Dr. Roane FQ EXAM 2 Flashcards
What is considered the old quinolone?
Nalidixic acid
What is Nalidixic acid used for?
Simple UTI infections
What is the prototype of Fluoroquinolones?
Ciprofloxacain 2nd Gen (Cipro)
How are Fluoroquinolones diffrent from Quinolones?
Flourid-atom added to the core structure
-> Improvement in safety and efficacy
Spectrum activity of FQ
-Legionella, Salmonella, Shigella
-E. coli, Neisseria (gonorrhea) Proteus sp, Vibrio cholerae, Campylobacter jejuni
BUT IT CHANGES
Spectrum activity of FQ by generation
1st GEN: Gram (-) rods
2nd GEN: more Gram (-) rods, Gram (+) cocci, Mycoplasma and Chlamydia
3rd: retain gram (-) and Mycoplasma, Chlamydia; more specific gram (+) cocci
4th: retain gram (-), improves gram (+) cocci and bacilli, gains anaerobic coverage
JUST NEED TO KNOW: Coverage increases with GEN
How are Fluoroquinolones classified?
Older group: Ciprofloxacin, norfloxacin, and ofloxacin
Newer group (respiratory FQ): Gemifloxacin, levofloxacin, and moxifloxacin
Despite activity against resistant bacteria, what is the downside of FQ?
-variety of serious adverse effects causing multiple FQs to be withdrawn
-Grepafloxacin, Sparfloxacin, Trovafloxin, Gatifloxacin,…
-Delafloxacin (Baxdela): indicated for acute skin infections (ABSSSI) -> Blackbox warning: Tendinitis and tendon rupture, Peripheral neuropathy, CNS effects
What is the MOA for FQs?
-Binding and inhibiting DNA Gyrase (gram (-)) and topoisomerase IV (gram (+)) -> involved in unwinding DNA for replication
-Bacteriocidal
Where does FQ bind to inhibit the bacteria?
-it binds to the subunit GyrA
-The DNA Gyrase consists of the Gyr A and Gyr B subunit
How does the resistance of bacteria against FQ occur?
Ciprofloxacin binds to a specific acid -> after mutation it doesn’t bind anymore
Which serious disease is resistant to Ciprofloxacin?
Meningococcal disease caused by Ciprofloxacin-resistant N. gonorrhea (10-14% fatal)
-colonizes mucosal surfaces of the nasal pharynx -> transmitted through direct contact with the nasal secretion of infected patients
What is the MOA of Nitrofurantoin?
-When chemically reduced by bacteria, it forms highly reactive free radicals that cause DNA damage in microbes
Side effects of Nitrofurantoin
-Colors the urine brown
-Hemolytic anemia in pts. with glucose-6-phosphate dehydrogenase deficiency
Why might Nitrofurantoin cause harm to patients with G6PD deficiency?
-G6PD converts NADP+ to NADPH
-NADPH replenishes GSH (Glutathione)
GSSG (oxidized) to GSH (reduced)
-GSH is an Antioxidant which provides protection against free radicals, like those caused by Nitrofurantoin
MOA of Methenamine (hexamine)
- At low pH in the urine Methenamine is converted to Formaldehyde -> antiseptic in the UTI (and analgesic) - no resistance against Formaldehyde
-Alternate use: topical for hyperhidrosis, antiperspirant, solid fuel for camping
What is the consequence of DNA Replication ahead of the two replication folks?
-Supercoiling
-increased tension
How is the tension relieved?
Topoisomerase I: cuts 1 strand -> passes the other strand through the cut -> reseals -> decrease in 1 twist on the supercoil
Topoisomerase 2: cuts 2 strands -> passes another double-strand to the cut -> reseal -> decrease in 2 twists on the supercoil
Which bacterial enzymes is responsible for removing superhelical twist on the bacterial DNA?
DNA Gyrase (Topoisomerase II)
-also involved in the initiation of replication and transcription of many genes
What does the bacterial DNA Gyrase consist of?
-2x Gyrase A subunits
-2x Gyrase B subunits
What is the role of Topoisomerase IV?
Separating the new from the old semiconservative (1 old and 1 new strand) DNA helices
MOA FQ Gyrase
-FQ binds to DNA Gyrase and Topoisomerase IV
-It stabilizes the Enzyme-DNA-complex -> breaks in the DNA -> cell death
-Interferes with DNA when binding to DNA Gyrase
The Gyrase of which organisms are used as a target for FQ?
Gram-negative bacteria
MOA FQ Topoisomerase IV
-In gram-positives (Staph, Strep) - Gyrase as the secondary target
-FQ disrupts the separation between the new and old DNA in the cell -> cell death
What affects the potency and spectrum of activity of different FQs?
Affinity to DNA Gyrase and Topoisomerase IV or both
How does bacteria require resistance?
-Mutations in chromosomal genes altering target enzymes DNA Gyrase and Topoisomerase IV
Frequency: 10^-6
What are the factors that affect the activity of FQs after mutation?
Number of mutations, location of the mutations, and which of the enzymes is affected
Where do mutations occur in Gyrases and Topoisomerase IV?
Gyrase: gyrA or gyrB genes
Topoisomerase IV: ParC or ParE gene
-> reduced affinity of FQ for the enzymes
Why are FQ antibiotics with similar affinity and potency against both target enzymes beneficial?
Because mutation on both enzymes are required for resistance
What kind of improvements were accomplished due to the addition of the Fluor atom to the quinolone structure?
-Potency
-Antimicrobial spectrum
-Pharmacokinetics
-Safety
Spectrum of activity of Ciprofloxacin (oldest FQ)
Narrow mainly gram-negative
The spectrum of activity of the “newer” FQ
-Gram-negative
-Gram-positive: Pneumo cocci
-atypical pathogens
->called respiratory FQ
What are the respiratory FQs?
-Levofloxacin
-Gemifloxacin
-Moxifloxacin
Common Clinical use of FQ
-Community-acquired pneumonia
-UTI -> compromised due to resistance (especially E.coli (most common for UTI)
Strep pneumonia
Haemophilus influenzae
Moraxella spp
atypical species
