Earlier compounds like Nalidixic acid, Norfloxacin, Pefloxacin, Ofloxacin and ciprofloxacin enjoyed great success particularly in Gram negative infections. They are excluded for use in children (except- Ciprofloxacin in cystic fibrosis, and Nalidixic acid for UTI in children) because of the fear of Chondrotoxicity. The newer generation of quinolones has greater activity against –

• pneumococci, Str.pneumoniae, MRSA, Staph aureus, S.epidermides, Enterococci, anaerobic organisms and IC pathogens like Chlamydiae, Mycoplasmae, legionellae, Mycobactriae etc.,

Newer quinolones are; 
- Levofloxacin 
- Trovafloxacin 
- Grepafloxacin 
- Sparfloxacin and 
the following quinolones are undergoing various phases of clinical trials viz., 
- Moxifloxacin 
- Clinafloxacin 
- Gatifloxacin 
- Sitafloxacin 
- Gemifloxacin. 
Quinolones in earlier phases of development are; 
- Ecinofloxacin 
- Balofloxacin 
- Nadifloxacin etc., 
- Prulifloxacin 

MAJOR CLINICAL INDICATION:

Bacterial infections of ;

• Respiratory tract- Acute Exacerbation of Chronic Bronchitis, (AECB), Pneumonia. 

• Urinary Tract Infection (uncomplicated & complicated). 

• Skin, Soft tissue, bone and joint . 

• Gastro Intestinal Tract – diarrhoea due to E.coli, Salmonellosis, Shiegellae, Campylobacter, Aeromonas, Vibrio, Plesiomonas shigelloides. Intra abdominal infection, Post surgical infection and obstetric and gynecological infections – Excellent with Trovafloxacin.Central Nervous System Infections (Trovafloxacin has greater penetrability into CNS) . 

• Immuno compromised patients . 

PHARMACOLOGICAL ASPECTS OF NEWER QUINOLONES:

Pharmacokinetics / Pharmacodynamics  

1.Excellent oral absorption
2.Good tissue distribution
3.Excellent interstitial fluid concentration
4.Significant entry into phagocytic cells
5.Excellent urinary concentration on oral administration
6.Longer plasma half life and o/d drug regimen
7.[Grepafloxacin, Sparfloxacin, Trovafloxacin, Moxifloxacin,Gatifloxacin,Gemifloxacin and Sitafloxacin]

ABSORPTION

The absorption of quinolones are reduced by Antacids containing Al+++, Ca++, Mg++, and Fe++ salts and dairy products . Some of the quinolones are available for IV use viz., Ciprofloxacin, Ofloxacin. Almost all the newer quinolones have excellent tissue distribution and attain high concentration in the interstitial fluid but only a few quinolones viz., Trovafloxacin, Ciprofloxacin, Pefloxacin, and Ofloxacin penetrate blood barrier. Protein binding varies to some extent.

      Norfloxacin, Lomefloxacin & Gatifloxacin  - Lowest binding

      Trovafloxacin, Rulofloxacin & Clinafloxacin – Highest binding

EXCRETION

Similarly quinolones exhibit differences the route of elimination Viz.,

Predominanatly by Renal elimination include; Ofloxacin, Levofloxacin,Lomefloxacin,Rufloxacin, and Gatifloxacin.

While those predominantly by hepatic elimination include; Nalidixic acid,Pefloxacin,Sparfloxacin and Grepafloxacin.

DOSAGE AND ADMINISTRATION

Flouroquinolones exhibit concentration dependent killing and therefore adminsitered O/day,twice a day regimen. In animal models a 24 hour AUC/MIC     (Area under the concentration-time curve/minimum inhibitory concentration) ratio to be the best predictor of bacterial killing in vivo. With the peak plasma concentration C_max / MIC ratio being important for some bacteria to prevent emergence of resistance during treatment. Human  studies ( and animal models) with ciprofloxacin, Grepafloxacin,  and Levofloxacin show that a 24 hrs AUC/MIC  ratio of about 100, or a C_max / MIC ratio of about 10  gives maximum clinical and bacteriological efficacy. These values can be used to predict the efficacy of different agents against different pathogens , and to define" Pharmacodynamic Breakpoints".

DRUG REGIMEN

The dosage schedules for the following quinolones have “Break points” ranging from 0.25 to 1  namely.,

• Ciprofloxacin                                 500mg bd

• Norfloxacin                                   400mg bd  

• Pefloxacin                                      200mg bd

• Ofloxacin                           400mg/d  or    200mg bd  

• Fleroxacin                                      400mg/d

• Gatifloxacin                                    400mg/d

• Grepafloxacin                                  400mg/d

• Livofloxacin                                    500mg/d

• Lomefloxacin                                  400mg/d

• Moxifloxacin                                   500mg/d

• Sparfloxacin                                   200mg/d

• Trovafloxacin                                  200mg/d   

• Sitafloxacin                                    100mg bd  

Antibacterial efficacy of quinolones depends  on;

Ø      Activity against the target enzyme DNA Gyrase

Ø      Uptake by the bacterial cell

Physicochemical properties like – Hydrophobicity

          - Acid base properties   and

            - Affinity for divalent cations.  

Quinolones  primary target is DNA Gyrase(Topoisomerase II ) in many of the gram-ve organisms whereas in the case of gram+ve organisms Topoisomerase IV  appears to be the primary target as is  the case of Ciprofloxacin, Norfloxacin, and Sparfloxacin.

For Sparfloxacin in the case of  Strerptococci pneumoniae ,DNA gyrase appears to be the primary target.

Peculiarly in case of Sitafloxacin  both DNA Gyrase -Topoisomerase II & Topoisomerase IV appears to be the targets and hence it is expected  that there is little or no chance for development of resistance.  

Adverse Drug Effects

1. Gastro Intestinal Tract – All quinolones have varying degrees of GIT irritation ranging from mild nausea to severe gastritis which can be limited by administering ½ hr after food. Antacids / Divalent cations /H2 antagonists reduce GIT absorption and hence should not be used for treating GIT adverse effects. 

2. Central Nervous System effects- The mechanism is not known probably interfering with GABA activity ? A direct pharmacological effect.

3. Cardio Vascular System Toxicity :- Both Sparfloxacin and Grepafloxacin are implicated in producing QT prolongation syndrome often mild but assumes significance when administered together with other agents like antiarrythmics, Macrolides, Cisapride, Azole antifungals, H1 antagonists like astemizole,cetrizine, terfinadine etc.,  

4. Phototoxicity: Skin reactions like erythema,pruritus,urticaria and rashes with phototoxicity are often associated. Sun burns occur when exposed to UV rays of UVA 320-400nm especially transmitted by the clouds & window panes. 
          Sparfloxacin, Lomefloxacin Fleroxacin, show increased incidence of phototoxicity while Trovafloxacin, Grepafloxacin, and Moxifloxacin have reduced potential for Phototoxicity. Quinolones exhibit Photomutagenic & even photocarcinogenic effect in animals.. The underlying mechanism appears to be due to the formation of photodegradation products and  leading to the generation of reactive oxygen species. In this context Newer quinolones are synthesized with chiral modification. It is not definite whether Tocopherols have any protective effect on phototoxicity. 

5. Arthropathy- Interest has been focussed on proteoglycan synthesis and mitochondrial function. Occurrence of this adverse effect precludes the use of very good antibacterials in paediatrics. Human data from the experience with 3 compound have revealed that Nalidixic acid has poor tissue penetrability and hence did not manifest chodrotoxicity and in the case of ciprofloxacin and norfloxacin there was reduced AUC and therefore low systemic exposure. In case of Pefloxacin with 5-10 times higher systemic exposure ( Higher AUC) is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage & epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued. The use of Nalidixic acid in UTI and ciprofloxacin in cystic fibrosis (pseudomonal) are officially permitted to be used in paediatrics. Recently many clinical studies revealed that newer quinolones might appear to be safer for paediatric use. 

Review of 31 reports involving 7045 paediatric patients use of  Ciprofloxacin,Nalidixic acid,Pefloxacin,Norfloxacin, Ofloxacin in paediatric cystic fibrosis, no arthropathy was observed. 

Similarly the use of Norfloxacin, Trovafloxacin, and Ciprofloxacin in shigellosis, Salmanellosis, Meningococcal meningitis showed in incidence of arthropathy in paediatric group. Trovafloxacin, Gatifloxacin, Clinafloxacin, and Moxifloxacin appears more promising for paediatric use.

Further studies are planned in selected paediatric age groups with quinolones before concluding for official use of quinolones (except those already approved) in paediatric infections.  

6. Tendinopthy: In 1991 Flouroquinolone associated Tendinopathy and tendon rupture have been reported. More than 1000 cases of quinolone induced tendinitis have been reported as per French surveillance in 1997. Clinically manifested as congestion and /or inflammation and oedema of tendon leading to pain and swelling and in more than 50% of cases it was bilateral and then tendon ruptures. 400 cases with in 18 months of treatment with Ofloxacin, Norfloxacin, Ciprofloxacin and Pefloxacin. In more than 70% patients aged 60yrs or above and in 10% of patients receiving concurrent steroid medication. Achilles tendon rupture reported to have occurred 120 days after the start of treatment and can occur even after withdrawal of the drug. Pathologically there was ultrastructure alteration in tendinocytes. In animals ,Mg deficiency aggravated tendinopathy.

Drug Interactions:

Primary drug-  Quinolones . Interact with

          X  Warfarin  = enhanced  anticoagulation

           X   H2 Antagonists =  quinolone absorption

          X   Cyclosporin  =   toxicity

           X   Rifampicins  = decreases serum concentration      of quinolone

           X   NSAIDs  = Convulsions

           X   Insulin & oral hypoglycemics = hypoglycemia.

SPARFLOXACIN:  

Sparfloxacin is an orally effective and it is a new diflourinated quinolone with structure similar to ciprofloxacin with broad antibacterial spectrum including improved activity against Grampositive, Mycobacteriae, Chlamydiae, Mycoplasmae, and anaerobes with good tissue penetration and long elimination half life. Its effect is superior against Staphylococci epidermides, E.fecalis, Streptococci pneumonia, C.perfringes & other anaerobes. It is the most appropriate agent for treatment of Urinary Tract Infection, Respiratory tract infection and other systemic infection having both improved patient compliance and greater efficacy . 

1. Sparfloxacin is well tolerated and effective against obstetric & gynecological  infection

2. Sparfloxacin  exerted strong antimicrobial activity against  Shigellae, Salmonellae, Camphylobacter,  and marked clinical efficacy against enteritis induced by the above organisms.

3. Sparfloxacin found to be very useful in post- surgical infections.

4. Sparfloxacin  in respiratory infections – Excellent activity against S.aureus, Streptococci pneumoniae, Br.catarrhalis,H.influenzae, Mycoplasmae and therefore indicated in URI, ACEB, Diffuse panbronchiolitis, Bronchiectasis, & pneumonia.
5. Sparfloxacin has excellent activity in the following dermatological conditions viz., Folliculitis, Pustular acne, Furunculosis, carbuncles, Impetigo, Erysipelas, Cellulitis, Felon, Lymphangitis, paronychia,SC abscess, Hidradenitis, Infected atheroma, Infected pilinoidal sinus  etc.,

6. Sparfloxacin in Leprosy:

   • Radio respirometric  activity undetectable  after 4 weeks of therapy

   • Serum phenolic glycolipid 1 antigen diminished in all patients

   • Among 20 quinolones, Sparfloxacin was the most active in leprosy

7. Sparfloxacin exerted very good effect in Mycobacterial infections with the exception of M.scrofulaceum and M.chelonae.
8. Sparfloxacin  exhibits highest antimicrobial  potency against Legonellairs infection because of its enhanced penetration into human neutrophils with Intra Cellular concentrations exceeding extracellular concentrations several times. Therefore sparfloxacin is superior bactericidal against M.homins, M.pneumoniae, M.genitaklium, U.urealyticum, M.fermentans.
9. Sparfloxacin has good activity against MAC infection but the role of quinolones in multi- drug regimen for opportunistic infections by MAC in AIDS remains unclear.  

1. Grepafloxacin in o/d regimen is superior to ciprofloxacin in Streptococci pneumoniae

2. Gatifloxacin o/d is highly effective in Respiratory & UTI and did not exhibit any phototoxicity.
3. Sitfloxacin useful in treatment of Catheter associated  nosocomial and other infections by Pseudomonas species with less chance for resistance induction .
4. Oral Trovafloxacin is very effective against MDR respiratory pathogen because of its greater penetration into respiratory fluids and secretion.
5. Moxifloxacin is highly effective in  M. catrrhalis, Chlamydiae, Mycoplasmae, Legionellae because of its 10 fold Intra Cellular concentrations  on oral administration.

6. Moxifloxacin is highly active against str. peumoniae (Penicillin/macrolide resistant)

7. Newer quinolones  have greater activity than macrolide or cephalosporins against common respiratory pathogens and therefore useful in;                

   -         community acquired pneumonia

   -         Penicillin resistant Streptococci pneumonia

   -         Beta-lactamase resistant H.influenzae

   -         Beta-lactamase resistant Mor.catarrhalis.  

H.  Once /day alatrovafloxacin/Trovafloxacin  IV to oral treatment is clinically effective as twice/day IV to oral ciprofloxacin for treatment of nosocomial infections with no additional anaerobic coverage.

Future Quinolones:

• Greater potency

• Reduced frequency of resistance selection

• Better CNS/CSF penetration

• Improved safety & tolerability

• Greater activity against gram+ve species

• Effective against IC pathogens

• Enhanced activity against anaerobes

• Suitable for paediatric use.

Conclusion:

NEWER QUINOLONES APPEAR TO HAVE A HEALTHY FUTURE ?

Glossary

MBC - Min bactericidal concentration @ which no colony forms after 24 hrs of incubation @ 35’ C

MIC – Defined as the lowest concentration of antibacterial agent that inhibits the development of visible growth in the broth.

PAE – Post Antibiotic Effect is the term used to describe suppression of bacterial growth that persists after short exposure of organism to antimicrobial agent. PAE may have a clinical effect on antimicrobial dosage.