Drug Interactions of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

Theophylline, non-steroidal anti-inflammatory drugs and corticosteroids enhance the toxicity of fluoroquinolones.

Products containing multivalent cations, such as aluminum- or magnesium-containing antacids and products containing calcium, iron, or zinc, invariably result in marked reduction of oral absorption of fluoroquinolones.

Other drugs that interact with fluoroquinolones include Antacids, Sucralfate, Probenecid, Cimetidine, Warfarin, Antiviral agents, Phenytoin, Cyclosporine, Rifampin, Pyrazinamide, and Cycloserine.

Many fluoroquinolones, especially ciprofloxacin, inhibit the cytochrome P450 isoform CYP1A2.This inhibition causes an increased level of, for example, antidepressants such as amitriptyline and imipramine, Clozapine (an atypical antipsychotic), Caffeine, Olanzapine (an atypical antipsychotic), Ropivacaine (a local anaesthetic), Theophylline (a xanthine) and Zolmitriptan (a Serotonin receptor agonist).

Mechanism of action of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

Quinolones and fluoroquinolones are chemotherapeutic bactericidal drugs, eradicating bacteria by interfering with DNA replication. The other antibiotics used today, (e.g., tetracyclines, lincomycin, erythromycin, and chloramphenicol) do not interact with components of eukaryotic ribosomal particle and thus have proven not to be toxic to eukaryotes, as opposed to the fluoroquinolone class of drugs. Safer drugs used to treat bacterial infections, such as penicillins and cephalosporins, inhibit cell wall biosynthesis, thereby causing bacterial cell death, as opposed to the interference with DNA replication as seen within the fluoroquinolone class of drugs.

Quinolones are synthetic chemotherapeutic agents which have a broad spectrum of antimicrobial activity as well as a unique mechanism of action resulting in inhibition of bacterial DNA gyrase and topoisomerase IV. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily via porins and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. It is believed that eukaryotic cells do not contain DNA gyrase or topoisomerase IV.

However, there is debate concerning whether the quinolones still have such an adverse effect on the DNA of healthy cells, in the manner described above, hence contributing to their adverse safety profile. This class has been shown to damage mitochondrial DNA.

Pharmacology of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

The basic pharmacophore, or active structure, of the fluoroquinolone class is based upon the quinoline ring system. The addition of the fluorine atom at C6 is what distinguishes the successive generations, fluoroquinolones, from the first generation, quinolones. It has since been demonstrated that the addition of the C6 fluorine atom is not a necessary requirement for the antibacterial activity of this class (circa 1997).

Various substitutions made to the quinoline ring resulted in the development of numerous fluoroquinolone drugs that we see today. Each substitution is associated with a number of specific adverse reactions, as well as increased activity against bacterial infections, where as the quinoline ring, in and of itself, has been associated with severe and even fatal adverse reactions.

Contraindications of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

Quinolones are contraindicated if a patient has epilepsy, QT Prolongation, pre-existing CNS lesions, central nervous system inflammation or those who have suffered a stroke. There are safety concerns of fluoroquinolone use during pregnancy and as a result are contraindicated except for when no other safe alternative antibiotic exists.

They are also contraindicated in children due to the risks of damage to the muscoskeletal system.[ Their use in children is not absolutely contraindicated however. For certain severe infections where other antibiotics are not an option their use can be justified. Quinolone should also not be given to people with a known hypersensitivity to the drug.

Adverse effects of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

Fluoroquinolones are generally well tolerated with most side effects being mild to moderate. Occasionally serious adverse effects occur.

Some of the serious adverse effects which occur more commonly with fluoroquinolones than with other antibiotic drug classes include CNS and tendon toxicity.

The currently marketed quinolones have safety profiles similar to that of other antimicrobial classes. Fluoroquinolones are sometimes associated with an QTc interval prolongation and cardiac arrhythmias, convulsions, tendon rupture, torsade de pointes and hypoglycemia.

These adverse reactions are a class effect of all quinolones, however, certain quinolones are more strongly associated with increased toxicity to certain organs. For example, moxifloxacin carries a higher risk of QTc prolongation, and gatofloxacin has been most frequently linked to disturbed blood sugar levels, although all quinolones carry these risks.

Some quinolones were withdrawn from the market because of these adverse events (for example, sparfloxacin was associated with phototoxicity and QTc prolongation, thrombocytopenia and nephritis were seen with tosufloxacin and hepatotoxicity with trovafloxacin).

Simultaneous use of corticosteroids is present in almost one-third of quinolone-associated tendon rupture.The risk of adverse events is further increased if the dosage is not properly adjusted, for example if there is renal insufficiency.

The serious events may occur during therapeutic use at therapeutic dose levels or with acute overdose. At therapeutic doses they include: central nervous system toxicity, cardiovascular toxicity, tendon / articular toxicity, and rarely hepatic toxicity.

Caution is required in patients with liver disease.Events that may occur in acute overdose are rare and include: renal failure and seizure.Susceptible groups of patients such as children and the elderly are at greater risk of adverse reactions during therapeutic use. Adverse reactions may manifest during, as well as after fluoroquinolone therapy has been completed.

Fluoroquinolones are considered high risk antibiotics for the development of C Difficile and MRSA infections. A previoualy rare strain of C Difficile which produces a more severe disease with increased levels of C Difficile toxins is becoming epidemic, may be connected to the use of fluoroquinolones.

Fluoroquinolones are more strongly associated with C difficile infections than other antibiotics including clindamycin, 3rd generation cephalosporins beta lactamase inhibitors. One study found that fluoroquinolones were responsible for 55% of C difficile infections.

The European Center for Disease Prevention and Control recommend that fluoroquinolones and the antibiotic clindamycin are avoided in clinical practice due to their high association with clostridium difficile, a potentially life-threatening super-infection.

The central nervous system is an important target for fluoroquinolone mediated neurotoxicity. Adverse event reporting in Italy by doctors showed fluoroquinolones among the top 3 prescribed drugs for causing adverse neurological and psychiatric adverse effects. These neuropsychiatric effects included tremor, confusion, anxiety, insomnia, agitation and in severe cases psychosis. Moxifloxacin came out worst amongst the quinolones for causing CNS toxicity.

Some support and patient advocacy groups refer to these adverse events as "fluoroquinolone toxicity". Some people from these groups claim to have suffered serious long term harm to their health from using fluoroquinolones. This has led to a class action lawsuit by people harmed by the use of fluoroquinolones as well as action by the consumer advocate group Public Citizen.

Partly as a result of the efforts of Public Citizen the FDA ordered a black box warnings on all fluoroquinolones advising consumers of the possible toxic effects of fluoroquinolones on tendons.

Indications of Quinolone ( fluoroquinolones) - Antibiotics and Antibacterials

It continues to be debatable as to whether or not the effectiveness of fluoroquinolones for the treatment of respiratory disorders is similar to other antibiotic classes.

Fluoroquinolone use for pneumonia is increasing and with it so is bacterial resistance to fluoroquinolones. The majority of the prescribing of fluoroquinolones is inappropriate with less than 4 percent of people prescribed quinolones being appropriate according to clinical guidelines. Clinical guidelines in Canada only recommend fluoroquinolones for outpatient treatment of pneumonia in a small number of patients such as those with certain co-morbid conditions such as patients with a history of COPD, or recent use of antibiotics.

For severe forms of community-acquired pneumonia the fluoroquinolones are associated with improved treatment rates, but with no differences found in mortality between other antibiotic classes.

Fluoroquinolones are not recommended as first line antibiotics for acute sinusitis as this condition is usually self-limiting and the risks outweigh the benefits in comparison to other antibiotic classes.

Antibiotics including fluoroquinolones can be effective in some cases of bronchitis. However, only about 5-10% of bronchitis cases are caused by a bacterial infection; most cases of bronchitis are caused by a viral infection and are self-limiting and resolve themselves in a few weeks. It has been recommended that antibiotics are limited in most cases to those whose symptoms fail to resolve on their own.

Fluoroquinolones are often used for genitourinary infections; in general they are recommended only after other antibiotic regimes have failed. However, for serious acute cases of pyelonephritis or bacterial prostatitis where the patient may need to be hospitalised fluoroquinolones are recommended as first line therapy.

Prostatitis has been termed "the waste basket of clinical ignorance" by prominent Stanford University Urologist Dr. Thomas Stamey. Campbell's Urology, the urologist's most authoritative reference text, identifies only about 5% of all patients with prostatitis as having bacterial prostatitis which can be "cured" at least in the short term by antibiotics. In other words, 95% of men with prostatitis have little hope for a cure with antibiotics alone since they don't actually have any identifiable bacterial infection.

The American Thoracic Society recommends that fluoroquinolones are not used as a first line agent, instead recommending macrolide or doxycycline as first line agents. The Drug-Resistant Streptococcus pneumoniae Working Group recommends fluoroquinolones are only used after other antibiotic classes have been tried and failed or in those with demonstrated drug-resistant Streptococcus pneumoniae. The Center for Disease Control are concerned that fluoroquinolones are being used as a "one-size-fits-all" treatment unnecessarily by doctors without considering suitability and differences due to age and other risk factors. Effective interventions have been recommended to reduce the excessive fluoroquinolone prescribing in the United States.

History of Quinolone ( fluoroquinolones) antibiotics

Nalidixic acid is considered to be the predecessor of all members of the quinolone family, including the second, third and fourth generations commonly known as fluoroquinolones. This first generation also included other quinolone drugs such as pipemidic acid, oxolinic acid and cinoxacin, which were introduced in the 1970s.

They proved to be only marginal improvements over nalidixic acid. Though it is generally accepted that nalidixic acid is to be considered the first quinolone drug, this has been disputed over the years by a few researchers who believe that chloroquine, from which nalidixic acid is derived, is to be considered the first quinolone drug rather than nalidixic acid.

Since the introduction of nalidixic acid in 1962, more than 10,000 analogs have been synthesized, but only a handful have found their way into clinical practice.[11]The Fluoroquinolone drugs are the most toxic and dangerous antibiotics in clinical practice today.[

Quinolone ( fluoroquinolones) family antibiotics

The quinolones also referred to as fluoroquinolones are a family of synthetic broad-spectrum antibiotics. The term Quinolone(s) refers to potent synthetic chemotherapeutic antibacterials the first generation of which was derived from an attempt to create a synthetic form of chloroquine, which was used to treat malaria during World War II. Hans Andersag discovered chloroquine in 1934, at Bayer I.G. Farbenindustrie A.G. laboratories in Eberfeld, Germany. The first generation of the quinolones begins with the introduction of nalidixic acid in 1962 for treatment of urinary tract infections in humans. Nalidixic acid was discovered by George Lesher and coworkers in a distillate during an attempt at chloroquine synthesis.

They prevent bacterial DNA from unwinding and duplicating. Recent evidence has shown that topoisomerase II is also a target for a variety of quinolone-based drugs. Thus far, most of the compounds that show high activity against the eukaryotic type II enzyme contain aromatic substituents at their C-7 positions.

Quinolones in comparison to other antibiotic classes have the highest risk of causing colonisation with MRSA and C Difficile. A general avoidance of fluoroquinolones is recommended based on the available evidence and clinical guidelines. The parent of the quinolone (aka fluoroquinolone) class is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position.

Side effects and Allergic reaction of Azithromycin-250/500 tablets

Allergic reaction

Patients who suffer from an allergic reaction to Azithromycin can experience blood in the stool 4–10 days after ingestion, although cases of this have been recorded as early as after the first day of ingestion.

These allergies are usually non-severe if the treatment is immediately stopped. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness.

Side effects

Most common side effects are gastrointestinal; diarrhea (5%), nausea (3%), abdominal pain (3%) and vomiting. Fewer than 1% of patients stop taking the drug due to side effects. Serious allergic reactions, nervousness, dermatologic reactions, and fatalities have been reported. As with all antimicrobial agents, pseudomembranous colitis can occur during and up to several weeks after azithromycin therapy. This drug may interfere with the effectiveness of birth control pills; other forms of contraception may be required during the treatment period.

Azithromycin suspension tastes bad, which can make it difficult to administer to young children (e.g. 2 - 5 years) who may spit it out.

Metabolism of Azithromycin-250/500 tablets

Following a single 500 mg dose, plasma concentrations of azithromycin declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Pharmacokinetics of Azithromycin-250/500 tablets

Unlike erythromycin, azithromycin is acid-stable and can therefore be taken orally with no need of protection from gastric acids. It is readily absorbed, but its absorption is greater on an empty stomach. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms.

Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility.

Azithromycin's half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.

Mechanism of action and Microbiology of Azithromycin-250/500 tablets

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. Azithromycin binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA. Nucleic acid synthesis is not affected.

Microbiology

Azithromycin has a similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Haemophilus influenzae. Azithromycin resistance has been described and is endemic in many areas.

Azithromycin has been most effective against isolates of the following microorganisms:

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Chlamydia pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

Helicobacter pylori

Salmonella typhi

Azithromycin has been shown to be effective against malaria when used in combination with artesunate or quinine; the optimal dose for this is not yet known.

Azithromycin-250 and Azithromycin-500 tablets - Antibiotics and Antibacterials

Azithromycin is an azalide, a subclass of macrolide antibiotics.

Azithromycin is one of the world's best-selling antibiotics, sold in the US under the name Zithromax as well as under generic labels. It is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered.

Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia, Typhoid, and sinusitis. In recent years it has primarily been used to prevent bacterial infections in infants and those with weaker immune systems. It is also effective against certain urinary tract infections and venereal diseases, such as non-gonococcal urethritis, chlamydia, gonorrhea and cervicitis. Recent studies have also indicated it to be effective against late-onset asthma, but these findings are controversial and not widely accepted.