Quinolones - Antimicrobials

Quinolones

Among the very few members of the classic quinolones used today is nalidixic acid, while there are several fluorinated 4-quinolones (fluoroquinolones) which are very popular as broad spectrum antibacterials. Examples include amifloxacin, balofloxacin, ciprofloxacin, enoxacin, enrofloxacin, fleroxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxi-floxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, sparfloxacin and trovafloxacin.

Fluoroquinolones are used mainly for urinary tract infec-tions, lower respiratory tract infections and skin structure infections.

Uses

·            Nalidixic acid is used only for urinary tract infections against gram-negative organisms. It is not related to sulfonamides, antibiotics, or nitrofurans.

·            Cinoxacin is an antibacterial closely related (structurally) to nalidixic acid. It differs in that its activity is reduced only slightly in the presence of serum, has a lower inci-dence of side effects, less resistance development, and less CNS and neuromuscular toxicity.

·            Rosoxacin is a 4-quinolone antibacterial agent, active against Neisseria gonorrhoea.

·            Fluoroquinolones are effective in the treatment of infections caused by E.coli, Salmonella, Shigella,Enterobacter, Campylobacter, and Neisseria. Someof them (e.g. ciprofloxacin) are also effective against Staphylococci, Chlamydia, Mycoplasma, Pseudomonas, Legionella, Brucella, and Mycobacterium.

Toxicokinetics

These drugs are well absorbed after oral administration (except nalidixic acid), and are widely distributed in body tissues. Peak serum levels are usually obtained in 1 to 3 hours and the volume of distribution is high. Excretion may be renal (e.g. lomefloxacin, ofloxacin), or non-renal (e.g. nalidixic acid, pefloxacin). The estimated half-life of nalidixic acid is 3.2 hours in overdose, and could be as short as 85 minutes and as long as 6 to 7 hours therapeutically.

Mode of Action

These drugs inhibit DNA topoisomerase and DNA gyrase in susceptible cells.

Adverse Effects

·            While the quinolones and fluoroquinolones are generally well tolerated, the following adverse effects have been reported: skin rash, nausea, abdominal discomfort, head-ache, vertigo, and rarely, delirium with hallucinations. Crystalluria and nephrolithiasis have been reported with therapeutic use. Haemolytic anaemia has been reported in therapeutic and occupational exposures, primarily in patients exposed to nalidixic acid, and with erythrocyte G6PD deficiency. Arthralgias, myalgias, and polyarthritis have been reported.

·              Fluoroquinolones are not recommended for children (under 15 years) because of the risk of inducing arthralgia and joint swelling. Rare adverse effects of fluoroqui-nolones include rhabdomyolysis, tendonitis, tendon rupture, delirium, altered mental status, QT prolongation and ventricular arrhythmias. Tendinopathy (a rare effect) appears to be a class-related adverse effect of fluoroqui-nolones and includes first and second generation drugs.

·            Disturbances of blood glucose have been reported with levofloxacin therapy, usually in diabetic patients receiving an oral hypoglycaemic agent or insulin. Both hyperglycaemia and hypoglycaemia have been reported in these patients.

·            Cerebellar dysfunction and an extrapyramidal syndrome, characterised by confusion, irregular asymmetrical invol-untary movements, and slurred speech have been reported after therapeutic use of pefloxacin.

·            In June 1999, the USFDA issued a health advisory regarding the possible risk of liver toxicity associated with trovafloxacin.

·            In October 1999, the manufacturer announced the volun-tary withdrawal of grepafloxacin due to severe cardio-vascular events that were observed in a small number of patients. According to the company, the benefits did not outweigh the potential risks to patients based on the availability of alternative antibiotics.

·            Due to observed quinolone toxicity on growing cartilage in animals, use of all fluoroquinolone antibiotics during pregnancy is contraindicated.

Drug Interactions

Concomitant administration of theophylline or NSAIDs with fluoroquinolones is associated with a risk of CNS excita-tion resulting in delirium and convulsions. Drug interactions involving caffeine, cimetidine, and antacids have also been reported with these agents.

Clinical (Toxic) Features

·      Therapeutic nalidixic acid levels are thought to be 20 to 50 mcg/ml. Serious symptoms have occurred at nalidixic acid serum levels between 146 to 185 mcg/ml, but symptoms have been noted with as little as 25 mcg/ml.

o     Acute toxicity with nalidixic acid is relatively common, resulting in vomiting, convulsions, hyperglycaemia, benign intracranial hypertension, behaviour disorders, lethargy, toxic psychosis, and metabolic acidosis.

o     Visual disturbances (hazy vision, halos, inability to focus, colour perception changes, diplopia, visual hallu-cinations) and photophobia have also been reported.

o     The CNS effects of cinoxacin are primarily those of CNS depression, with seizures not reported in animal studies. Mydriasis and musculoskeletal changes were reported.

·      Overdose with fluoroquinolones has caused dizziness, drowsiness, disorientation, slurred speech, nausea, vomiting, and tremors.

o     Overdose with ciprofloxacin has been occasionally reported with manifestations such as nausea, arthralgias, crystalluria, convulsions, and renal and hepatic failure.

o     Ofloxacin overdose has also been reported, and is said to cause vomiting, convulsions, vertigo, psychosis, dysgeusia and anosmia.

·      Chronic use of quinolones and fluoroquinolones can cause hypersensitivity reactions (rashes, pneumonitis, anaphy-laxis), haematologic effects (thrombocytopenia, haemolytic anaemia, leukopenia), GI effects (nausea, vomiting, abdom-inal pain, diarrhoea), CNS effects (convulsions, psychosis), nephrotoxicity, lactic acidosis, arthropathy and myopathy.

o     One report indicates that ciprofloxacin can cause fatal bone marrow suppression.

o     Hepatic injury including hepatitis, acute liver failure and subfulminant hepatic failure have been reported with the use of fluoroquinolones in both short and long-term use.

o     At therapeutic doses haematuria, crystalluria, and inter-stitial nephritis have been associated with ciprofloxacin therapy in humans. No permanent renal impairment has resulted from ciprofloxacin therapy.

o     Vaginitis has been associated with the therapeutic use of ciprofloxacin.

Diagnosis

·      HPLC quantitation of the drug in plasma.

·      Urine levels can be estimated by GC/MS.

·      Blood picture: eosinophilia, neutropenia.

·      Elevated serum transaminase.

·      Haematuria.

Treatment

·      Stomach wash (within 2 hours of ingestion).

·      Activated charcoal may be helpful.

·      Treatment of seizures with benzodiazepines or phenytoin.

·      Periodic evaluation of renal function: urinalysis for crystal-luria, serum creatinine, blood urea nitrogen.

·      Adequate hydration (to prevent crystalluria).

·      Supportive care including replacement of fluid and electro-lytes lost during prolonged vomiting remains the corner-stone of treatment.

·      Alkaline diuresis is thought to increase the rate of excretion of the quinolone antibiotics. It has never been shown to affect outcome after overdose and is not routinely recom-mended.

·      Haemodialysis and haemoperfusion are not very effective owing to the high volume of distribution of most of these drugs. It may be of some benefit in fluoroquinolones (espe-cially ciprofloxacin).

·      Steroids may help in ameliorating arthralgias and interstitial nephritis, if present.