzae - sinusitis

Other: Pneumocystis jiroveci (carinii) - pneumonia; Toxoplasmosis - encephalitis

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Resistance mechanisms for TMP/SMX

Sulfamethoxazole (SMX): mutation of dihydropteroate synthase, enhanced acquisition of PABA

Trimethoprim (TMP): mutation of DHFR, over expression of DHFR

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Pathogens resistant to TMP-SMX

P. aeruginosa
Bactericides fragilis (and most anaerobes)
M. tuberculosis - respiratory tract
T. pallidum - syphilis
Campylobacter - enteritis, diarrhea symptoms
PCN-resistant pneumococci - pneumonia
Rickettsiae

Folic acid auxotrophs naturally resistant (E. faecalis)

MRSA variable susceptible

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Main therapeutic uses of SMX-TMP

Uncomplicated UTI
Prevention and tx of PCP in HIV patients
Toxoplasmosis in immunosuppressed

Kernicterus in sulfonamide usage

Excess bilirubin in brain

neonatal encephalopathy due to sulfa drugs displacing bilirubin from albumin and poor bilirubin clearance

Developmentally inadequate glucuronidation in neonates

Contraindicated in near term and breast fed neonate due to liver immaturity

Acute hemolytic anemia in sulfonamides

oxidative stress on erythrocytes
G6PD deficiency generate insufficient NADPH and excess GSSG and H2O2

Oxidants cause hemoglobin denaturation, acute hemolysis and RBC loss

Adverse effects of trimethoprim

birth defects due to folate deficiency

Fluoroquinolone properties

enter gram - via porins

bactericidal if concentration >30 fold MIC

concentration dependent killing

Gen 2, 3, 4 - effective against range of gram - rods, high bone penetration even with oral administration

active against atypical organisms causing pneumonia

Fluoroquinolone MOA

inhibits DNA gyrase (topoisomerase II in gram - bacteria) and topoisomerase IV (more significant in gram + bacteria)

disruption of DNA lasting, post-antibiotic effect

Mechanism of resistance in fluoroquinolone

Mutation of DNA gyrase and topoisomerase

cellular membrane efflux mechanisms

decreased number of porins - MDR

2nd generation fluoroquinolone

Ciprofloxacin
Norfloxacin
Ofloxacin

3rd generation fluoroquinolone

Levofloxacin | L-isomer of ofloxacin

4th generation fluoroquinolone

Moxifloxacin | Gemifloxacin

Ciprofloxacin organisms

``` Atypical organisms: Mycoplasma Chlamydia Mycobacteria Legionella ``` Gram +: Bacillus anthraces - anthrax ``` Distinctive uses: Anthrax Osteomyelitis Febrile neutropenia Typhoid fever Abdominal infections + Metronidazole ```

Levofloxacin

Atypical organisms: More active against mycoplasma Chlamydia Legionella Gram + cocci - S. pneumonia Distinctive uses: Septic and pneumonic plague Pyelonephritis

Moxifloxacin

Atypical organisms: Moer active against mycoplasma, chlamydia, legionella Gram + cocci - enhanced gram + cocci and bacilli and anaerobes No activity against p. aeruginosa Distinctive uses: Complicated intra-abdominal infections - anaerobic

Treatment of CAP

Ciprofloxacin Levofloxacin Moxifloxacin Gemifloxacin

tx of Acute exacerbation of chronic bronchitis

Levofloxacin Moxifloxacin Gemifloxacin

tx of Acute bacterial rhinosinusitis

Ciprofloxacin Levofloxacin Moxifloxacin

tx of skin and skin structure infection

Ciprofloxacin Levofloxacin Moxifloxacin

tx of Nosocomial pneumonia

Ciprofloxacin | Levofloxacin

tx of bacterial prostatitis

Ciprofloxacin | Levofloxacin

tx of UTI

Ciprofloxacin | Levofloxacin

factors impacting absorption and bioavailability of fluoroquinolones

Antacids with Mg or aluminum Dietary products with Calcium (milk, yogurt) Vitamin mineral supplements with iron or zinc Take separately, not together

Fluoroquinolone elimination

Moxifloxacin - 20% urinary excretion and 60% hepatic Ciprofloxacin - 50% urinary excretion, 20% hepatic Levofloxacin - 85% urinary excretion, less than 5% hepatic

Connective tissue problems associated with fluoroquinolone

Pediatrics: cartilage erosion, arthropy Geriatric: tendon rupture, tendonitis (also athletes with tendon stress)

Cardiac adverse effects of fluoroquinolones

Prolonged QTc interval via block of rapidly inactivating delayed rectifier Ik (hERG) -blocks slow depolarization Channel block and resultant QT prolongation dose-dependent and reversible Moxifloxacin > gemifloxacin > levofloxacin

Topically applied fluoroquinolones

administered to eye, ear drops do not show adverse effects Ciprofloxacin - eye and ear drops Levofloxacin and Moxifloxacin - eye drops

Peripheral neuropathy in Fluoroquinolones

oral or injection | no risk with topical formulations