Living Textbook MC610

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These are also synthetic agents that were discovered by accident. The first agent, Nalidixic acid was discovered in 1963 as an impurity in the synthesis of Chloroquine, an antimalarial agent, and showed significant antimicrobial activity, but had a relatively narrow spectrum.

The first group of agents were used only for UTI as they were eliminated too quickly for successful systemic treatment, and were effective only against Gram negative bacteria, with no appreciable activity against Gram positive or pseudomonas. Modifications to the chemical structure yielded more useful structures that are in use today.

Structure Activity Relationship:

1-position, substitutions can lead to changes in activity, these can include:

Alkyl, small groups like methyl, ethyl or cyclopropyl.

Aryl, 2,4-difloro phenyl is the best

2-position, a carbon or nitrogen will show activity.

3-position, you need an unsubstituted carboxylic acid.

4-position, the ketone is a must.

The first ring can be reduced to a Dihydro ring

5, 6, 7 and 8-position, substitutions are allowed and may enhance activity. At the 6 and 8-positions, flourine, chlorine and methoxy are the best substitution, steric effect (?).

Placing a flourine at the 6-position increases activity significantly.

Replacing ring carbons with nitrogens will retain activity.

Placing nitrogen containing rings at the 7-position especially piprazinyl ring, will give the agent good antipseudomonal activity.

You can also have a third fused ring to the quinolone ring.

In general the 6-flouro, 7-piprazyl agents showed the most extended spectrum including pseudomonas. The molecule must be co-planner

Mechanism of Action:

These agents inhibit DNA Topoisomerases type II, specifically DNA Gyrase and Topoisomerase IV that are responsible for negative supercoiling of DNA, important for packing of DNA and further ability to replicate and be transcribed.

What is the basis for its use as an antimicrobial agent?

Topoisomerase type II are the enzyme in prokaryotes only. It is made up of two units, A and B. The A subunit forms a nick in the circular DNA, forms the supercoil and then closes the formed nick. The B subunit is an ATPase to supply energy for the process. Quinolones bind to the A subunit and block the last step, that is the resealing of the nick. This results in DNA breaks.

The importance of inhibition of one topoisomerase (DNA gyrase vs. Topoisomerase IV) depends on the bacterial species. Inhibition of DNA gyrase is more important in Gram negative bacteria, while Topoisomerase IV is more important in Gram positive bacteria.

Quinolones do not bind to human Topoisomerases.

Thus these agents are bactericidal.


Quinolones are well absorbed and are highly protein bound.

These agents are able to enter the cells via porin channels in Gram negative bacteria, and by lipophilicity in Gram positive bacteria.

Resistance occurs through mutations in the enzyme (gyrase and topoisomerase) to decrease their affinity to Quinolones. Agents that can inhibit both enzymes have a lower risk of developing resistance.
Other forms of resistance include changes in porins to diminish uptake into the cells and active efflux of the drugs.

The carboxylic acid at the 3-position has a relatively high pKa of about 6 - 6.4, due to hydrogen bond formation with the 4-keto group. If you have a 7-piprazinyl group, it will have a pKa around 8.1 - 9.3. This means there is a potential for a Zwitterion formation, which will not affect absorption, but may lead to crystalluria.

Another problem is the possibility of chelation with metals, and should not be administered with antacids, mineral supplements or dairy products, which can affect absorption.

Some agents such as ciprofloxacin may inhibit CYP450, which can lead to drug interactions. An example is Warfarin and caffiene. They also compete for renal excretion with some drugs such as Probencid and Theophylline.

Another clinically relevant interaction is concomitant use with NSAIDs, which can lead to increased risk of seizures, due to inhibition of GABA signaling.

Side effects include GI and CNS effects, rasha nd photosensitivity. They may cause neuromuscular blocking activity that can exacerbate muscle weaknesses in myasthenia gravis. Hemolytic anemia may arise in G6PD deficient patients.

Other rare but serious side effects include CNS toxicities, peripheral neuropathy, QT prolongation and tendonopathy, espacially in children and the elderly. They are not generally recommended for children under 18 years, during the first trimester of pregnancy or to females who are considering pregnancy.

Individual Agents:

Nalidixic acid is very polar with 96% absorption, but excreted very quickly. It is metabolized to the 7-hydroxy agent, which is more active. Used for uncomplicated UTI against gram negative.bed with less protein binding.

Cinoxacin is also used for UTI and is better absorbed with less protein binding.

Fluoroquinolones are not as rapidly excreted but are still very well absorbed. They were first introduced in 1986 and since thousands of analogs have been synthesized and tested:

Norfloxacin is used both systemically and in ophthalmic preparations. It is more effective against Gram negative agents and pseudomonas. It has a PI of 7.5, which can be a problem with crystalluria. It is used in UTI and as a single dose in gonorrhea.

Enoxacin has excellent oral bioavailability. It is also used with hydrocortisone in eye drops. It can inhibit Cytochrome P450.

Ciprofloxacin shows good oral bioavailability, 70-80%, and is used both orally and parenterally. It is widely distributed to all parts of the body including the CSF. It has a PI of 7.42 (crystalluria), and competes with probencid for excretion. It is incompatible with alkaline drugs, especially in IV preparations.

Ofloxacin is used orally and in ear and eye drops. It has better oral bioavailability, 95 - 100%, and is combined with Doxycillin for gonococcal infections.

The 3 S(-), Levofloxacin (Levaquin®) is much more active than the 3 R(+).

Lemefloxacin has a longer half life, due to tissue distribution and renal reabsorption, and a high oral bioavailability, 95 - 98%. It is given once a day.

Sparfloxacin is very potent, and shows very good activity against Gram positive bacteria. It also has a long half life and is given in a once a day dosing. Used in respiratory infections, UTI and gonococcal infections.

Gatifloxacin and Moxifloxacin show a high bioavailabilty, around 96% and a long half life allowing once a day dosing, and show no drug interactions except with antacids. The 8-methoxy group seems to improve activity.

Finafloxacin and Delafloxacin were recently approved for specific indications (see below). Delafloxacin does not form Zwitterions, which makes it non-ionized in acidic environment. This may play a role in why it is useful in skin infections and may also improve penetration through Gram positive bacteria.

Gemifloxacin is a fluoroquinolone antibacterial indicated for the treatment of susceptible respiratory and urinary tract infections. It is used as a once a day dose

Trovafloxacin was introduced in 1998. It is more effective than other agents against Gram positive bacteria, but has since been shown to cause liver injuries and is reserved to institutional use.

Grepafloxacin was withdrawn from the market by Glaxo wellcome due to a serious side effect on cardiac repolarization, prolonging the QT intervals and leading to arrythmiasis.

Clinical Applications:

General: Bactericidal, older agents with a narrow spectrum, which improved with newer agents.

Nalidixic acid:

Coverage includes Gram negative bacteria

Indications and Uses: Uncomplicated UTI


Coverage includes aerobic Gram negative rods (Enterobacteriaceae, Hemophilus, Pseudomonas spp. and Salmonella typhi), Gram negative cocci (Neisseria spp.) and limited Gram positive bacteria (Bacillus anthracis)

Non-susceptible organisms include most Gram positive bacteria such as MRSA and Streptococcus pneumonia and anaerobes.

Indications and Uses:Urinary tract and bladder infections, sexually transmitted diseases (such as gonococcal infections), prostatitis, bone and joint infections, complicated intra-abdominal infections (in combination with metronidazole), infectious diarrhea, typhoid fever, and hospital-acquired pneumonia (HAP/HCAP/VAP to cover Pseudomonas spp.), but not CAP.

It is also used as prophylaxis against meningitis caused by Neisseria meningitidis.

Levofloxacin and Moxifloxacin:

Coverageincludes wider range of Gram positive bacteria, in expense of some Gram negative bacteria.  They add penicillin-sensitive and penicillin-resistant Streptococcus pneumonia coverage to ciprofloxacin with expanded activity against atypical intracellular pathogens that cause pneumonia such as Mycoplasma pneumoniae and Chlamydophila pneumoniae.  They are also effective against Legionella pneumophila and Mycobacterium tuberculosis.

Anti-pseudomonal activity depends on the institution.  Levofloxacin generally shows better pseudomonas spp. coverage than moxifloxacin. Not effective in MRSA.

Indications and Uses: Both agents are useful in CAP, while their use in HAP is limited by their antipseudomonal coverage (or lack thereof). They are also used in UTIs (only levofloxacin), acute chronic bronchitis, sinusitis (last resort) and second line in TB


Indications and Uses: Otitis externa caused by Staphylococcus aureus and Pseudomonas aeruginosa.


Coverage include Gram positive agents such as Staphylococci aureus (including MRSA) Streptococci spp. and Enterococcus faecalis, Gram negative agents such as E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa

Indications and Uses: Indicated for the treatment of acute bacterial SSSIs including those caused by MRSA and may be approved for CAP and UTIs.