Fluroquinolone Flashcards
What are the fluoroquinolones MOA
✓ Fluoroquinolones enter bacteria through porin channels and exhibit
antimicrobial effects on DNA gyrase (bacterial topoisomerase II) and
bacterial topoisomerase IV.
✓ Inhibition of DNA gyrase results in prevention of supercoiled DNA
relaxation that is required for normal transcription and replication.
✓ Inhibition of topoisomerase IV impacts chromosomal stabilization
during cell division, thus interfering with the separation of newly
replicated DNA.
✓ The result of these effect is an increased number of permanent
chromosomal breaks thus triggering cell lysis
What is the spectrum for fluoroquinolones
Fluoroquinolones are commonly considered alternatives for patients
with a documented severe β-lactam allergy.
✓ Fluoroquinolones may be classified into “generations” based on their
antimicrobial targets( spectrum of activity).
✓ The nonfluorinated quinolone nalidixic acid is considered to be first
generation, with a narrow spectrum of susceptible organisms.
✓ Ciprofloxacin and norfloxacin are second generation because of their
activity against aerobic g-ve and atypical bacteria.
✓ In addition, these fluoroquinolones exhibit significant intracellular
penetration, allowing therapy for infections in which a bacterium
spends part or all of its life cycle inside a host cell (for example,
chlamydia, mycoplasma, and mycobacteria).
✓ Levofloxacin is classified as third generation because of its increased
activity against g+ve bacteria.
✓ The fourth generation includes moxifloxacin( gemifloxacin, delafloxacin)
because of their enhanced activity against anaerobic and g+ve
organisms
Fluoroquinolones are bactericidal and exhibit (AUC/MIC)–dependent
killing.
✓ Bactericidal activity is more pronounced as serum drug concentrations
increase to approximately 30-fold the MIC of the bacteria.
✓ In general, fluoroquinolones are effective against:
✓ g-ve organisms (E. coli, P. aeruginosa, H. influenzae),
✓ atypical organisms (Legionellaceae, Chlamydiaceae),
✓ g+ve organisms (streptococci),
✓ and some mycobacteria (M. tuberculosis).
✓ Levofloxacin and moxifloxacin are sometimes referred to as “respiratory
fluoroquinolones,” because they have excellent activity against S.
pneumoniae, which is a common cause of community-acquired
pneumonia (CAP).
✓ Moxifloxacin also has activity against many anaerobes.
✓ Unfortunately, fluoroquinolone use has been closely tied to Clostridium
difficile infection and the spread of antimicrobial resistance in many
organisms
✓ The unfavourable effects of fluoroquinolones on the induction and
spread of antimicrobial resistance are sometimes referred to as
“collateral damage,” a term which is also associated with third-
generation cephalosporins (for example, ceftazidime).
When do we use the different fluoroquinolones (spectrum)
- Ciprofloxacin:
✓ Ciprofloxacin is effective in the treatment of many systemic infections caused
by g-ve bacilli (Figure 31.2).
✓ Of the fluoroquinolones, it has the best activity against P. aeruginosa and is
commonly used in cystic fibrosis patients for this indication.
✓ With 80% bioavailability, IV and oral formulations are frequently interchanged.
✓ Traveler’s diarrhea caused by E. coli as well as typhoid fever caused by
Salmonella typhi can be effectively treated with ciprofloxacin.
✓ Ciprofloxacin is used as a second-line agent in the treatment of tuberculosis.
✓ Although typically dosed twice daily, an extended-release formulation is
available for once-daily dosing, which may improve patient adherence to
treatment. - Levofloxacin:
✓ Due to its broad spectrum of activity, levofloxacin is utilized in a wide range of
infections, including prostatitis, skin infections, CAP, and nosocomial
pneumonia.
✓ Unlike ciprofloxacin, levofloxacin has excellent activity against S.
pneumoniae respiratory infections. Levofloxacin has 100% bioavailability and
is dosed once daily. - Moxifloxacin:
✓ Moxifloxacin not only has enhanced activity against g+ve (ex., S.
pneumoniae)
✓ but also has excellent activity against many anaerobes, although resistance
to Bacteroides fragilis has been reported.
✓ It has poor activity against P. aeruginosa.
✓ Moxifloxacin does not concentrate in urine and is not indicated for the
treatment of UTIs.
▪ 4. Geifloxacin:
▪ Indicated for community –acquired respiratory infections
▪ 5. Delafloxacin:
▪ improved activity against gram +ve cocci including MRSA & enterococcus
species
How is resistance formed for fluoroquinolones
- Altered target
- Decreased accumulation:
Reduced intracellular concentration is linked to
1) porin channels and
2) efflux pumps.
What are the pharmacokinetics for fluoroquinolones
- Absorption:
✓ Only 35%-70% of orally administered norfloxacin is absorbed,
compared with 80%-99% of the other fluoroquinolones (Figure 31.3).
✓ IV preparations of ciprofloxacin, levofloxacin, and moxifloxacin are
available .
✓ ophthalmic preparations of levofloxacin, moxfloxacin, gatifloxacin are
used to treat bacterial conjunctivitis
✓ Ingestion of fluoroquinolones with sucralfate, Al+3
, Mg+2 containing
antacids, or dietary supplements containing iron or zinc can reduce the
absorption.
✓ Ca+2 and other divalent cations also interfere with the absorption of
these agents - Distribution:
✓ Binding to plasma proteins ranges from 10%-40%.
✓ The fluoroquinolones distribute well into all tissues and body fluids,
which is one of their major clinical advantages.
✓ Levels are high in bone, urine (except moxifloxacin), kidney, and
prostatic tissue (but not prostatic fluid), and concentrations in the lungs
exceed those in serum.
✓ Fluoroquinolones also accumulate in macrophages and
polymorphonuclear leukocytes, thus having activity against intracellular
organisms. - Elimination:
✓ Most fluoroquinolones are excreted renally. Therefore, dosage
adjustments are needed in renal dysfunction.
✓ Moxifloxacin is excreted primarily by the liver, and no dose adjustment
is required for renal impairment.
What are the side effects for fluoroquinolones
✓ Like most antibiotics, the most common adverse effects of
fluoroquinolones are nausea, vomiting, and diarrhea.
✓ Headache and dizziness or light headedness may occur.
✓ Patients with CNS disorders, such as epilepsy, should be treated
cautiously with these drugs.
✓ Peripheral neuropathy and glucose dysregulation (hypoglycemia) have
also been noted.
✓ Fluoroquinolones can cause phototoxicity, and patients taking these
agents should be advised to use sunscreen and avoid excess exposure
to sunlight.
✓ If phototoxicity occurs, discontinuation of the drug is advisable.
✓ Articular cartilage erosion (arthropathy) has been observed in
immature animals exposed to fluoroquinolones.
✓ Therefore, these agents should be avoided in pregnancy and lactation
and in children under 18 years of age. [Note: Careful monitoring is
indicated in children with cystic fibrosis who receive fluoroquinolones
for acute pulmonary exacerbations.]
✓ An increased risk of tendinitis or tendon rupture may also occur with
systemic fluoroquinolone use.
✓ Moxifloxacin and other fluoroquinolones may prolong the QTc interval
and, thus, should not be used in patients who are predisposed to
arrhythmias or those who are taking other medications that cause QT
prolongation.
✓ Ciprofloxacin inhibits CYP1A2 mediated metabolism, leading to
increased blood concentrations of medications such as alprazolam,
tizanidine, warfarin, duloxetine, caffeine, zolpidem(
What are folate antagonists
• Folic acid is a coenzyme essential for synthesis of DNA, RNA
and amino acids.
• In the absence of folic acid , cells can not grow or divide
• Human vs bacteria in utilization of folic acid( figure 31.7)
• Sulfonamides are drugs that inhibit the de novo synthesis of
folate
• Trimethoprim inhibits the 2nd step : conversion dihydrofolic
acid to tetrahydrofolic acid
What are sulfonamides MOA
. Mechanism of action
✓ In many microorganisms, dihydrofolic acid is synthesized from p-
aminobenzoic acid (PABA), pteridine, and glutamate (Figure 31.7).
✓ All the sulfonamides currently in clinical use are synthetic analogs of PABA.
✓ Because of their structural similarity to PABA, the sulphonamides compete
with this substrate for the bacterial enzyme, dihydropteroate synthetase.
✓ They thus inhibit the synthesis of bacterial dihydrofolic acid and, thereby,
the formation of its essential cofactor forms.
✓ The sulfa drugs are bacteriostatic.
What is the spectrum for sulfonamides
Sulfa drugs are active against select Enterobacteriaceae in UT and
Nocardia infections.
✓ In addition, sulfadiazine in combination with the dihydrofolate reductase
inhibitor pyrimethamine is the preferred treatment for toxoplasmosis.
✓ Sulfadoxine in combination with pyrimethamine is used as an antimalarial
drug.
How is resistance formed for sulfonamides
✓ Bacteria that can obtain folate from their environment are naturally
resistant to these drugs.
✓ Acquired bacterial resistance to the sulfa drugs can arise from plasmid
transfers or random mutations.
✓ Organisms resistant to one member of this drug family are resistant to all.
✓ Resistance is generally irreversible and may be due to
✓ 1) an altered dihydropteroate synthetase,
✓ 2) decreased cellular permeability to sulfa drugs,
✓ 3) enhanced production of the natural substrate, PABA.
What are the pharmacokinetics for fluoroquinolones
❑ Absorption:
✓ After oral administration, most sulfa drugs are well absorbed (Figure 31.8).
✓ An exception is sulfasalazine. It is not absorbed when administered orally or
as a suppository and, therefore, is reserved for treatment of chronic
inflammatory bowel disease (ex., ulcerative colitis).
✓ IV sulfonamides are generally reserved for patients who are unable to take
oral preparations.
✓ Because of the risk of sensitization, sulfa drugs are not usually applied
topically.
✓ However, in burn units, creams of silver sulfadiazine or mafenide acetate (α-
amino-p-toluene sulfonamide) have been effective in reducing burn-
associated sepsis because they prevent colonization of bacteria.
❑ Distribution:
✓ Sulfa drugs are bound to serum albumin in the circulation.
✓ Sulfa drugs distribute throughout the bodily fluids and penetrate well into
CSF—even in the absence of inflammation. They can also pass the placental
barrier and enter fetal tissues.
❑ Metabolism:
✓ The sulfa drugs are acetylated and conjugated primarily in the liver.
✓ The acetylated product is devoid of antimicrobial activity but retains the
toxic potential to precipitate at neutral or acidic pH. This causes crystaluria
(“stone formation”) and, therefore, potential damage to the kidney.
❑ Excretion:
✓ Sulfa drugs are eliminated by GF & secretion and require dose adjustments
for renal dysfunction. Sulfonamides may be eliminated in breast milk.
What are the adverse effects for fluoroquinolones
- Crystalluria (Adequate hydration and alkalinization of urine).
- Hypersensitivity: rashes, angioedema or Stevens-Johnson syndrome, may
occur. - Hematopoietic disturbances:
Hemolytic anemia is encountered in patients with G6PD deficiency.
Granulocytopenia and thrombocytopenia can also occur.
Fatal reactions have been reported from associated agranulocytosis, aplastic
anemia, and other blood dyscrasias. - Kernicterus:
✓ This disorder may occur in newborns, because sulfa drugs displace bilirubin
from binding sites on serum albumin. The bilirubin is then free to pass into
the CNS, because the BBB is not fully developed. - Drug potentiation:
✓ Transient potentiation of the anticoagulant effect of warfarin results from
the displacement from binding sites on serum albumin.
✓ Serum methotrexate levels may also rise through its displacement. - Contraindications:
✓ Due to the danger of kernicterus, sulfa drugs should be avoided in
newborns and infants less than 2 months of age, as well as in pregnant
women at term.
✓ Sulfonamides should not be given to patients receiving methenamine,
since they can crystallize in the presence of formaldehyde produced by this
agent (Figure 40.10)
What is trimethoprim
✓ A potent inhibitor of bacterial dihydrofolate reductase, exhibits an
antibacterial spectrum similar to that of the sulfonamides.
✓ Trimethoprim is most often compounded with sulfamethoxazole,
producing the combination called cotrimoxazole.
A. Mechanism of action
✓ Figure 31.7
✓ The bacterial reductase has a much stronger affinity for trimethoprim than
does the mammalian enzyme, which accounts for the selective toxicity of
the drug.
B. Antibacterial spectrum
✓ The antibacterial spectrum of trimethoprim is similar to that of
sulfamethoxazole. However, trimethoprim is 20- to 50-fold more potent
than the sulfonamides.
✓ Trimethoprim may be used alone in the treatment of UTIs and in the
treatment of bacterial prostatitis (although fluoroquinolones are
preferred).
C. Resistance
✓ Resistance in g-ve bacteria is due to the presence of an altered dihydrofolate
reductase that has a lower affinity for trimethoprim.
✓ Efflux pumps and decreased permeability to the drug may play a role.
D. Pharmacokinetics
✓ Trimethoprim is rapidly absorbed following oral administration.
✓ Because the drug is a weak base, higher concentrations of trimethoprim are
achieved in the relatively acidic prostatic and vaginal fluids.
✓ The drug is widely distributed into body tissues and fluids, including penetration
into the CSF.
✓ Trimethoprim undergoes some O-demethylation, but 60% to 80% is renally
excreted unchanged.
E. Adverse effects
✓ Trimethoprim can produce the effects of folic acid deficiency.
✓ These effects include:
✓ megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant
patients and those having very poor diets.
✓ These blood disorders may be reversed by the simultaneous administration of
folinic acid, which does not enter bacteria.
What is cotrimoxazole
✓ The combination of trimethoprim with sulfamethoxazole, called
cotrimoxazole, shows greater antimicrobial activity than equivalent
quantities of either drug used alone (Figure 31.10).
✓ The combination was selected because of the synergistic activity and the
similarity in the half-lives of the two drugs.
A. Mechanism of action
✓ The synergistic antimicrobial activity of cotrimoxazole results from its
inhibition of two sequential steps in the synthesis of THFA (Figure 31.7).
B. Antibacterial spectrum
✓ Cotrimoxazole has a broader spectrum of antibacterial action than the
sulfa drugs alone (Figure 31.12).
C. Resistance
✓ Resistance to the trimethoprim–sulfamethoxazole combination is less
frequently encountered than resistance to either of the drugs alone,
✓ because it requires that the bacterium have simultaneous resistance to
both drugs. Significant resistance has been documented in a number of
clinically relevant organisms, including E. coli.
D. Pharmacokinetics
✓ Cotrimoxazole is generally administered orally (Figure 31.12).
✓ IV dministration may be utilized in patients with severe pneumonia caused
by P.jirovecii
✓ Both agents distribute throughout the body.
✓ Trimethoprim concentrates in the relatively acidic milieu of prostatic fluids,
and this accounts for the use of trimethoprim–sulfamethoxazole in the
treatment of prostatitis.
✓ Cotrimoxazole readily crosses BBB.
✓ Both parent drugs and their metabolites are excreted in the urine.
E. Adverse effects
✓ Glossitis and stomatitis have been observed. Hyperkalemia may occur,
especially with higher doses.
✓ Megaloblastic anemia, leukopenia, and thrombocytopenia may occur and
have been fatal. The hematologic effects may be reversed by the concurrent
administration of folinic acid, which protects the patient and does not enter
the microorganism. Hemolytic anemia may occur in patients with G6PD
deficiency due to the sulfamethoxazole component.
Adverse effects
✓ Immunocompromised patients with PCP frequently show drug-induced
fever, rashes, diarrhea, and/or pancytopenia.
✓ Prolonged prothrombin times (increased INR) in patients receiving both
sulfamethoxazole and warfarin have been reported,
✓ and increased monitoring is recommended when the drugs are used
concurrently.
✓ The plasma half-life of phenytoin may be increased due to inhibition of its
metabolism.
✓ Methotrexate levels may rise due to displacement from albumin-binding
sites by sulfamethoxazole.
