Quinolones and Fluoroquinolones

Quinolones

• Ciprofloxacin (CIPRO) and Levofloxacin (LEVAQUIN) and Moxifloxacin (AVELOX), Norfloxacin (NOROXIN), and Ofloxacin are Fluoroquinolones
• Nalidixic acid is a Quinolone

Mechanism of Action

• Inhibits the ligation step of bacterial DNA gyrase and bacterial topoisomerase IV
• Inhibition of gyrase increases the number of permanent chromosomal breaks
• Inhibition of topoisomerase IV interferes with the separation of newly replicated DNA

Antibacterial Spectrum

• Bactericidal and exhibits time-dependent killing
• Effective against gram-negative bacteria (E. coli and Pseudomonas), atypical bacteria, gram-positive bacteria (streptococci), and mycobacteria

Quinolone Generations

• First-generation (nonfluorinated): Nalidixic acid, with a narrow spectrum
• Second-generation: Ciprofloxacin and norfloxacin, with activity against gram-negative bacteria (Pseudomonas, H influenzae) and atypical bacteria
• Third-generation: Levofloxacin, with activity against gram-negative, atypical, and gram-positive bacteria (including S. pneumoniae and MSSA)
• Fourth-generation: Moxifloxacin, Gemifloxacin, and delafloxacin, with enhanced gram-positive effects including staph and strep and coverage of gram-negative Enterobacteriaceae

Clinically Useful Fluoroquinolones – Ciprofloxacin

• Effective against gram-negative bacteria, including P. aeruginosa
• Clinically indicated for gastroenteritis (traveler's diarrhea), typhoid fever, anthrax (drug of choice), and urinary tract infections (UTIs)
• High doses are used for pseudomonal infections

Clinically Useful Fluoroquinolones – Levofloxacin

• Similar to ciprofloxacin, but also effective against gram-positive bacteria (streptococci but not staphylococci)
• First-line therapy for community-acquired pneumonia

Clinically Useful Fluoroquinolones – Moxifloxacin

• Effective against gram-negative bacteria, S. pneumoniae, and Mycobacterium
• Used for community-acquired pneumonia (weak against Pseudomonas) and as a second-line treatment for TB

Clinical Use Cases

• Ciprofloxacin is the drug of choice for postexposure prophylaxis and for the treatment of anthrax
• Doxycycline is an alternate agent
• Ciprofloxacin and levofloxacin are effective in treating uncomplicated and complicated urinary tract infections
• Moxifloxacin has notable anti-anaerobic activity
• Levofloxacin is often effective in treating infections that are unresponsive to B-lactam antibiotics
• Ciprofloxacin is highly efficacious in treating acute diarrheal illnesses due to enteric pathogens

Fluoroquinolones – Pharmacokinetics

• Absorption: Mainly oral, but also available in IV/ophthalmic preparations
• Food (Ca2+, Al+3, and Mg2+) interferes with absorption
• Distribution: Well distributed in bone, urine, and lung tissue, with good CSF distribution
• Concentrates in macrophages and neutrophils
• Elimination: Most fluoroquinolones are excreted renally, while moxifloxacin is excreted by the liver

Quinolones – Adverse Effects

• Generally well-tolerated
• Nausea, vomiting, and diarrhea
• Headache and dizziness
• Peripheral neuropathy and glucose dysregulation
• Phototoxicity
• Boxed warning for Articular cartilage erosion, tendinitis, and tendon rupture
• QT prolongation

Quinolones – Drug-Drug Interaction

• Ciprofloxacin can inhibit the metabolism of theophylline
• Quinolones can raise serum warfarin levels

Folic Acid Antagonists

• Purine and pyrimidine synthesis requires folate-derived cofactors
• Folic acid is necessary for DNA replication and cellular growth
• Many bacteria are impermeable to folate and rely on de novo synthesis
• Folic acid must be converted into tetrahydrofolate

Sulfonamides

• Synthetic analogues of PABA
• PABA synthesizes dihydrofolate
• Bacteriostatic
• Inhibits dihydropteroate synthetase

Sulfonamides – Antibacterial Spectrum

• Effective against Enterobacteriaceae causing UTIs
• Effective against H. influenzae, streptococci, and staphylococci spp.

Sulfonamides – Mechanisms of Resistance

• Altered dihydropteroate synthetase
• Decreased cellular permeability
• Enhanced production of PABA

Sulfonamides – Pharmacokinetics

• Absorption: Well-absorbed orally, except for sulfasalazine
• Distribution: Highly bound to serum albumin, distributes well through body fluids including CSF, crosses the placenta, and is eliminated in breast milk
• Metabolism: Metabolized in the liver (acetylation and conjugation), acetylated metabolites can crystalize in urine, causing renal stones
• Elimination: Eliminated by glomerular filtration and secretion

Sulfonamides – Adverse Effects

• Crystalluria, leading to nephrotoxicity, requires adequate hydration and urine alkalinization
• Hypersensitivity, including sulfa allergies
• Hematopoietic disturbances, including hemolytic anemia in patients with G6PD deficiency
• Kernicterus in newborns
• Sulfonamides displace protein-bound bilirubin in plasma
• Drug-drug interaction: increases the anticoagulant effect of warfarin
• Contraindications: Newborns, infants, breastfeeding women, and with methenamine

Trimethoprim

• Reduced to tetrahydrofolate by dihydrofolate reductase
• Inhibits dihydrofolate reductase
• Decreases purine and pyrimidine synthesis
• Bacterial vs mammalian selectivity
• Mostly combined with sulfa drugs

Trimethoprim – Adverse Effects

• Can produce the effects of folic acid deficiency, including megaloblastic anemia, leukopenia, and granulocytopenia,
• Reversed by administration of folinic acid, which does not enter bacteria
• Hyperkalemia

Trimethoprim/Sulfamethoxazole (Cotrimoxazole)

• Synergistic effect due to inhibition of two sequential steps in the synthesis of tetrahydrofolic acid.

Cotrimoxazole – Antibacterial Spectrum

• Effective in treating UTIs and respiratory tract infections (RTIs)
• Effective against Pneumocystis jirovecii pneumonia
• Treats Skin and soft tissue MRSA infections

Cotrimoxazole – Pharmacokinetics

• Administered orally (IV reserved for severe cases of PCP)
• Crosses the blood-brain barrier (BBB)
• Excreted in the urine

Cotrimoxazole – Adverse Effects

• Nausea, vomiting, and diarrhea
• Skin reactions
• Glossitis/stomatitis
• Hyperkalemia
• Megaloblastic anemia
• Hemolytic anemia in patients with G6PD deficiency
• Drug-drug interaction with warfarin

Metronidazole

• Nitroimidazole antiprotozoal drug with antibacterial activity against anaerobes, including Bacteroides and Clostridium
• Selectively absorbed by anaerobic bacteria and sensitive protozoa
• Well-absorbed after oral administration, is widely distributed in tissues
• Can be given intravenously or by rectal suppository
• Penetrates well into the cerebrospinal fluid and brain

Metronidazole – Clinical Indications

• Treatment of anaerobic or mixed intra-abdominal infections (in combination with other agents with activity against aerobic organisms)
• Vaginitis (trichomonas infection, bacterial vaginosis)
• Clostridium difficile colitis
• Brain abscess
• Mouth infections, including infected gum and dental abscesses

Metronidazole – Metabolism and Adverse Effects

• Metabolized in the liver and may accumulate in hepatic insufficiency
• Nausea and diarrhea
• Peripheral neuropathy with prolonged use
• Disulfiram-like effect, patients should avoid alcohol