Moxifloxacin pharmacology and clinical applications

Moxifloxacin (Pharmacology)

Composition/formulation & structure/nomenclature a) What is in the drug?

The drug is an antibiotic, and it comes under the classification of fluoroquinolones. It is primarily used to fight bacteria in the body, and to treat bacterial infections, including pneumonia, acute bronchitis, and sinusitis, and at times, for other purposes as well, depending upon the discretion of the attending physician. Its generic name is Moxifloxacin, and the brand names of this drug are Avelox, and Avelox IV.

A b) What form (solid, liquid, salt etc.) and doses of the active ingredient?

Moxifloxacin can be taken in either an oral dose, or can be given intravenously through an IV infusion. One must remember that when the drug Moxifloxacin is to be taken orally, then one must drink plenty of fluids, and even when consuming the drug, one must take care to consume a full glass of water along with it. However, Moxifloxacin can be taken with or also without food, and it is generally to be taken as a single dose, once a day. Every dose must be taken at the same time, every day. One must be very careful to talk to the Doctor first before attempting to take this drug in any form, because of the fact that the drug can be dangerous to those who are suffering from a heart condition of any kind, and are therefore under medication for that ailment, like for example, if they are taking drugs such as quinidine, branded as Cardioquin, Quinidex, and Quinaglute, and others, procainamide, which is branded as Pronestyl, Procan SR, and others, amiodarone, branded under Cordarone, Pacerone, and others, sotalol sold as Betapace, and others. (1)

In addition, if the patient is already suffering from a low level of potassium in his blood, or if he has a slow heart rate, any heart problems, liver diseases, or epilepsy, then he must inform the physician about it, so that extra precautions may be taken. The medicine can be taken about four hours before, or about eight hours after antacids which contain or have as their most important component magnesium, calcium, or aluminum. Even if the patient has had to have ulcer medication, like for example, sucralfate, then vitamin or zinc supplements, or powders which contain didanosyne as one of their ingredients may be given as an additional supplement, and this may well increase the absorption of the drug into the system. (1) The active ingredient in Moxifloxacin is moxifloxacin hydrochloride, and in its IV form, the drug, sold as Avelox, can be administered as an intravenous 0.8% sodium chloride solution which contains 400 mg moxifloxacin. (2)

What are the inactive ingredients (excipients)?

The inactive ingredients of the drug Moxifloxacin are as follows: "microscocrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and ferric oxide." (3) This is a list containing the excipients of the drug Moxifloxacin and the solution for that of infusion are "Sodium chloride Ph. Eur., USP, Ph. Jap., hydrochloric acid 1N, sodium hydroxide solution 2N, water for injection Ph. Eur., USP, Ph. Jap." (4) d) What is the chemical name and structure of the active component?

The chemical name of the drug Moxifloxacin is considered as "moxifloxacin, MXFX, IUPAC:1-cyclopropyl-7-(5,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid, MW: 401.431 | MF: C21H24FN3O4." (5) As far as the structure of the active component of Moxifloxacin is concerned, it must be noted that all drugs of this type, that is, quinolones, with antibacterial activity, have a 4-quinolone nucleus having nitrogen at position 1, a carboxyl group which is at position 3, and also a ketone coming at position 4. (6) It must also be noted that Moxifloxacin varies from other quinolones because of the fact that it has a methoxy function at the level of the 8 position, and an 'S-S' configured at the diazabicyclononyl ring moiety is found at the 7 position. (7) This can be understood by the following figure.

Diagram Reference: (38) e) What chemical class does it belong to?

The chemical class that the drug Moxifloxacin belongs to is that of a floroquinolone and the drug also is considered to have pneumococcal activity, which can be proved to be better than that of levofloxacin, and is found to be almost similar to that of trovafloxacin. (8) f) What aspects of its structure are important with respect to its function?

The newly developed moxifloxacin compound can be stated to be superior to the already existing ones in its potency, in its broad spectrum of activity, in its basic pharmacodynamics, and also in its pharmacokinetics. It has been found that its safety profiles are also infinitely superior to others of the same kind. (9) In general, when a person has a bacterial infection in his body, it is characterized by a systemic inflammation demonstrated in the massive activation of both the macrophages in the reticuloendothelial systems, and in the circulating leukocytes, and in the release of cytokines, the development of hypotension, and in the adhesion molecule expression on the epithelial cells. The inevitable consequences of all these events may be sepsis, septic shock, and even multiple organ failure. Also, in general, when such an infection is initially treated with appropriate antibiotics, there will inevitably be a certain type of reaction. Quinolones such as Moxifloxacin served to reduce the in-vitro production of TNF-a, IL-1b, and IL-6 by LPS-stimulated human monocytes. However, in alveolar macrophages, it was found that the TNF production after the introduction of LPS stimulation was not reduced by ciprofloxacin. (10)

2. Absorption, distribution, metabolism & excretion a) How is the drug absorbed and distributed?

When Moxifloxacin is given as an oral tablet, it gets absorbed by the gastrointestinal tract, which is the entire digestive tract, right from the mouth up to the anus. The complete 'bioavailability' of Moxifloxacin can be said to be about 90%, where bioavailability means the rate and also the extent to which an active drug is able to enter the general circulation of an individual, thereby allowing access to the very site of the action. The phenomenon is measured either by the measurement of the concentration of the drug in the system, or by the degree of the pharmacologic response being exhibited by the patient. When the drug is administered with a fatty meal, the absorption is not at all affected, and in the same way, the consumption of yoghurt also does not in a great way affect the absorption of Moxifloxacin. (11) It must be stated that the absorption of the drug happens almost immediately after it has been applied. In the case of an IV infusion, after a single 400 mg intravenous one hour infusion, the peak plasma concentrations were found at the end of the infusion. (12)

Diagram Reference: (38) b) What are the effects of protein binding and lipid/tissue uptake?

When experiments were conducted to evaluate the protein binding action of the drug Moxifloxacin, by a method called the 'ultra filtration method', the process is as described: the test materials in the form of fluids, like for example, human and rabbit serum, beef broth, and sterile water, were all incubated in ambient air for about two hours, and after the pH was adjusted, the drug was added to the various fluids in concentrations of 5, 10, 20, and 40 µg/ml, after which the fluids were incubated again for two more hours. Half the samples were centrifuged at 3000 into g for twenty minutes. The following protein binding was seen as being different for different samples: in human serum it was at "54%, + or - 14%, in rabbit serum it was 24% + or - 5%, in beef broth it was 33%, and in sterile water, it was 0%." (13) In addition, there was found to be no co-relation between the degree of protein binding and concentration of the drug. (13) Most of the time, the lasting equilibrium between blood and tissue cannot be always the same, and what this mean is that although in general all antibiotics manage to achieve equilibrium in blood and tissues, it need not happen all the time. When micro dialysis was used to measure the tissue drug absorption in the case of Moxifloxacin, it was found that concentrations in ISF of this drug corresponded to unbound concentrations in plasma, and was lower in whole tissue specimens. (14)

Describe its pharmacokinetic parameters.

The pharmacokinetics of moxifloxacin was studied in NMRI mice, and in monkeys, beagle dogs, and other animals, and in healthy human beings. The plasma concentration vs. time courses of the compound which was unchanged and the derived pharmacokinetic parameters were used to study the pharmacokinetic parameters. The results reveal a clear dependence on the species. The drug was absorbed quickly, and a major portion reached systemic circulation within two hours after absorption. (15) d) What is the drug's route and extent of metabolism

Moxifloxacin is a drug which attains good penetration into both peripheral tissues as well as into inflammatory fluids. It also shows in vitro activity in cases of staphylococci and streptococci. (16) The drug has better coverage against Gram-positive cocci and atypical pathogens, and it is able to achieve excellent penetration into respiratory fluids and tissues. One particular adverse effect of the drug is that it may result in gastrointestinal disturbances, and thereby affect the individual's metabolism. (17) e) How does metabolism influence clearance, bioactivity and elimination?

At times, the metabolism does tend to affect the absorption and the clearance of the drug from the system. For example, the changes in the INR or the International Normalized Ratio may happen in certain patients who have been receiving oral anticoagulants, with antibiotics, such as Moxifloxacin. The age, the state of the infectious disease, and so on are all risk factors. However, the drug does not interfere with the 1A2 subtypes of cytochrome P450 enzymes, and in the same way, there was no significant effect on apparent body clearance and also on the renal clearance of moxifloxacin on a human being. (4) f) Is the drug mainly excreted in urine or faeces?

Moxifloxacin is mainly bound to serum albumin, and it is therefore widely distributed throughout the body. It is also distributed to the saliva, nasal and bronchial secretions, and to the sinus mucosa. Therefore, the elimination rates from the tissues generally correspond with the elimination through plasma. Most of the drug is metabolized in the liver, and most of it is excreted in the feces, and a small part of it in the urine. (18)

3. Mechanism of action a) How does the drug exert its effect?

The drug Moxifloxacin, a fluoroquinolone, being a broad spectrum antibiotic, with a concentration dependent bactericidal action, exerts its mechanism by either binding to or inhibiting topoisomerase II, or the DNA gyrase, and the topoisomerase IV. These are the bacterial enzymes that are responsible for the coiling and the uncoiling of DNA, which are always required for the bacterial cell repair, and for their replication within the body. (19) b) What are the targets of the drug and what aspects of its structure relate to efficacy?

When the in vitro activity of the drug was studied, and its intracellular activities were also studied, it was found that the first step mutants bore amino acid substitutions at position 81 in the Gyr A subunit of DNA gyrase. This was indicative of the fact that moxifloxacin targets the Gyr A subunit of DNA gyrase as an initial lethal event, and this was precisely the action needed against pneumonia bacteria. (20) The third generation fluoroquinolone moxifloxacin have a typical gram positive, atypical and an anaerobic coverage as compared with the first and second generation fluoroquinolones. This is a drug that is not at all affected by bacterial efflux mechanisms because of the fact that they possess a bulky side chain moiety at position 7, which as a matter of fact, serves to affect export. It also exceeds the mutant prevention concentrations for S. Pneumoniae. (21)

Does the drug have other targets/actions other than its main therapeutic action?

Since moxifloxacin is made up or composed of a number of quinolones, and if one small alteration or variation were to be brought out with regard to one of the side chains of quinolones, then it could be said that in the entire anti-bacterial structure there would be alterations, and therefore, one should understand that the basic structure of the drug must be left as it is, so that there is no change being brought about in its efficacy. (22) It must be stated however that the mechanism of the action of quinolones is not yet fully known, and in susceptible bacterial infections, it serves to inhibit the activity of DNA gyrase. (6) d) Are there abnormalities/diseases that influence its activity?

Although it is today widely acknowledged that moxifloxacin is one of the most active fluoroquinolones that can fight against tuberculosis in vitro, relevant data about its efficacy has not yet become fully available, and, according to one particular study conducted on tuberculosis patients, it was found that calculated early bactericidal activities for isoniazid and moxifloxacin were 0.209 and 0.273 log10 CFU per ml of sputum per day, accordingly, and this meant that the drug moxifloxacin showed an early bactericidal activity that it was possible to compare with that of an isoniazid. Therefore, it may be said that tuberculosis may be one disease that may have an impact on the activity of the drug Moxifloxacin. (23)

Moxifloxacin can be utilized for the treatment of community acquired tuberculosis, and new evidence shows that the agent may be less likely to be selected for resistant SP subpopulations, wherein this resistance may happen in a series of gradual steps, as and when the organisms start to acquire mutations in their genes which encode the two topoisomerases, gyr, and par. (24)

4. Therapeutic applications/effects a) What is the evidence that the drug is effective in treating its particular condition?

Pneumonia is a disease wherein there is a serious inflammation of the lung, and which is caused by bacteria, viruses, and several other organisms. It generally occurs when an individual's immune system has been compromised due to some reason or the other, and where there is a bacterial growth along the upper respiratory tract. About 10% of all hospitalizations in the U.S.A. are due to this disease, and as far as the treatment is concerned, antibiotics are the only option. The quinolones levofloxacin and gatifloxacin are generally recommended for its treatment. These medicines interfere with the bacteria's genetic material so that it cannot reproduce, and this arrests the disease. The fourth generation moxifloxacin is safe against many gram negative and gram positive bacteria. (25)

Moxifloxacin is also at times referred to as being 'genetically smart' flouroquinolone. This is because the drug, because of its unique structure has improved potency against gram positive bacteria, and the kill curves for the drug are infinitely higher than ciprofloxacin. It has the adual mechanism; wherein it acts on two sides, and these are on the DNA gyrase side and on the topoisomerase IV, which should as a matter of fact, delay in the emergence of resistance. (26) b) What patients or conditions is it effective for?

The drug is useful for the treatment of almost all respiratory tract infections, and it kills the common bacteria that are responsible for such infections in adults. (27)

What aspects of disease/symptoms are alleviated by the drug?

Moxifloxacin has an excellent gram negative quality and also a moderate gram positive activity. This is in fact referred to as a broad spectrum of activity, and since they also have a unique mechanism of action, they are the best agents of the study of empiric therapy. This, in combination with its high levels of bioavailability, makes it something that is very attractive and perhaps this is why it is so widely used, and at times, indiscriminately as well. (28) "Airway obstruction, airway destruction, airway inflammation, and emphysema" are some of the symptoms of disease that are being alleviated by Moxifloxacin. (29) d) Is therapeutic monitoring required?

Monitoring is indeed required when taking moxifloxacin, because there are any people who are allergic to the drug. This is especially true when the patient is at present taking any other medication for any other types of ailment that he may have at that time, even if they are merely vitamins or herbal products. Moxifloxacin cannot be taken along with antacids which contain either magnesium or aluminum, like for example, Milk of Magnesia, Mylanta, and Maalox. In the same way, the drug must not be taken along with iron or zinc or any other vitamin supplements. When treating children, extreme caution and care must be taken, and the doctor must be informed if the child is on any other medication for any reason whatsoever. Pregnant women, and also women in the reproductive age are often advised not to take moxifloxacin, because of the adverse side effects it may have. (30)

Even breast feeding mothers must be closely monitored therapeutically. Unnecessary exposure to bright sunlight must be avoided at any cost, and the reason for this is that the drug has the result of making an individual extremely sensitive to light and the sun. If the patient is planning to have surgery of any kind, especially dental, then the doctor must be told that the patient is on Moxifloxacin. The drug has been known to cause lightheadedness and dizziness, and one must be aware of these facts before taking the medicine so that he may be able to avoid potentially dangerous situations. (30) e) Is the drug used in combination with other drugs/approaches?

The traditional gram negative coverage of moxifloxacin has today been extended to include certain gram positive coverage as well, and these are specifically gram positive organisms like upper and lower respiratory tract infections, gastrointestinal infections, gynecologic infections, and sometimes, sexually transmitted diseases. However, one must remember that inappropriate usage of the drug would have certain extreme adverse reactions in the patient. When it is used in combination with other drugs, from other antibiotic classes, such as beta-lactams and amino glycosides, then the quinolones will not be specifically synergistic. Although the impact and effects of most combinations are generally either additive or indifferent, ciprofloxacin and rifampin seem to be antagonistic against Staphylococcus aureus. (31)

5. Adverse effects/contraindications/drug interactions a) What are the side-effects (good and bad) of the drug, their frequency and severity, and in what patients are they likely to be most serious?

Most adverse effects reported in clinical trails of the drug Moxifloxacin were described as being either moderate or extreme, and where it affected the entire body, it resulted in headache, abdominal pain, asthenia, injection site pain, and allergic reactions, and also certain moliasis, and certain pains all over the body. Cardiovascular reactions included palpitation, vasodilatation, tachycardia, and hypertension, or the QT interval would be inordinately prolonged. In the nervous system, the side effects are insomnia and vertigo, or somnolence, tremors, nausea, diarrhea, a severe anxiety, and so on and so forth, and in the digestive system, vomiting and constipation.

Diagram Reference: (38) dryness of the mouth, dyspepsia, flatulence, and oral moniliasis, an increase in the GGTP, and also anorexia, nervousness, stomatitis, and a glositis may also occur in the digestive system. In the skin there may be rashes, which may be pustular, or maculopapular, pruritus, and excessive sweating and also urticaria may all occur. Myalgia is a possibility in the musculoskeletal system. Artralgia is also a strong possibility, and one must be very careful about this phenomenon. (32)

When it comes to the metabolic and the nutritional aspects, the drug Moxifloxacin may have certain unwanted adverse effects, and some of them may be as follows: the lactic dehydrogenase of a person may become greatly increased, or the amylase may also increase to significant levels. These reactions may occur in any patient regardless of age or ethnicity or gender, and may occur every time the patient has the drug, or at times. These were the results that were found after clinical testing of about 8,600 patients, who had been given the drug both orally as well as intravenously. Most of the patients had received a 400mg dosage of the drug. Some side effects in some patients were found to be only moderately serious, and these did not need any further treatment or medication. However, in about 2.9% of orally treated patients, and about 4.6 of the sequentially treated patients, wherein oral doses would be followed by intravenous treatment infusions, there were certain adverse reactions, and the drug had to be eventually discontinued because of this. (32) b) What patient conditions/characteristics render the drug unsafe or ineffective?

Patients with peripheral neuropathy, tendon damage, and various heart aliments must not take the drug. One patient was arrested for attacking his own brother, parents and grandparents. The bizarre behavior was attributed to the antibiotics that he was taking at that time. What the family members had to say about this patient was this: Jonathan Brewer was not a man who would be capable of inflicting such damage on his own family members, and not on anyone else too. It seems that Brewer had undergone a toe surgery recently, and he had been prescribed Cipro for about two weeks form the time after the completion of the surgery. The company had also stated that among the various side effects that were described, confusion and hallucinations and also hallucinations, and depersonalizations. (33)

The poor patient had been arrested and put in jail for something that was clearly beyond his own control, and his family states that their only hope is that the state would look at the case and decide that Jonathan Brewer need not be locked up in jail at all; rather, the court must appoint a doctor who would be able to decide whether or not this person was fit enough to be released to his family, who are fully supportive of him, and most definitely want him back, no matter what happens. Therefore, the side effects have to be well researched before the drug is prescribed to any individual. (33)

What effects do other drugs have on the drug's tolerability, efficacy, safety?

The doctor must be told about the other drugs that the patient is taking, because of the effects that these drugs may have on the body, especially if they are antibiotics or medicines for mental diseases or for depression. These drugs may have an impact on the safety and reliability of moxifloxacin. However, before using the drug Moxifloxacin, the patient must be careful to warn the doctor that he is taking other medication, and especially if he is allergic tomoxifloxacin, alatrofloxacin injection, or to cinoxacin, or to ciprofloxacin, or to enoxacin, or to gatifloxacin, or to levofloxacin, or to lomefloxacin, or to nalidixic acid, or to norfloxacin, or to ofloxacin, or to sparfloxacin, or to trofloxacin tablets, or to any other drugs, which may finally have an adverse reaction on the patient because of the eraction that that drug may have when it is combined with the drug Moxifloxacin. (30)

6. Regulatory issues for New Zealand a) What is the drug/marketed sold for?

The medicine Moxifloxacin is sold to treat bacterial infections; it is an antibiotic. The drug must be taken until the full course of treatment is completed. However, one must never take an extra dose to make up for a missed dose, as this would lead to drug abuse. As stated earlier, one must remember to tell the doctor that he has an allergic reaction to any drug, or even to this particular drug. (34) b) Is there're any potential for drug abuse?

It must be remembered that when taking this drug for the treatment of any form of infection, one must follow the directions of the attending physician must be followed to the letter, and one must never use more medicine than what the doctor has already recommended. Not only would this be extremely dangerous, but it would also lead to a certain form of drug abuse as well. In addition, one must not stop taking the medicine even after one feels much better, for it must be remembered that the drug starts to take effect aft just a few hours after infusions. One must follow the treatment, and finish the recommended course fully. The medicine must be stored in a closed container, and it must be kept in a cool place, and away from heat and direct light. Any leftover medicine must be disposed of properly, and care must be taken to see that it does not reach the hands of small children at any cost, as it can be deadly for them. (30)

Does the drug have applications in areas where treatment is (or is not) given high priority due to Governmental/cultural priorities?

While tuberculosis is a disease that is spread by way of air form one patient to another, and which is a disease which affects the upper respiratory tract, it is a world wide disease, with the highest number of cases occurring in South East Asia and in sub-Saharan Africa. There is today, multidrug resistant tuberculosis, which resists even the strongest drugs such as isoniazid and rifampicin. Today, we find that there is a global crisis which I sbeing caused by this disease alone, along with other deadly diseases like that of the AIDS. The new anti-tuberculosis drugs like moxifloxacin for instance should be in a position to combat the disease to some considerable extent, and they must also be in a position to reduce the period of the required treatment for this. Along with this they must also be active with regard to both resistant and non-resistant strains of the diseases, and they should also be careful with regard to addressing the prevalence of AIDS. Nowadays the drug is being used in the third world countries for the purpose of the treatment of the skin and also in relation to anti-respiratory tract infections and it has found to be been tested in India, for its treatment shortening effect. (35) d) Are there geo-political factors that influence the availability/marketing of the drug?

Today, Moxifloxacin is a fourth generation drug that is available both in an oral form as well as in an IV form, and it is sold under the brand name Avelox. (36) It must be noted that despite all the recent advances in the treatment of infectious diseases, especially those that affect the upper respiratory tract, infections like the CAP or the Community Acquired Pneumonia still persist to have a significant influence on the public health; in the United States of America, this is one of the seventh leading causes of death, that is, several million cases of pneumonia occur every year in the U.S.A., while in Germany it is about 0.5 million cases every year. Moxifloxacin the new 8 methoxy fluoroquinolone is today marketed in over fifty countries all over the whole world, and it is used extensively and at times exclusively for the treatment of community acquired pneumonia. It is also sold for the treatment of acute bronchitis, and for acute sinusitis. (37) recent study that was conducted in Germany on about 4,400 patients revealed that when Moxifloxacin was used for the treatment of their upper respiratory tract infections, they were able to experience a very quick relief from their symptoms. About 70% of the remaining patients showed a marked improvement after about three days. (37) There is no doubt that the drug Moxifloxacin is on of the better inventions today, and if it were to be more widely distributed and marketed, then more people would be able to get the full benefits of this wonderful fourth generation drug.