1.AZITHROMYCIN HISTORY (How was Azithromycin discovered?)

A team of Pliva's researchers, Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski and Zrinka Tamburasev led by Dr Slobodan Dokic, discovered Azithromycin in 1980. Azithromycin was patented in 1981.

Azithromycin was approved for the treatment of Mycobacterium avium complex (MAC) in June 1996. 

Note: World-drugs.net sells generic version of Azithromycin

2.AZITHROMYCIN FACTS

Azithromycin is the first macrolide antibiotic belonging to the azalide group. 

Azithromycin is derived from erythromycin by adding a nitrogen atom into the lactone ring of erythromycin A, thus making lactone ring 15-membered. 

Azithromycin is sold under the brand name of Zithromax and Sumamed, and is one of the world's best selling antibiotics.

3.ABOUT AZITHROMYCIN MEDICATION

What are antibiotics?

An antibiotic is a drug that destroys or slows the growth of bacteria. Antibiotics are one class of "antimicrobials", a larger group, which also includes anti-viral, anti-fungal, and anti-parasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infections. The term originally described only those formulations derived from living organisms, in contradistinction to "chemotherapeutic agents", which were purely synthetic. Nowadays the term "antibiotic" is also applied also to synthetic antimicrobials, such as the sulfonamides.

Antibiotics are labeled as "magic bullets": drugs, which target disease without harming the host. Antibiotics are not effective in viral, fungal and other nonbacterial infections, and individual antibiotics vary widely in their effectiveness on various types of bacteria. Some specific antibiotics target either gram-negative or gram-positive bacteria, and others are more wide-spectrum antibiotics.

The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection, and the ability of the bacteria to resist or inactivate the antibiotic. Some antibiotics actually kill the bacteria (bactericidal), whereas others merely prevent the bacteria from multiplying (bacteriostatic) so that the host's immune system can overcome them.

Classes of Antibiotics?

There are many ways to classify antibiotics.

One such classification is by chemical structure:

Aminoglycosides

• Amikacin
• Dibekacin
• Gentamicin
• Kanamycin
• Neomycin
• Netilmicin
• Paromomycin
• Sisomycin
• Streptomycin
• Tobramycin

Beta-lactam ring antibiotics

• Carbapenems
• Ertapenem
• Imipenem
• Meropenem

Cephalosporins and cephamycins

• Cephalexin
• Cefazolin
• Cefuroxime
• Cefadroxil
• Ceftazidime

Penicillins

• Amoxicillin

Monocyclic beta-lactams

Glycopeptide antibiotics

• Vancomycin
• Teicoplanin
• Ramoplanin
• Decaplanin

Oxazolidinones

• Linezolid
• Quinupristin/dalfopristin

Polyketides

Macrolides

• Erythromycin
• Azithromycin
• Clarithromycin
• Roxithromycin

Ketolides

• Telithromycin

Tetracyclines

• Doxycycline
• Oxytetracycline
• Chlortetracycline

Polymyxins

• Polymyxin B
• Colistin

Quinolones (fluoroquinolones)

• Nalidixic acid
• Ciprofloxacin (Cipro)
• Ofloxacin
• Norfloxacin (Norflox)
• Levofloxacin (Levaquin)
• Trovafloxacin (Trovan)

Streptogramins

Sulfonamides

• Prontosil

Other important antibiotics:

• Chloramphenicol
• Clindamycin
• Fusidic acid
• Trimethoprim

Another such classification is by their mechanism of action

Antibiotics, which interfere with cell-wall synthesis

• Beta-lactams, including penicillins like amoxicillin and cephalosporins; mono-lactams, such as Imipenem; vancomycin, bacitracin

Antibiotics that interfere with bacterial protein synthesis 

Antibiotics that bind to the 50S ribosomal unit

Lincosamides/lincosides including clindamycin and lincomycin; chloramphenicol, macrolides

Antibiotics, which interfere the 30S ribosomal unit

Tetracyclines; aminoglycosides including gentamicin

Drugs that inhibit folate synthesis

Sulfonamides and trimethoprim 

Drugs that interfere with DNA synthesis

Metronidazole, quinolones, novobiocin

Drugs that interfere with RNA synthesis

Rifampin (rifampicin)

Drugs that interfere with cell membrane function

Polymyxin B, gramicidin

Antibiotics can also be classified by the organisms against which they are effective, and by the type of infection in which they are useful, which depends on the sensitivities of the organisms that most commonly cause the infection and the concentration of antibiotic obtainable in the affected tissue. 

How does Azithromycin work?
Azithromycin works by preventing bacteria from producing proteins that are essential to them. Without these proteins the bacteria cannot grow, replicate and increase in numbers.

Azithromycin binds reversibly to the 50S subunit. Azithromycin can inhibit elongation of the protein by the peptidyltransferase, the enzyme that forms peptide bonds between the amino acids. 

Azithromycintherefore stops the spread of infection and remaining bacteria are killed by the body's immune system or eventually die.

Stage 1.

Stage 2. 

Stage 3 

Uses of Azithromycin

Azithromycin is a broad-spectrum antibiotic that is active against a wide variety of bacteria that cause a wide variety of infections. Azithromycin may be used to treat infections of the upper or lower airways, skin or soft tissue, or ears. It may also be used to treat the sexually transmitted infection chlamydia.

Azithromycin is mainly used for the treatment of Mycobacterium avium complex (MAC).

Mycobacterium Avium Complex disease is among the most common bacterial infections in people with HIV. In one study, MAC bacteria were found in the blood of 43% of people within two years of diagnosis with AIDS. MAC is most likely to occur in people with CD4+ cell counts below 50 and at least one other opportunistic infection (OI).

Routine blood tests from people with low CD4+ cell counts can detect MAC at an early stage when it can be treated fairly easily. Drugs can also be used to prevent MAC disease in people with low CD4+ cell counts.

If you develop MAC disease, treatment can ease symptoms and improve your quality of life. And, if you have had MAC disease, then you will need to continue taking drugs to stop the disease from returning. Drug resistance is a serious issue in treating MAC, but potent treatments can slow the development of drug-resistant MAC bacteria.

Cause

MAC is the term for two related bacteria: Mycobacterium avium and Mycobacterium intracellulare (MAI). These bacteria are found in water, dust, soil and bird droppings. They enter the body in food and water or sometimes through the lungs.

Most people usually have small numbers of these bacteria growing in their gut or lungs, but do not have any symptoms. This is because a weakened immune system allows the bacteria to attack the lining of the gut and multiply. From there, they can enter the blood and spread through the body, which is called disseminated infection.

Symptoms

The most common symptoms of MAC are persistent fevers plus night sweats, loss of appetite, weight loss, tiredness or worsening diarrhea. Symptoms of early disease often involve the gut: stomach cramps, nausea and vomiting. Disseminated disease can lead to bone, brain or skin infections, or cause painful joints.

Signs of MAC include swollen abdominal lymph nodes, usually on only one side of the body, and an enlarged liver and spleen. Coughing and wheezing are less common. Since many of these symptoms are similar to symptoms of other opportunistic infections (OIs), it's important to get a correct diagnosis before you start treatment. If you have symptoms like these, talk to your doctor.

A recent study showed that people who already have MAC when they start potent anti-HIV therapy sometimes have an unusual response. It has been called MAC reversal syndrome and results from improved immune function (increases in CD4+ cell counts). It involves fevers and the growth of lumps usually around the neck or spine. The drug prednisone can reduce these symptoms.

Over time, these people still benefit from anti-HIV therapy and their MAC infection stabilizes. So anti-HIV therapy does not always stop MAC in people with early MAC infection, but overall it seems to be beneficial whether or not MAC occurs. However, it may be useful to screen for MAC in people with symptoms like fevers before they start anti-HIV therapy.

Diagnosis

MAC is diagnosed by culture from blood, tissue or bone marrow. If MAC bacteria are found in stool and sputum samples, this could mean the infection has spread. Doctors may have to use special methods to get cells or tissue for MAC diagnosis. These include taking bone marrow from the hip using a needle, or inserting a flexible tube into the stomach or bowels (endoscopy) or the lungs (bronchoscopy).

Some doctors choose to treat MAC infection while waiting for the test results, which can take several weeks. New tests are being developed to give a faster diagnosis. These include PCR and bDNA tests for MAC (the same methods used for HIV viral load tests). Severe anemia and liver problems can occur in MAC, so doctors may take blood samples to look for a low red blood cell count or raised alkaline phosphatase levels. 

4.AZITHROMYCIN EFFECTIVENESS
When is Azithromycin best taken?

Following oral administration, Azithromycin dose is rapidly absorbed and widely distributed throughout the body. Rapid distribution of Azithromycin into tissues and high concentration within cells result in significantly higher Azithromycin concentrations in tissues than in plasma or serum.

The pharmacokinetic parameters of Azithromycin capsules in plasma after a loading Azithromycin dose of 500 mg (2-250 mg capsules) on day one followed by 250 mg (1-250 mg capsules) q.d. on days two through five in healthy young adults (age 18-40 years old) are portrayed in the following chart:

In this study, there was no significant difference in the disposition of Azithromycin between male and female subjects. Plasma concentrations of Azithromycin following single 500 mg oral and i.v. Azithromycin doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2-5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading Azithromycin dose, Azithromycin C min levels required 5 to 7 days to reach steady-state.

When Azithromycin capsules were administered with food to 11 adult healthy male subjects, the rate of absorption (C max ) of Azithromycin from the capsule formulation was reduced by 52% and the extent of absorption (AUC) by 43%.

In an open label, randomized, two-way crossover study in 12 healthy subjects to assess the effect of a high fat standard meal on the serum concentrations of Azithromycin resulting from the oral administration of two 250-mg film-coated tablets, it was shown that food increased C max by 23% while there was no change in AUC.

When Azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (C max ) was increased by 56% while the extent of absorption (AUC) was unchanged.

The AUC of Azithromycin was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with Azithromycin; however, the C max was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to Azithromycin had no effect on Azithromycin absorption.

When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of Azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

The serum protein binding of Azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL.

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

There are no pharmacokinetic data available from studies in hepatically- or renally-impaired individuals.

The effect of Azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple Azithromycin doses adequate to reach therapeutic steady-state plasma levels is not known

5.AZITHROMYCIN EFFECTS ON SPECIAL POPULATION
(How do different people react to Azithromycin?

Pregnancy : There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Azithromycin should be used during pregnancy only if clearly needed.

Labor and Delivery : It is not known whether use of Azithromycin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of forceps delivery or other obstetrical intervention or resuscitation of the newborn. 

Nursing Mothers: Azithromycin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when Azithromycin is administered to a nursing woman.

Pediatric Use : Because of incompletely developed renal function in neonates and young infants, the elimination of Azithromycin may be delayed. Dosing of Azithromycin should be modified in pediatric patients 12 weeks or younger (</=3 months).

Information for Patients : Azithromycin may be taken every 8 hours or every 12 hours, depending on the strength of the product prescribed.

Patients should be counseled that antibacterial drugs, including Azithromycin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

6.AZITHROMYCIN EFFECTS ON MEDICAL CONDITIONS
(How does Azithromycin affect your existing condition/ailment?)

Azithromycin should not be used incase of liver or kidney dysfunction. 

7.OTHER/ALTERNATE USES OF AZITHROMYCIN
What else does Azithromycin treat?

Azithromycin can also be used to treat some bacteria caused sexually transmitted diseases.

8.ADVERSE/SIDE EFFECTS of AZITHROMYCIN
What are the side effects of Azithromycin?

In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients (adults and children) from the multiple-dose clinical trials discontinued Azithromycin therapy because of treatment-related side effects. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. Potentially serious side effects of angioedema and cholestatic jaundice were reported rarely.

Clinical:

Adults:
Multiple-dose regimen: Overall, the most common side effects in adult patients receiving a multiple-dose regimen of Azithromycin were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported.

No other side effects occurred in patients on the multiple-dose regimen of Azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:

Cardiovascular: Palpitations, chest pain.

Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice

Genitourinary: Monilia, vaginitis, and nephritis.

Nervous System: Dizziness, headache, vertigo, and somnolence.

General: Fatigue.

Allergic: Rash, photosensitivity, and angioedema.

Single 1-gram dose regimen: Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of Azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen.

Side effects that occurred in patients on the single one-gram dosing regimen of Azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).

Single 2-gram dose regimen: Overall, the most common side effects in patients receiving a single 2-gram dose of Azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). The majority of these complaints were mild in nature. 

Children:

Multiple-dose regimens : The types of side effects in children were comparable to those seen in adults, with different incidence rates for the two dosage regimens recommended in children.

Acute Otitis Media: For the recommended Azithromycin dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5, the most frequent side effects attributed to treatment were diarrhea/loose stools (2%), abdominal pain (2%), vomiting (1%), and nausea (1%).

Community-Acquired Pneumonia: For the recommended Azithromycin dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5, the most frequent side effects attributed to treatment were diarrhea/loose stools (5.8%), abdominal pain, vomiting, and nausea (1.9% each), and rash (1.6%).

Pharyngitis/tonsillitis: For the recommended Azithromycin dosage regimen of 12 mg/kg on Days 1-5, the most frequent side effects attributed to treatment were diarrhea/loose stools (6%), vomiting (5%), abdominal pain (3%), nausea (2%), and headache (1%).

With either treatment regimen, no other side effects occurred in children treated with Azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:

Cardiovascular: Chest pain.

Gastrointestinal: Dyspepsia, constipation, anorexia, flatulence, and gastritis.

Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness, insomnia.

General: Fever, fatigue, malaise.

Allergic: Rash.

Skin and Appendages: Pruritus, urticaria.

Special Senses: Conjunctivitis.

Post-Marketing Experience:

Adverse events reported with Azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include:

Allergic: Arthralgia, edema, urticaria, angioedema.

Cardiovascular: Arrhythmias including ventricular tachycardia.

Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis and rare reports of tongue discoloration.

General: Asthenia, paresthesia and anaphylaxis (rarely fatal).

Genitourinary: Interstitial nephritis and acute renal failure, oral candidiasis, vaginitis.

Hematopoietic : Thrombocytopenia.

Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.

Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, and agitation. 

Psychiatric: Aggressive reaction and anxiety.

Skin/Appendages: Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome, and toxic epidermal necrolysis.

Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, rare reports of taste perversion.