Macrolides

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Macrolides

- Erythromycin, Clarithromycin, Azithromycin Erythromycin used as alternative to penicillin in patient with allergic to penicillin.

Mechanism of action

Macrolide inhibit bacterial protein synthesis by binding reversibly to 50S ribosomal subunit and inhibit RNA dependant protein synthesis .


Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block peptide bond formation. The tetracyclines (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit .

Erythromycin

Erythromycin :effect against many of the same MO as Penicillin group so it use as alternative . - Absorption: incompletely but adequately absorbed from intestine inactivated by gastric acid , so it is given as enteric coated tab. or as cap. food impair absorption Higher concentration can be achieved by I.V administration

Distribution -diffuse into intracellular fluids, not enter CSF & brain -protein binding is 70-80% -cross placenta and milk Elimination .erythromycin t1\2 is 1.6 hr -metabolized by liver and excreted by bile, urine . Dosage 1-2 gm\day in divided dose i.e 6 hourly 30-50 mg\Kg\day for children (can be doubled in sever infection)

Clarithromycin

-absorbed rapidly from GIT -hepatic first pass metabolism reduces bioavailability to 50% -can be given with or without food -have higher intracellular conc. -protein binding is 40-70% The advantages of clarithromycin compared with erythromycin are lower incidence of gastrointestinal intolerance and less frequent dosing.


Azithromycin
Although less active against streptococci and staphylococci than erythromycin, azithromycin is far more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Azithromycin is now the preferred therapy for urethritis caused by Chlamydia trachomatis. It also has activity against Mycobacterium in patients with acquired immunodeficiency syndrome

azithromycin

The drug is slowly released from tissues (tissue half-life of 2–4 days) to produce an elimination half-life approaching 3 days. These unique properties permit once-daily dosing. For example, a single 1-g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500-mg loading dose, followed by a 250-mg single daily dose for the next 4 days.

Therapeutic uses of macrolides

Drug of choice for mycoplasma pneumonia Chlamydial infection Diphtheria Syphilis Streptococcal (alternative to P) Staphylococcal Prophylaxis for endocarditis Chronic periodontitis(azithromycin use as adjunct treatment)

Adverse effect macrolides

1- large dose cause epigastic pain , increase GIT motility 2- ototoxicity : transient deafness (high dose) 3-Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin 4- drug interaction : its enzyme inhibitor so it inhibit metabolism of number drugs which lead to toxic accumulation of drug like Warfarin and digoxin Others drugs interact with it : Carbamazepine, Glucocorticoids, Cyclosporine, theophylline

Telithromycin

is approved for clinical use. It is active in vitro against Streptococcus pyogenes, S pneumoniae, S aureus, H influenzae,, mycoplasmas, Chlamydia, H pylori, N gonorrhoeae

Telithromycin is indicated for treatment of respiratory tract infections, including community-acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and streptococcal pharyngitis.

Adverse effects

1.It is a reversible inhibitor of the CYP3A4 enzyme system and may slightly prolong the QT interval (ECG). 2.Rare cases of hepatitis and liver failure have been reported.

Chloramphenicol

Active against wide range of gram+ and anaerobic gram –ve organism It administer orally or IV. Mechanism of action : binding to 50S ribosomal subunit

Clinical Uses

Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to β -lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci..Chloramphenicol is used topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor.

Adverse effects

The clinical use of chloramphenicol is limited to life-threatening infections because of the serious adverse effects associated with its administration. 1.gastrointestinal upsets 2.overgrowth of Candida albicans in mucous membranes 3.Anemias [Note: Aplastic anemia is independent of dose and may occur after therapy has ceased.]

CONT.

4. Gray baby syndrome occur in neonates if the dosage regimen of chloramphenicol is not properly adjusted. Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped renal function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes. This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death. Adults who have received very high doses of the drug can also exhibit this toxicity

Gray baby syndrome

clindamycin
Mech. of action Bind to 50S subunit of bacterial ribosome and suppress protein synthesis

Antibacterial effects similar to erythromycin more than 90% of strains of streptococci ,including that are macrolides resistant are susceptible to clindamycin Clindamycin is more active against anaerobic bacteria than erythromycin and clarithromycin.



Kinetic -complete absorption orally , food not affect -t1\2 3hr -wide distribution including bone (not CSF) -excreted in urine and feces

Dose Oral: 150-300 mg\6hr for sever infection : 300-600 mg\6hr Injection (i.v , i.m): 600-1200 mg\day

Theraputic uses

Side effects
1-pseudomembranous colitis, abdominal pain, fever, bloody diarrhea, it could be lethal 2-rashs, anaphylactic reaction 3-granulocytopenia, thrombocytopenia 4-local thrombophlebitis after i.v injection 5-minor effects: nausea , vomiting , esophagitis, , allergy , Glossitis ,stomatitis ,metallic taste

Quinolones

Classification
First Generation Nalidixc Acid (NegGram) G-ve Bacteria like Escherichia coli No systemic effect Urinary Tract Infection(UTI)

Fluorination at position 6 Resulted in Systemically Active Fluoroquinolones

Second Generation Fluoroquinolones Systemic effect G-ve > G +ve Bacteria Ciprofloxacin Lomefloxacin Norfloxacin Ofloxacin

Third Generation Enhanced G+ve Effect Lower Respiratory Tract Infection Levofloxacin Moxifloxacin Fourth Generation (Anaerobes) Clinafloxacin Gemifloxacin


Mechanism of action
It enter bacterium by passive diffusion through water – filled protein channels (porins) in the outer membrane then it inhibit bacterial DNA replication and can cause cell death by inducing cleavage of DNA (( bactericidal )) .

Mechanism of action

Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II(DNAgyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.

Mechanism of action

Inhibition of Enzymes:

Pharmacokinetics

Well absorbed bioavailability nearly 100% Concentration dependant bactericidal effect. Food does not alter the absorption Elimination half life vary from 1.5-10 hours Allowing once or twice daily dosing ( Serum half life 3-10 hours) Elimination is renal except moxifloxacin, trovafloxacin, sparfloxacin High concentrating in neutrophils and macrophage

Approved Indications

Acute uncomplicated cystitis in females Chronic bacterial prostatitis Lower Urinary tract infection(UTI) respiratory tract infection Acute sinusitis Skin and skin structure infection Bone and joint infection Infectious diarrhea Enteric fever Uncomplicated gonorrhea

Ciprofloxacin

This is the most frequently used fluoroquinolone in the United States - useful in treating infections caused by many Enterobacteriaceae and other gram-negative bacilli.

Clinical uses

effective in urinary tract infections even when caused by multidrug-resistant bacteria alternative to more toxic drugs, such as the aminoglycosides. It may act synergistically with B-lactams benefit in treating resistant tuberculosis Gastrointestinal infection(acute diarrhea) used in the treatment of pseudomonal infections associated with cystic fibrosis the drug of choice for prophylaxis and treatment of anthrax


Ciprofloxacin
In dentistry use in aggressive periodontitis Caused by

Norfloxacin

effective against both gram-negative (including P. aeruginosa) and gram-positive organisms in treating complicated and uncomplicated UTIs and prostatitis. It is not effective in systemic infections.

Levofloxacin

is an isomer of ofloxacin and has largely replaced it clinically. It can be used in the treatment of prostatitis due to E. coli and of sexually transmitted diseases, with the exception of syphilis. It may be used as alternative therapy in patients with gonorrhea. range of infections, including skin infections, acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia Levofloxacin has excellent activity against respiratory infections due to S. pneumoniae

Moxifloxacin

has enhanced activity against gram-positive organisms (for example, S. pneumoniae) but also has excellent activity against many anaerobes. It has very poor activity against P. aeruginosa

Adverse reactions

Gastrointestinal nausea, vomiting, and diarrhea, which occur in three to six percent of patients.2. CNC headache and dizziness or light-headedness. patients with CNS disorders, such as epilepsy, should be treated cautiously with these drugs.3. cardiacProlongation of QT interval…............ Fatal ArrhythmiaHypokalaemia, antiarrhythmics

Adverse reactions

4.Connective tissue problems: Fluoroquinolones should be avoided in pregnancy, in nursing mothers and in children under 18 years of age, because articular cartilage erosion Children with cystic fibrosis who receive ciprofloxacin have had few problems, but careful monitoring is indicated. In adults, fluoroquinolones can infrequently cause ruptured tendons.


Adverse reactions
4.Hepatotoxicity: Some Quinolones (like Moxifloxacin) were associated with severe hepatotoxicity 5. Children: Quinolones are contraindicated in Children and adolescents less than 17 years.

6-drug interactions:Inhibition of CYP 1A2Warfarin …………………..BleedingSulfonylurea …………….HypoglycemiaMethotrexat…………….Increased Conc.Theophylline…………….Increased Conc.

Folic acid antagonist

Sulfonamide trimethoprim

Sulfonamides, Trimethoprime, Sulfamethoxazole,

Chemistry -derivatives of para-aminobenzenesulfonamide -they are insoluble in water -their sodium salt are soluble in water -One of the oldest - broad spectrum - gram - & gram + - Bacteriostatic inhibits bacterial synthesis of folic acid, essential for bacterial growth

Bacteria are able to synthesize folic acid from PABA However, we are unable to synthesis folic acid and must get it from our diet.

Mechanism of action

In many microorganism dihydrofolic acid is synthesized from p-aminobenzoic acid (PABA), pteridine, and glutamate All the sulfonamides currently in clinical use are synthetic analogs of PABA. Because of their structural similarity to PABA, the sulfonamides compete with this substrate for the bacterial enzyme, dihydropteroate synthetase.They thus inhibit the synthesis of bacterial dihydrofolic acid.

Pharmacokinetics

Rapid,well absorption from GIT. Peak plasma level after 2-6hr. Widely distributed through out the body. Reach CSF in effective concentration. Cross the placenta Metabolized by liver. Elimination by urine ,feces, milk, bile Orally,IV, topical.

Antibacterial spectrum

Sulfa drugs are active against selected enterobacteria in the urinary tract and nocardia. sulfadiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine is the preferred form of treatment for toxoplasmosis and chloroquine-resistant malaria.

Therapeutic uses

Most sulfa are well absorb by small intestine (sulfasalazine ) so it usein treatment of chronic inflammatory bowel disease.2- Use in UTI’s, ear infections, newborn eye prophylaxis.3- ointment for ophthalmic use & Cream- Silver sulfadiazine (Silvadene) - for burns. 4- Alternative for people allergic to PCN.

Adverse effects

Crystalluria Hyper sensitivity Kernicterus this disorder may occur in newborns, because sulfa drugs displace bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the CNS, because the baby's blood-brain barrier is not fully developed Hemopoietic disturbances ,Hemolytic anemia is encountered in patients with glucose 6-phosphate dehydrogenase deficiency. Granulocytopenia and thrombocytopenia can also occur.

Drug potentiation

Transient potentiation of the hypoglycemic effect of tolbutamide. or potentiation the anticoagulant effect of warfarin results from their displacement from binding sites on serum albumin. Free methotrexate levels may also rise through displacement.

Contraindications

Due to the danger of kernicterus, sulfa drugs should be avoided in newborns and infants less than 2 months of age in pregnant women. in patients with glucose 6-phosphate dehydrogenase deficiency.

SULFONAMIDE EXAMPLES

SINGLE AGENTSsulfadiazinesulfamethoxazolesulfasalazineCOMBINATION AGENTtrimethoprim- sulfamethoxazole (for UTI’s)


trimethoprim
Mechanism of action Inhibit tetrahydrofolate reductase enzyme which is requir for purin and pyrimidine amino acid its similar to sulfamethoxazole but it (20- 50) fold more potent .

Therapeutic uses

Pneumocystic pneumonia. Respiratory infection. GIT infection: use to treat non typhoid salmonella . Prostate and urinary tract infection.

Adverse effect

Megaloplastic anemia Leucopenia Granulcytopenia

CO-TRIMOXAZOLETRIMETHOPRIM+SULFAMETHOXAZOLE

Mechanism of action Synergistic antimicrobial activity result from inhibition of 2 step in synthesis of tetrahydrofolic acid . Sulfamethoxazole inhibit incorporation of PABA into folic acid and trimethprim inhibit reduction of dihydrofolate . It has broad spectrum of antibacterial actions than sulfa drug alone.

Clinical uses

has a broader spectrum of antibacterial action than the sulfa drugs It is effective in treating UTIs. respiratory tract infections as well as in Pneumocystis pneumonia. ampicillin- or chloramphenicol-resistant systemic salmonella infections

Adverse effect

Dermatologic. GIT: glositis and stomatitis. Hematologic : megaloblastic anemia, leukopenia , thrombocytopenia and it reversed by administration of folic acid. Drug inter action: prolong prothrombine time in patient receiving both trimethprim and warfarin , plasma half life of phenytoin may be increased due to inhibition of metabolism .

DNA synthesis inhibition

Metronidazole(antiprotozoal) Its synthetic Nitromidazol , its effective against obligate anaerobic and microaerophilic M.O involving acute orofacial infection . Metronidazole (Flagyl) - treatment of various disorders associated with organisms of GI tract given orally and IV.


Mechanism of action
It enter into the cell and reduction of its Nitro group to produce metabolite that damage DNA this lead to cell damage . The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.

Spectrum

Metronidazole a nitroimidazole, is the mixed amebicide of choice for treating amebic infections; it kills the E. histolytica trophozoites. Metronidazole also use in the treatment of infections caused by Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, and anaerobic gram-negative bacilli (for Bacteroides species).

Metronidazole

distributes well throughout body tissues and fluids. Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF). Metabolism of the drug depends on hepatic oxidation of the metronidazole side chain by mixed-function oxidase, followed by glucuronylation.

Therapeutic uses

1- anaerobic abdominal and CNS infection. 2- treatment of Clostridium difficile associated diarrhea and colitis.3- treatment of various human parasites. 4-Uses in dentistry gram –ve anaerobic pathogen responsible for acute orofacial infections and chronic periodentitis .5-Also used to treat H. pylori associated with peptic ulcers

Adverse effects

gastrointestinal tract, including nausea, vomiting, epigastric distress, and abdominal cramps An unpleasant, metallic taste is often experienced. Other effects include oral moniliasis (yeast infection of the mouth) rarely, neurotoxicologic problems, such as dizziness, vertigo, and numbness or paresthesias in the peripheral nervous system. If taken with alcohol, a disulfiram-like effect occurs.