This document discusses quinolones, a class of antibiotics. It describes their mechanism of action as inhibiting DNA gyrase and topoisomerase enzymes in bacteria, making them bactericidal. It notes their spectrum of activity varies between generations, from gram-negative to expanded gram-positive and atypical pathogen coverage. A case study examines drug interactions between a quinolone and calcium supplements, advising separation of administration.

1. QUINOLONES
ANTIBIOTICS
Case study

2. • MOA: Inhibitor of DNA replication and transcription by inhibiting DNA gyrase (topoisomerase II)
enzyme in gm-ve bacteria and topoisomerase IV enzyme in gm+ve bacteria (2nd - 4th generations).
• Bactericidal
• C/I: epilepsy and hypersensitivity.
 Spectrum of activity:
First generation Gram-negative, but not Pseudomonas
Second generation Gram-negative including Pseudomonas, some gram-positive
Third generation Same as for second plus expanded gram-positive and activity against atypical pathogens
Fourth generation Same as for third generation plus expanded activity against anaerobic pathogens

3.  BG comes into the chain-store pharmacy in California, where you work, with a prescription for his wife AG. The
prescription calls for twelve 500-mg of drug A tablets, with the directions to take two tablets daily for diarrhea.
The customer explains that his wife has just returned from a vacation in Acapulco, only to come down with a
severe case of traveler’s diarrhea on the last day. You recall that AG is a regular customer and make a quick
check of her patient record to see if there are any drug interactions involving her other medications and drug A.
You discover that AG is currently takes OTC calcium supplements to prevent osteoporosis. Then answer the
following questions.

4. QUESTION 1:
 What advice should you give to BG to convey to the patient regarding the ciprofloxacin and the
medication she is taking?
 The correct answer is:
 4–carbonyl and 3 carboxylic groups are excellent sites for chelating with metals either di- or trivalent metals to produce
complexes with lost potency, thus quinolones are incompatible with antacids (Ca+2, Mg+2, Bi+2), Heamatinics (Fe+2),
mineral supplements (Zn+2) and dairy products (Ca+2).
 So, avoid taking Ciprofloxacin with Calcium supplements, since decrease its absorption resulting in lower serum and
urine levels than the desired, so shouldn't use concurrently and should be separated in their administration.

5.  Question 2:
 Mention the mechanism of action of this class of agents.
 The correct answer is:
 Mechanism of action of Quinolones: (as bactericidal)
 Quinolones are bactericidal agents; they inhibit the replication and transcription of bacterial DNA by stabilizing the complex
formed between DNA and topoisomerases.
 By inhibiting of DNA gyrase enzymes (bacterial topoisomerase II in gm -ve) and topoisomerase IV in gm +ve.
 Question 3:
 Classify the provided drugs according to their chemical structure and also according to their generation
providing the spectrum for each generation.
1,8-Naphthyridine derivative 6
4-Quinolone All others
The correct answer is:
•According to chemical classification

6.  According to generation and spectrum
First generation F Gram-negative, but not Pseudomonas
Second generation A,D,E
Second-generation agents (Cipro, Nor, and Ofloxacin)
Gram-negative including Pseudomonas, some gram-positive.
Third generation C
Third-generation agents (e.g. Levo and Sparfloxacin)
Same as for second plus expanded gram-positive and activity against atypical pathogens.
Fourth generation B
Fourth-generation agents: (e.g. Gatifloxacin): Same as for third generation plus expanded
activity against anaerobic pathogens

7.  Question 4:
 What is the effect of the presence of fluorine atoms in the provided fluorinated
derivatives?
 The correct answer is:
 Fluorine atom increases the activity due to increased lipophilicity, leading to increased cell and tissue penetration
besides (increased potency against Gram-positive organisms)
 It also increases the photosensitivity (phototoxicity).
 Question 5:
 What is Effect of piperazine moiety at position 7 in the provided derivatives
 The correct answer is:
 Improves the spectrum of activity especially against Gram negative organisms (and improves antipseudomonal
activity).
 Unfortunately, such substitutions increase binding to CNS γ- aminobutyric acid (GABA) receptors→ GABA
antagonist → CNS stimulation side effects (e.g., irritability, tremor, sleep disorders, vertigo, anxiety, agitation,
convulsions).
 Overcome by either Adding a methyl or ethyl gp to the N of piperazine ring. eg. Ofloxacin.

8.  G.H 25 year old HIV patient with HIV induced erythema came to hospital suffering from congestion, and cough with
greenish sputum. Her blood and sputum cultures yielded beta lactamase producing Pseudomonas aeruginosa. She also
had a history of panic attacks. Her physician asked you to choose an oral quinolone derivative that best suits her case
from Medicinal chemistry point of view.

9.  Question 1:
 Select the most suitable oral quinolone derivative for this case, justify your selection.
 The correct answer is:
 Drug (C) (moxifloxacin) is the DOC.
 You have to choose quinolone derivative that is:
 Active against P.aurigonoasa (2nd, 3rd or 4th generation of quinolones)
 Has lower CNS side effects
 (CNS side effects due to piperazinyl substituent at 7 position with free secondary amine).

10.  Question 2:
 Select drug(s) that may exacerbate her HIV induced erythema (skin redness & inflammation), justify your
selection.
 The correct answer is:
 Drug (B) (Lomefloxacin) mainly
 Justify
 You have to avoid quinolone derivative that contains 8 fluoro substitution (as it increases drug induced photosensitivity
(erythema)).
 How to overcome?
 Addition of amino or methoxy group at 5 or 8 position decreases drug induced photosensitivity.
 Question 3:
 Clarify the role of methoxy group in drug C.
 8-Methoxy group enhances target inhibition, especially for:
 Dual inhibition against both DNA gyrase and topoisomerase IV in the bacterial cell.
 Decreases drug induced photosensitivity.