Fluoroquinolone antibiotics: An overview

INTRODUCTION

Antimicrobial agents are chemical agents which are used to treat the infections by bacterial, viral, fungal, and microorganism infections. A variety of antimicrobial agents were used in the past decades to treat different types of infections. Beta-lactam antibiotic penicillins and sulfonamides were commonly used in clinical usage.^[1] Later on, quinolones and fluoroquinolones were established as new class of synthetic antibiotics with broad-spectrum activity and potent bactericidal agents which are active against to important pathogens that cause the variety of infections including urinary tract infections (UTIs),^[2] gastrointestinal infections (GITs), respiratory tract infections (RTIs), sexually transmitted diseases (STDs), and skin infections.^[3,4]

The fluoroquinolones are a class of broad-spectrum antimicrobial agents, therefore, they are highly active against both aerobic Gram-positive and Gram-negative organisms. Gram-positive includes penicillinase and non-penicillinase-producing staphylococci, Streptococcus pneumoniae and Streptococcus viridans, Enterococcus faecalis, Listeria monocytogenes, and Nocardia species. Gram-negative includes Neisseria meningitides and Neisseria gonorrhoeae, Haemophilus influenzae, and most important Enterobacteriaceae species, Pseudomonas aeruginosa, and Vibrio species.^[5]

In 1962, nalidixic acid, first clinically useful quinolone, was discovered by Lesher et al.^[1] In 1980, an analog of nalidixic acid, enoxacin was derived with increased spectrum of activity against Gram-negative or Gram-positive bacteria.^[6] In 1986, another fluoroquinolone drug that is ciprofloxacin was marketed,^[1,7] due to its more pharmacokinetic property and potent activity against various pathogens.^[7,8]

CLASSIFICATION OF FLUOROQUINOLONES

Fluoroquinolones are classified on the basis of their spectrum of activity [Table 1].^[9-11]

STRUCTURE–ACTIVITY RELATIONSHIP (SAR)

Fluoroquinolones are synthetic fluorinated analogues of nalidixic acid, a 1,8-naphthyridine and possess a 4-quinolone nucleus.^[11] The quinolone structure consists of a bicyclic system with a substituent at position N-1, a carboxyl group at position 3, a keto group at position 4, a fluorine atom at position 6, and a substituent (often nitrogen heterocycle moiety) at the C-7. Normally, in position 2, there are no substituents, various 1-methyl-2-alkenyl-4(1H).^[12]

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3-Fluro-2(1H)-quinolinone

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The research on quinolones started in 1962 along with of nalidixic acid, the prototype 4-quinolone antibiotic.^[13] The structural modification may enhance the antibacterial activity and pharmacokinetic properties. The nucleus of quinolone is consisting of nitrogen and 8-membered heterocyclic aromatic quinoline ring. In SAR of the early 4-quinolones, the 3-carboxyl group and 4-oxo groups were linked to antibacterial activity.^[14]

MECHANISM OF ACTION

Fluoroquinolones show their action by inhibiting the replication and transcription of bacterial DNA that is responsible for proper functioning of the cell.^[15,16] During DNA replication and transcription, double-stranded DNA goes to uncoil into a single-stranded structure by enzymes called DNA gyrase or DNA topoisomerase. DNA gyrase is an essential adenosine triphosphate-hydrolyzing topoisomerase II enzyme that prevents the detachment of gyrase from DNA. It consists of two A subunits (gyrA) and two B subunits (gyrB). DNA gyrase establishes negative super-helical twists in the bacterial DNA [Figure 1].^[17] Quinolones and fluoroquinolones inhibit this enzyme by binding to the A subunit of the enzyme due to which the bacteria are unable to replicate or even synthesize proteins. There is DNA-binding groove between the A and B subunits so that binding of the fluoroquinolones to this groove may conformity change the DNA gyrase molecule. Then, DNA becomes another binding site itself, as a result fluoroquinolones bind with both DNA and DNA gyrase. In many bacteria, DNA gyrase acts as the primary site of fluoroquinolone action, including E. coli.^[18] Fluoroquinolones have also been found to inhibit the in vitro activities of topoisomerase IV, having structure similar to DNA gyrase.^[2] The 2^nd target site for the fluoroquinolones is topoisomerase IV, this is made up from two ParC subunits (parC) and two ParE subunits (parE). The protein subunits coded for by parC (ParC) and parE (ParE) are homologous to the A and B subunits of DNA gyrase, respectively. Topoisomerase IV carries out decatenation and relaxation of DNA and assists with the segregation of replicating chromosomes or plasmids in bacteria.^[19] The bactericidal activity of the fluoroquinolones is enhanced by inhibition of topoisomerase IV.

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Figure 1:

Mechanism of action of fluoroquinolone.

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MECHANISM OF RESISTANCE

Resistance to fluoroquinolones mostly occurs by two mechanisms that are mutations in the both target enzymes DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria. The second way that reduced accumulation of the fluoroquinolones can occur is through an efflux system. Resistance is due to increased expression of chromosomal gene leading to increased efflux of the fluoroquinolones [Figure 2].^[20]

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Figure 2:

Resistance to fluoroquinolone.

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THERAPEUTIC USES

1. UTIs

   Norfloxacin is used for UTIs and fluoroquinolones are more effective than trimethoprim-sulfamethoxazole for the treatment of UTIs.^[21]

2. Prostatitis

   The 2^nd generation fluoroquinolones are effective in the treatment of prostatitis due to after oral administration of these drugs produce the highest concentration in prostatic fluid and prostatic tissue. Fluoroquinolones are effective in patients not responding to trimethoprim- sulfamethoxazole.^[21]

3. STDs

   A single oral dose of fluoroquinolones such as ofloxacin or ciprofloxacin is effective treatment for sensitive strains of N. gonorrhoeae due to its good efficacy. Sparfloxacin is an alternative treatment with doxycycline or a single dose of azithromycin, but increasing resistance to fluoroquinolones has led to ceftriaxone being the first- line agent for this infection.

4. Gastrointestinal and abdominal infections

   The quinolones are equal to trimethoprim- sulfamethoxazole in effectiveness for traveler’s diarrhea mainly caused by Escherichia coli.^[22] Norfloxacin, ciprofloxacin, and ofloxacin have been effective in the treatment of patients with shigellosis, enteric fever caused by S. typhi, as well as non-typhoidal infections in AIDS patients. Shigellosis is treated effectively with either ciprofloxacin or azithromycin.^[23]

5. RTI

   The key restriction to the use of quinolones for the treatment of community-acquired pneumonia and bronchitis had been observed because of poor in vitro activity of ciprofloxacin, ofloxacin, and norfloxacin against S. pneumoniae and anaerobic bacteria. Many newer fluoroquinolones, including gatifloxacin and moxifloxacin, have excellent activity against S. pneumoniae. These newer quinolones show comparable efficacy to β-lactam antibiotics.^[24]

6. Bone, joint, and soft-tissue infections The treatment of chronic osteomyelitis requires prolonged antimicrobial therapy with agents active against S. aureus and Gram-negative rods. The fluoroquinolones may be used appropriately in some cases.^[25]

CONCLUSION

The new fluoroquinolones show greatest activity against Gram-negative bacilli and improved Gram-positive activity. Ciprofloxacin still maintains the best in vitro activity against P. aeruginosa. Gatifloxacin, moxifloxacin, sparfloxacin, and trovafloxacin display improved activity against anaerobes versus ciprofloxacin. All of the new fluoroquinolones display excellent bioavailability and have longer serum half-lives than ciprofloxacin allowing for once daily dose administration. Prudent use of the new fluoroquinolones will be required to minimize the development of resistance to these agents.