URDANETA CITY College of Pharmacy

UNIVERSITY
Owned and operated by the City Government of Urdaneta

ANTIBIOTICS
III. SULFONAMIDES, TRIMETHOPRIM AND QUINOLONES
A. Drugs that interfere with folic acid synthesis
1. SULFONAMIDES
 History
- Protonsil red: prototype drug discovered by G. Domagk
- Foerster: person who gave Protonsil to 10th month old infant with Staphylococcal septicaemia
- Colebrook and Kenny, with Buttler and coworkers: reported the favourable clinical results
with protonsil and its active metabolite sulphanilamide

 Chemistry
- Sulphonamide: derivatives of para- aminobenzenesulfonamide (sulphanilamide)
- Structure is similar to para- aminobenzoic acid

 Mechanism of action
- Competitive inhibitors of dihydropteroate synthase, the bacterial enzyme
responsible for the incorporation of PABA into dihydropteroic acid, the
immediate precursor of folic acid.
- Prevent normal bacterial utilization of PABA for the synthesis of
pteroylglutamic acid
- Sulfonamides replace the PABA, the enzyme cannot recognize PABA

 Mechanism of resistance
- Low affinity: production of folic- synthesizing enzyme that has a low affinity
for sulphonamides
- Decrease bacterial permeability of adaptive efflux of the drug
- Alternative metabolic pathway for synthesis of an essential metabolite, folic acid

 Untoward effects
- Crystalluria
- Acute haemolytic anemia
- Aplastic anemia
- Kernicterus
- Stevens- Johnson syndrome

 Contraindication
- Near term and breastfeeding mothers: enter breastmilk and can increase level of
unconjugated bilirubin and increase risk of kernicterus in the fetus or neonates

Compiled by:
Maricar Grace F. Mararac, RPh
 URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

 Classes of Sulfonamides
a. Oral absorbable agents:
Short acting Intermediate acting Long acting
Sulfisoxazole Sulfadiazine Sulfadoxine
Sulfamethizole Sulfapyridine
Sulfacytine
b. Oral, non- absorbable
- Sulfasalazine (salicylazosulfapyridine): ulcerative colitis, enteritis and other inflammatory
bowel disease

c. Topical agents
- Sodium sulfacetamide: bacterial conjunctivitis and adjunct for trachoma
- Mafenide acetate: burn. Mafenide and carbonic anhydrase can cause metabolic acidosis
- Silver sulfadiazine: less toxic topical agent used for prevention of infection of burn wounds.

2. Trimethoprim
 Mechanism of action
- Trimethoxybenzylpyrimidine which selectively inhibits bacteria dihydrofolate reductase,
which converts dihydrofolic acid to tetrahydrofolic acid, a step needed on the synthesis of
purines and eventually DNA.

 Clinical uses (TMP/ SMX)

- Infrequently used as single agents (Sulphonamides)
- DOC: treatment of Pneumocystis jirovecii pneumonia and prophylaxis on this infection in
patients with AIDS or cancer
- DOC: oral treatment of community associated methicillin resistant S. aureus
- Chronic bacterial prostatitis
- Uncomplicated cystitis in women
- Prophylaxis for recurrent UTI in women and children
- Intestinal infections due to Shigella spp, Vibrio spp, E. coli, Cyclospora spp
- Nocardia and Listeria monocytogenes infection
- Acute exacerbations of chronic bronchitis

3. Combination drugs

- Co- trimoxazole: Combination of the action of sulphonamides and trimethoprim

- Sulfadiazine + Pyrimethamine
- Sulfadoxine + Pyrimethamine

B. DNA gyrase inhibitors (Fluoroquinolones)

 History
- Nalidixic acid: isolates as a byproduct of the synthesis of Chloroquine
- Used in the treatment of UTI because there is a high concentration in kidneys and urine
- Introduction of chlorinated 4- quinolones became one of the major advancements
- With carboxylic acid at C- 3
- Fluorine substituent at C- 6
- Piperazine moiety at C- 7

Compiled by:
Maricar Grace F. Mararac, RPh
URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

- Addition of fluorine increases potency of the drug

 Mechanism of action
- Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and
topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supecoiled
DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV
interferes with the separation of replicated chromosomal DNA into the respective daughter
cells during cell division.

 Drugs under Quinolones:

1. 1st generation:
- Nalidixic acid, Cinoxacin

2. 2nd generation:
- Active against gram positive and gram negative cocci, atypical pneumonia
- Ciprofloxacin
- Lomefloxacin
- Ofloxacin
- Norfloxacin

3. 3rd generation
- Respiratory fluoroquinolones
- Mnemonic: LeGS Mo Pa Ba To? GGL
- Levofloxacin
- Gemifloxacin
- Sparfloxacin
- Pazufloxacin
- Balofloxacin
- Tosufloxacin
- Grepafloxacin
- Gatifloxacin

4. 4th generation: broad spectrum

- Clinafloxacin
- Alatrofloxacin
- Prulifloxacin
- Trovafloxacin

 Untoward effects:
- GI disturbances
- Inhibits CYP 450 enzyme for Theophylline: Ciprofloxacin and Pefloxacin
- Rashes
- Photosensitivity by Cinafloxacin
- Tendon rupture
- Renal disease
- QT interval prolongation leading to ventricular arrhythmias

Compiled by:
Maricar Grace F. Mararac, RPh
URDANETA CITY College of Pharmacy
UNIVERSITY
Owned and operated by the City Government of Urdaneta

 Pharmacokinetics
- Oral absorption is diminished by coadministration of polyvalent cations such as aluminium,
magnesium, calcium, zinc and iron preparations.

 Spectrum of activity
- Active against H. influenzae, M. catarrhalis, Mycoplasma spp, Chlamydia spp, Legionella spp,
Enterobacteriaceae, P. aeruginosa (esp Ciprofloxacin), M. tuberculosis, some atypical
mycobacteria, some methicillin sensitive Staphylococci
- Delafloxacin (most recently approved fluoroquinolones is the most broad spectrum
fluoroquinolone with activity against gram negative bacteria including P. aeruginosa, gram
positive bacteria including MRSA, as well as respiratory tract pathogens, anaerobes)
- DOC for UTI when E. coli resistance to TMP- SMX is > 15% except Moxifloxacin
- DOC for L. pneumophila- newer fluoroquinolones

Compiled by:
Maricar Grace F. Mararac, RPh