Quinolones, Antifolate Drugs, and Other Agents
A. Antifolate drugs: used to treat bacterial infections, protozoal infections, and cancer
Drug
MoA & use
Side effect
Sulfonamides
1. Analogs of para-aminobenzoic acid (PABA)
1. hypersensitivity reactions
-> competitively inhibit dihydropteroate synthase
-> form dihydropteroate then converted to dihydrofolate
2. converted to inactive compounds by N-acetylation
(a) mild reaction: skin rash
(b) serious or life-threatening:
erythema multiforme
-> acetylated metabolites precipitate in the renal tubules: crystalluria.
3. against wide range: streptococci, gonococci, meningococci, G(-) bacilli, chlamydiae.
4. significant resistance to sulfonamides developed in many species
-> primarily used to prevent or treat UTI (because of high urinary concentration)
(Stevens-Johnson syndrome)
2. crystalluria, gastrointestinal
reactions, headaches, hepatitis, and
hematopoietic toxicity.
1. Sulfamethoxazole: combination with trimethoprim
2. Sulfadiazine: silver sulfadiazine ointment
-> prevent or treat burn infections and other superficial skin infections.
3. hemolytic anemia
-> In persons with G6PDH. deficiency
-> silver ions: antibacterial activity and contribute to efficacy
3. Sulfacetamide (topical):
treat blepharitis and conjunctivitis, ocular infection and trachoma (Chlamydia trachomati)
Trimethoprim
(oral)
1.○
- dihydrofolate reductase and the formation of tetrahydrofolate.
-> folate reductase is found in both microbial and mammalian cells, the affinity of
trimethoprim for the bacterial enzyme is ~ 105 times greater than mammalian enzyme.
2. weak base and is concentrated in acidic prostate tissues and vaginal fluids via ion trapping
-> treatment of bacterial prostatitis and vaginitis
3. against many aerobic G(-) bacilli and a few G(+) organisms
TrimethoprimSulfamethoxazole
(oral,IV)
1. Urinary tract and prostatic infections cause by Enterobacteriaceae:
Escherichia coli, Klebsiella pneumoniae, Proteus species, and Enterobacter
->not recommended for UTI in locations where > 20% of E. coli isolates are resistant to
TMP-SMX (use nitrofurantoin or Fosfomycin)
2. pulmonary infections caused by Pneumocystis jiroveci (carinii) and Nocardia
3. against Burkholderia cepacia and some H. influenzae, Moraxella catarrhalis.
4. against some strains of Salmonella and Shigella (Currently fluoroquinolone usually preferred)
1. nausea, vomiting, epigastric distress
2. rashes and hypersensitivity reactions;
3. hepatitis
4. thrombocytopenia, leukopenia, and
other hematologic disorders
(megaloblastic anemia)
megaloblastic anemia in persons who
have a low dietary intake of folic acid
B. Fluoroquinolones
MoA
1. ○
- two types of bacterial type IIA
topoisomerase
(a) DNA gyrase
-> selectively bind to the A subunits
(contain the catalytic site)
-> primary target of in G(-)
(b) Type IV topoisomerase
(for decatenation)
-> primary target in G(+)
2. chelate (bind) divalent and trivalent
cations (calcium, iron, magnesium, and
Side effect and interaction
Resistance
1. tendonitis and tendon rupture.
1. alterations in the target Topo
(a) high affinity and exert direct toxic effects on the tendon matrix
-> tendon cell apoptosis
(b) >60 y; taking corticosteroids; kidney, heart, lung transplants
have higher risk
2. peripheral neuropathy
(a) tingling; weakness; and shooting pain in the. limbs, hands,feet.
(a) may begin within a few days of starting systemic therapy and
last for months or even be permanent
-> not for children, adolescents, nursing mothers, pregnancy
3. hypoglycemia and hyperglycemia
zinc) forming nonabsorbed compounds.
4. seizures
-> should be taken 2 hours before or after 5. phototoxicity (dermatitis after sun exposure)
ingesting foods and drugs containing
6. prolongation of the QT interval
7. ○
- P450 1A2 -> ○
- metabolism of caffeine, theophylline
these metallic cations.
3. concentration-dependent- killing effect
4. long postantibiotic effect
(a) should reduce caffeine intake and theophylline doses to
avoid excessive CNS stimulation
(b) can cause restlessness, anxiety, light- headedness, confusion,
and insomnia. ( Even in absence of caffeine)
(a) in bacterial DNA gyrase: G(-)
(b) in type IV topoisomerase: G(+)
2. alterations in drug access to the target
enzymes
3. expression of membrane transport
proteins or efflux pumps
-> multidrug resistance
4. ○
- levels of porins in G(-) outer
membrane-> decreased drug uptake
Drug
Use
Norfloxacin
UTI
Ciprofloxacin
1. UTI, prostatitis, and pelvic inflammatory disease: G(-)bacilli, gonococci, chlamydia, and P. aeruginosa
(oral, IV, topical)
(a) reserved for treating serious urinary tract infections and those not responding to other drugs
(b) acute uncomplicated cystitis recommends that trimethoprim-sulfamethoxazole, nitrofurantoin, and Fosfomycin
2. bacterial diarrhea and Traveler’s diarrhea: Campylobacter, Salmonella, and Shigella species, Yersinia enterocolitica
3. intraabdominal infections, bone and joint infections, skin infections, and febrile neutropenia.
4. anthrax and for postexposure prevention: Bacillus anthracis
Levofloxacin (oral, IV)
Moxifloxacin(oral, IV)
broad-spectrum fluoroquinolones
1. community-acquired pneumonia: pneumococci, Chlamydia pneumoniae, K. pneumoniae, Mycoplasma pneumoniae,
Gemifloxacin (oral)
Legionella pneumophila
2. sinusitis and bronchitis: pneumococci, H. influenzae, M. catarrhalis.
3. second line treatment for TB: Mycobacterium avium-intracellulare infections and drug-resistant tuberculosis
ciprofloxacin
Gatifloxacin
Levofloxacin
Topical for Conjunctivitis and bacterial corneal ulcers.
Moxifloxacin
Ofloxacin
C. Other antibacterial drug
Drug
MoA & Use
Nitrofurantoin acute lower urinary tract infections G(+) & G(-):
(oral)
Daptomycin
(IV)
E. coli, Enterococcus fecalis, K. pneumoniae, Staphylococcus saprophyticus.
(not active against Proteus species, Serratia species, or P. aeruginosa)
cyclic lipopeptide
1. insertion of the lipophilic daptomycin tail into cell membrane
->membrane depolarization and K+ efflux
-> ○
- nucleic acid and protein synthesis -> cell death
Side effect
1. gastrointestinal irritation, nausea, vomiting, and diarrhea.
-> Ingesting with food ○
+ absorption ○
- risk of GI irritation.
-> New macrocrystalline formulation
2. pulmonary fibrosis, hepatitis, and hematologic toxicity.
muscle toxicity.
->giving the drug once a day IV to diminish the SE
2. against strains of MRSA, vancomycin intermediate and resistant S. aureus,
and some strains of vancomycin- resistant enterococci.
(a) skin and skin-structure infections that are a complication of surgery,
diabetic foot ulcers, and burns: MARS
(b) MRSA bacteremia , right-sided infective endocarditis (but not left-sided)
3. binds to lung surfactant and should not be used for treating pneumonia
Polymyxin B
(IV, Oral)
1. interacts with the phospholipid component of bacterial cell membranes
-> disrupt cell membrane integrity
-> cytoplasmic components to leak out of the cell.
2. most G(-) bacilli: Pseudomonas aeruginosa (but not active against Proteus )
3. With bacitracin, neomycin, and trimethoprim (active against G(+))
-> topical treatment of minor skin and ocular infections.
Rifaximin
1. Traveler’s diarrhea in patients 12 years of age or older
(a) as effective as ciprofloxacin for traveler’s diarrhea caused by E. coli
(b) not effective in with fever or blood in the stool, or Campylobacter jejuni
(c) mild to moderate traveler’s diarrhea: loperamide, bismuth subsalicylate
severe case: rifaximin and other antibacterial agents
2. hepatic encephalopathy
3. irritable bowel disease (IBS).
ephrotoxicity and neurotoxicity when given parenterally
Fidaxomicin
1. ○
- RNA polymerase and RNA synthesis
2. treatment of diarrhea caused by Clostridium difficile infection
(a) metronidazole for mild to moderate C. difficile infections
(b) vancomycin for severe infections,
(c) fidaxomicin to prevent recurrences after treatment.