Quinolones

Quinolones and Flouroquinolones Antibiotics

1. QUINOLONES By Shubham Marbade M.Pharm Pharmacology

2. Quinolones Synthetic, broad spectrum and bactericidal. Effective after oral administration for wide variety of infectious diseases, Play an increasingly important role in treatment of multi-drug resistant bacterial infections. They are widely used because of their relative safety, availability both orally & parenterally and their favorable pharmacokinetics.

3. Nalidixic acid was the first quinolone discovered in 1960s and primarily used for urinary tract infection.

4. Fluoroquinolones Wide variety of application and broad spectrum antibiotic More potent than quinolones. Modified quinolones with one or more fluorine atom in their structure.

5. Classification

6. PHARMACOKINETIC Rapidly and almost completely absorbed after oral administration and are widely distributed in body tissues. Peak serum levels are obtained within 1- 3 hours of an oral dose of 400mg with peak levels ranging from 1.1 ug / ml for sparfloxacin to 6.4 ug /ml for levofloxacin . Food does not impair oral absorption but may delay. Bioavailability is > 50% for all agents and > 95% for several.

7. Half life s 3- 5 hours for norfloxacin and ciprofloxacin. The volume of distribution of quinolones is high with concentration of quinolones n urine, kidney, lung, and prostate tissue, stool, bile and macrophage and neutrophils higher than serum levels. Concentration in CSF, bone and Prostatic fluid are lower than in serum. The fluoroquinolones are also metabolized by hepatic conjugation and glucuronidation . Dosage , peak serum levels, percent protein binding, urine concentrations, and degree of metabolism differ to varying degrees among the quinolones .

8. It is excreted primarily in urine, both by glomerular filtration and tubular secretion . Urinary and biliary concentrations are 10–50 fold higher than plasma.

9. Mechanism of action These agents targets DNA gyrase and Topoisomerase IV. For Gram – ve bacteria DNA gyrase , and for Gram + ve bacteria topoisomerase IV is primary site for their activity. These drugs binds to A- subunit of DNA gyrases and four subunits of topoisomerase IV enzyme which are responsible for unwinding of supercoiled DNA for process of replication and transcription. Thus it results in blockade of unwinding and inhibition of replication. Synthesis of protein inhibited. inhibition of growth of bacteria and kills bacteria.

10. Antibacterial spectrum Quinolones have broad spectrum antibacterial activity against various Gram + ve and Gram - ve bacterias including E. coli, Salmonella, Sheigella , P. aeruginosa , Clamydia , mycoplasma, Brucella , Mycobacterium, legionella etc.

11. Antibacterial Resistance Resistance to the quinolones develops due to mutation to bacterial chromosomal genes of Gyrase A and Topoisomerase IV encoding information to unwind Supercoiled DNA. No quinolone modifying or inactivating activity has been seen to develop resistance.

12. Therapeutic Uses 1. Urinary tract infections: High cure rates, even in complicated cases or those with indwelling catheters/ prostatitis , have been achieved. ChronicPseudomonas infections respond less completely. 2. Gonorrhoea : Initially a single 500 mg dose was nearly 100% curative in non-PPNG as well as PPNG infections, but cure rate has declined in the recent years due to emergence of resistance. 3. Chancroid : 500 mg BD for 3 days is an excellent alternative to ceftriaxone /erythromycin. 4. Bacterial gastroenteritis: Severe cases due toEPEC , Shigella , Salmonella and Campy. jejunirespond quickly. It has also been used to reducestool volume in cholera.

13. 5. Typhoid: Ciprofloxacin is the first choice drug in typhoid fever since chloramphenicol , ampicillin and cotrimoxazole have become unreliable due to development of resistance. A dose of 500–750 mg BD for 10 days is recommended. Patients unable to take the drug orally may be treated with 200 mg. i.v . 12 hourly in the beginning. 6 . Bone, soft tissue, gynaecological and wound infections : caused by resistant Staph. and gramnegative bacteria : high cure rates have been obtained but prolonged treatment with high doses is required in osteomyelitis and joint infections.Used along with clindamycin / metronidazole ( to cover anaerobes) it is a good drug for diabetic foot .

14. 7. Respiratory infections: Ciprofloxacin can treat Mycoplasma ,, H. influenzae , Branh . catarrhalis and some streptococcal and pneumococcal infections besides gram-negative ones. 8. Tuberculosis It is now frequently used as a component of combination chemotherapy against multidrug resistant tuberculosis. Recently, even FQ-resistant TB have arisen . 9 . Gram-negative septicaemias: Parenteral ciprofloxacin may be combined with a third generation cephalosporin or an aminoglycoside .

15. 10. Meningitis: Though penetration in CSF is not very good, ciprofloxacin has been successfully used in gram-negative bacterial meningitis, especially that occurring in immunocompromised patients or those with CSF shunts .

16. Adverse Effects GI tract- (2–13 %) these include nausea, vomiting, diarrhea, and abdominal pain . CNS effects- (1–8 %) such as drowsiness, weakness, headache , dizziness, and in severe cases, convulsions and toxic psychosis, have been reported . sparfloxacin and lomefloxacinv shows photosensitivity included second-degree burns, discoloration and sometimes permanent discoloration and scarring of the skin due to halogen substitution on the eighth position, as found in

17. Adverse cardiovascular effects (6–7%; vascular embolism, cardiac insufficiency, hypotension) also occur with sparfloxacin . Sparfloxacin , moxifloxacin , and gatifloxacin can exacerbate QT prolongations. Fulminant hepatotoxicity associated withtrovafloxacin has resulted in acute liver failure, and the FDA has recommended limiting therapy to life- threateninginfections .

18. Allergic reactions (e.g., rashes, urticaria , and eosinophilia ) have been observed . These drugs have occasionally been associated with cholestatic jaundice, blood dyscrasias , hemolytic anemia, hypoglycemia, and nephrotoxicity . Recently the use of ciprofloxacin for prophylaxis protection against anthrax infection has been associated with damage to muscle ligaments.

19. Drug Interactions All quinolones interact with multivalent cations , forming chelation complexes resulting in reduced absorption. Major offenders are antacids; vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin , didanosine , and phenytoin , resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance , which leads to theophylline toxicity.

20. Contraindications The use of the quinolones in pregnant or breastfeeding women and children whose epiphysial plates have not closed is generally contraindicated. Their use for treating young cystic fibrosis children infected with Pseudomonas species is an exception; the patient should be monitored carefully for untoward effects.

21. These drugs contraindicated in arrhythmia because it prolong the heart's QT internal by blocking voltage-gated potassium channels lead to a life-threatening arrhythmia.

22. Nalidixic acid It is active against gram-negative bacteria, especially E . coli, Proteus, Klebsiella , Enterobacter , Shigella but not Pseudomonas. It acts by inhibiting bacterial DNA gyrase and isbactericidal . Absorbed orally, highly plasma protein bound and partly metabolized in liver. It is excreted in urine with a plasma t½ ~8 hrs. Concentration of the free drug in plasma and most tissues attained with the usual doses is non therapeutic for systemic infections. Dose: 0.5–1 g TDS or QID

23. Ciprofloxacin It is the most potent first generation FQ active against a broad range of bacteria, the most susceptible ones are the aerobic gram-negative bacilli , especially the Enterobacteriaceae and Neisseria . It binds to divalents cations which decreases absorption. Because of its good penetration into bone, orally administered ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms . Dose- 250, 500, 750 mg tab, 200 mg/100 ml i.v . infusion, 3 mg/ml eye drops.

24. Levofloxacin It is the levoisomer of ofloxacin having improved activity against Strep. Pneumoniae and some other gram-positive and gramnegative bacteria. Oral bioavailability of levofloxacin is nearly 100%; oral and i.v . doses are similar . The primary indication of levofloxacin is community acquired pneumonia and exacerbations of chronic bronchitis in which 87–96% cure rate has been obtained. High cure rates have been noted in sinusitis, enteric fevers, pyelonephritis and skin/soft tissue infections as well . Dose- 500 mg tab, 500 mg/100 ml inj.

25. Trovafloxacin Trovafloxacin is a broad spectrum antibiotic   inhibit the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV . It was shown to be more effective against Gram-positive bacteria than Gram-negative bacteria when compared to previous fluoroquinolones . Gonorrhea in males and endocervical and rectal gonorrhea in females  as well as non gonoccocal urethritis and cervicitis . Well-absorbed from the gastrointestinal tract after oral administration and does not depend on concomitant food intake. The absolute bioavailability is approximately 88 %. Dose- 300 mg iv and 100 mg tid

26. Repositioning to Anticancer agents Several FQs just like anyother anticancer drug have been shown to cause cell cycle arrest primarily in S and G2phase of progression . Several studies reveals the ability of ciprofloxacin to induce S/G2-phase arrest in bladder and prostate cancer cells. Similarly, enoxacin revealed its ability to induce S/G2-phase in prostate cancer cells and G2/M-phase arrest in breast cancer cells. Later on, few more studies showed similar S/G2-phase arresting effects of other FQs like lomefloxacin , ofloxacin and levofloxacin in epidermoid carcinoma and breast cancer cells respectively. Ciprofloxacin possesses the maximum efficacy in inducing apoptosis . It shows potent anti-proliferative effect to induce apoptosis in bladder cancer cells and then later on in prostate cancer cells.

27. Clinafloxacin Methicillin resistant Staphylococcus aureus (MRSA) has developed numerous mechanisms of virulence and strategies to evade the human immune system which are difficult to treat infections in human beings , and becoming important cause of morbidity and mortality. Acts as novel inhibitors of bacterial efflux pump, FtsZ , DNA gyrase , and topoisomerase IV and have the potential to exert multiple mechanisms of action.

28. Fluoroquinolones in treatment of TB Fluoroquinolones like moxifloxacin , gatifloxacin and levofloxacin , are the most valuable second-line anti-TB agents according to the current WHO guidelines. These drugs are currently under clinical trial for pulmonary tuberculosis and tuberculosis meningitis. The aim of this study is to provide an alternative to resistant drug to prevent failure of treatment and emergence of drug resistance.

29. Delafloxacin in ABSSSI Delafloxacin is a novel anionic fluoroquinolone (FQ) approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by a number of Gram-positive and Gram-negative organisms including MRSA and Pseudomonas aeruginosa . It is more potent than other quinolones against Gram + ve bacteria and Gram – ve bacteria. It is considered a dual-targeting FQ and displays nearly equivalent affinity for DNA gyrase and topoisomerase IV. This property likely explains delafloxacin’s broad spectrum of in vitro activity against both GN and GP bacteria

30. Delafloxacin in CABP Approved for use in adults for the treatment of community-acquired bacterial pneumonia, delafloxacin was shown in a phase III clinical trial to be superior to moxifloxacin in patients with CABP who also have chronic obstructive pulmonary disease (COPD) or asthma as a comorbidity , and in CAP patients who may have severe illness. Additionally , delafloxacin appeared to be better tolerated compared to commonly used FQs.

31. Levonadifloxacin It is a novel antibacterial agent belonging to benzoquinolizine subclass of fluoroquinolones which is under clinical development as a parenteral formulation and its prodrug alalevonadifloxacin as an oral option. Both the drugs have been approved recently in India based on phase III trial completed for ABSSSI .

32. Fluoroquinolones in catheter coating Antimicrobial catheter coatings were prepared by immobilizing fluoroquinolones either with the use of linkers (covalent binding) or by activating the polymer matrix with iodine/bromine ( noncovalent binding). The new antimicrobial coatings, obtained with the participation of fluoroquinolone antibiotics in an uncomplicated way, are able to protect the urinary catheters against bacterial infections during catheterization. Since the ideal antibacterial material has not yet been found, there is still a need to look for new ways of the prevention of catheter-associated urinary tract infections

33. Sparfloxacin Ocular diseases affect a growing number of people across the globe. Some pathological ophthalmic conditions, such as glaucoma, diabetic retinopathy, or age-related macular degeneration, cause severe visual impairment that can ultimately lead to blindness . Nanosuspensions were prepared via a solvent diffusion technique and loaded with sparfloxacin used against bacterial conjunctivitis . The optimal formulation was the one based on N- carboxymethyl CS nanosuspension in combination with sustainable sparfloxacin release.

34. Antifungal activity Quinolones and Flouroquinolones displayed potential anti-fungal activity and some of them could significantly increase the susceptibility of antifungals . Metal complexes of Flouroquinolones with specified antimicrobial activities, are a new entry in the field of bioinorganic. Zone of inhibition values of fluoroquinolones are compared with parent drug. Some of them found to exhibit excellent potency against both drug‐susceptible and drug‐resistant fungi where as some found to show lesser or no antifungal behavior as compared to the parent drug .

35. Bioprinting Technology liver bioengineering has picked up momentum in recent years for the development of both artificial substitutes for supporting repair/regeneration as well as in vitro hepatic models for clinical and diagnostic application. Trovafloxacin is used to induce liver txicity at tissue level. Compared to conventional 2D models, trovafloxacin treatment resulted in significant, dose-dependent toxicity at clinically relevant doses (≤4 μM ) in the developed 3D models.

36. Sitafloxacin According to study carried out in Japan : Sitafloxacin based therapy is a potent candidate for third-line Helicobacter pylori eradication treatment. The 7-day regimen with vonoprazan 20 mg b.i.d ., sitafloxacin 100 mg b.i.d ., and amoxicillin 750 mg b.i.d . or 500 mg q.i.d . is a good option as the third-line H. pylori eradication treatment

37. Immunomodulatory Effects of Fluoroquinolones Immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators.

38. References Yadav V, Talwar P, Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: Anunderestimated truth, Biomedicine and pharmacotherapy, 2019, 111, 934- 946. Xuemei Ge , Zhi Xu , 1,2,4-Triazole hybrids with potential antibacterial activity against methicillin resistant Staphylococcus aureus , Arch Pharm DPhG , 2020, 1- 10. Dorota Kowalczuk et al, FTIR Characterization of the Development of Antimicrobial Catheter Coatings Loaded with Fluoroquinolones , coating, 2020, 10, 818 Alexandra Zamboulis et al, Chitosan and its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments, Polymers, 2020, 12, 1519 Savita Khatria , Manoj Kumara, Pratibha , Rajesh Kumar, A Review of Antifungal Activities of Various Flouroquinolone and Its Metal Complexes, annals of R S C B 2021, 21(5 ), 396- 405 Tarun Agarwal et al., Recent advances in bioprinting technologies for engineering hepatic tissue, Materials Science & Engineering C, 2021, 123 Toshihiro Nishizawa et al, Sitafloxacin for Third-Line Helicobacter pylori Eradication: A Systematic Review, J. Clin. Med. 2021, 10, 2722.

39. Shokrollah Assar et al, A Review of Immunomodulatory Effects of Fluoroquinolones , A Journal of Molecular and Cellular Immunology, 2020 Pranger AD et al, The Role of fluoroquinolones of in the treatment of tuberculosis 2019, Cross Mark, 2019, 79, 161- 171. Sharma R, et al, Community Acquired Bacterial Pneumonia- Changing Epidemiology, Resistance Patterns and Newer Antibiotics: Spotlight n Delafloxacin , Clinical drug Investigation, 2020, 40, 947- 960 . Chabner B, Knollman B, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12 th Edition, 1470 Tripathi KD, Essentials of Medical Pharmacology, 6 th edition, Jaypee Brothers Medical Publishers, 2003, 687. Craig CR, Stitzel RE, Modern Pharmacology with Clinical Application, 5 th Edition, 519.