SYSTEMIC ANTIBIOTICS IHAB YOUNIS,MD. ß-LACTAM ANTIBIOTICS 1-Penicillins 2-Cephalosporins ß-lactam ring.

SYSTEMICANTIBIOTICS

IHAB YOUNIS,MD

ß-LACTAM ANTIBIOTICS

1-Penicillins

2-Cephalosporins

ß-lactam ring

PENICILLINS History• Penicillin was discovered by

Sir Alexander Fleming working

at St. Mary's Hospital in London

in 1928

• He observed that a plate

culture of Staphylococcus had been contaminated by a blue-green mold &

that colonies of bacteria adjacent

to the mold were being dissolved

• Curious, Alexander Fleming grew the mold in a pure culture and found that it produced a substance that killed a number of disease-causing bacteria

• Naming the substance penicillin, Dr. Fleming in 1929 published the results of his investigations, noting that his discovery might have therapeutic value if it could be produced in quantity

• It was not until 1939 that Dr. Howard Florey and three colleagues at Oxford University began intensive research and were able to demonstrate penicillin's ability to kill infectious bacteria

• As the war with Germany continued to drain industrial and government resources, the British scientists could not produce the quantities of penicillin needed for clinical trials on humans and turned to the United States for help

• They were quickly referred to the Peoria Lab where scientists were already working on fermentation methods to increase the growth rate of fungal cultures

• Ironically, after a worldwide search, it was a strain of penicillin from a moldy cantaloupe in a Peoria market that was found to produce the largest amount of penicillin when grown in the suitable conditions

• Penicillin production was quickly scaled up and available in quantity to treat Allied soldiers wounded on D-Day. As production was increased, the price dropped from nearly priceless in 1940, to $20 per dose in July 1943, to $0.55 per dose by 1946

• As a result of their work, two members of

the British group and Dr. Andrew J. Moyer from the Peoria Lab became Nobel laureates

• Physicians and the industry seem to have decided to discard penicillin. In Switzerland, long-acting slow-release penicillin preparations are not available any longer. The oral penicillin V is also being superseded more and more, whether this is justified or not remains open. Only the intravenous treatment (e.g. of meningitis or other severe infections) is still relatively indisputable

Variants in clinical use 1- Benzathine penicillin(Durapen,Penicid,Lastipen,1.2

megaunit/vial)

• It is slowly absorbed into the circulation, after IM injection. It is the drug-of-choice when prolonged low concentrations of penicillin are required, allowing prolonged antibiotic action over 2–4 weeks after a single IM dose e.g. for syphilis

2- Benzylpenicillin(Penicillin G,Aqua-pen,1 megaunit/vial)

• Penicillin G is typically given by a parenteral route of administration because it is unstable to the hydrochloric acid of the stomach

• It is used when higher tissue concentrations of penicillin e.g. in pneumonia

3- Phenoxymethylpenicillin(Ospen tab,1 megaunit;Cliacil tab,1.2megaunit)

• Commonly known as penicillin V

• It is the orally-active form of penicillin

• It is less active than benzylpenicillin, so it is only appropriate in conditions where high tissue concentrations are not required e.g. in skin infections

• 4- Procaine penicillin(Penicillin procain

vial,100,000 IU+300,000 IU proc./vial)

• is a combination of benzylpenicillin with the local anaesthetic agent procaine. This combination is aimed at reducing the pain and discomfort associated with a large IM injection of penicillin

5-Ampicillin(Ampicillin,Epicocillin,Amphpen125*-250-

500 mg)

• It was approved by the FDA in 1963

• Ampicillin is one of the most widely prescribed antibiotics

6- Amoxicillin(Hiconcil,Ibiamox,Amoxil,Emox, 125*-250-

500 mg)

• It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other ß-lactam antibiotics

7-Methicillin

• It is deactivated by gastric acid so, it has to be administered by injection

• Methicillin was previously used to treat infections caused by penicillin resistant bacteria, e.g staph but it has now been largely replaced by the oxacillin series

Mode of action:

• ß-lactam antibiotics work by inhibiting the formation of peptidoglycan cross links in the bacterial cell wall

• The ß-lactam moiety of penicillin binds to the enzyme)transpeptidase) that links the peptidoglycan molecules in bacteria, and this weakens the cell wall of the bacterium when it multiplies

Adverse effects • Allergic reactions to any β-lactam

antibiotic may occur in up to 10% of patients receiving that agent

• Anaphylaxis will occur in approximately 0.01% of patients

• Common reactions include: diarrhoea, nausea, urticaria, superinfection (including candidiasis)

Resistance

• Resistance to penicillin is now common amongst many hospital acquired bacteria due to the rise of ß-lactamase producing bacteria which secrete an enzyme that breaks down the ß-lactam ring of penicillin, rendering it harmless to the bacteria. These bacteria may remain sensitive to other ß-lactam antibiotics

• Resistance also arises through modifications to the bacterial cell wall; this resistance usually extends to other ß-lactam antibiotics

Methicillin-resistant Staphylococcus aureus(MRSA)

• It is a strain of the Staphylococcus aureus that has developed antibiotic resistance, first to penicillin since 1947 and later to methicillin and related anti-staphylococcal drugs and is now widespread

• MRSA causes as many as 20% of Staphylococcus aureus infections in populations that use intravenous drugs

• As of early 2005, the number of deaths in the UK attributed to MRSA has been estimated by various sources to lie in the area of 800 to 955 per year

• While an MRSA colonisation in an otherwise healthy individual is not usually a serious matter, infection with the organism can be life-threatening to patients with deep wounds, intravenous catheters or as a secondary infection in patients with compromised immune system

• The antibiotic of choice for an infected inpatient is vancomycin given intravenously. Oral clindamycin may be used in minor soft tissue infections in outpatients

Drug Interactions

Penicillin should be used with caution if

the patient is taking the following drugs:

• Anti-inflammatories, as these may compete for elimination and result in penicillin toxicity

• Oral contraceptives, as penicillin antibiotics occasionally reduce their effectiveness

Cephalosporins• Discovered in the 1940s by Giuseppe

Brotzu, a professor at the University of Cagliari, Sardinia

• He isolated a fungus called Cephalosporium acremonium

• One product of this fungus, cephalosporin C, became the prototype of our current cephalosporins

Mode of action

As with the penicillins, the cephalosporins inhibit a series of enzymes, known as penicillin-binding proteins, that catalyze important steps in the formation of the bacterial cell wall

Antimicrobial activity

• They have been grouped into “generations” on the basis of their general antimicrobial activity

I-First Generation Cephalosporins -Cephalexin (Ceporex,Keflex,125*-250-500 mg tab)

-Cephradine (Velosef,Farcocef 125*-,250-500-1000 mg tab)

-Cefadroxil (Duricef,Curisafe,Ibidroxil,125*-250-500-1000 mg tab)

• The most active of all the cephalosporins against staph & nonenterococcal streptococci

• Methicillin-resistant S. aureus are usually resistant to these agents

II-Second Generation Cephalosporins

– Cefprozil (Cefzil, 125*-250-500 mg tab)

– Cefuroxime) Zinnat,Cefumax 125*-250-500 mg tab) – Cefaclor (Cefaclor,Ceclor,250-500 tab)

• Have increased gram-negative activity, but decreased gram-positive activity

III-Third Generation Cephalosporins

– Cefotaxime (Claforan,Cefotax, 250-500-1000 mg / vial)

– Ceftriaxone )Rocephin,Cefotrix, 500-1000 mg / vial)

– Cefoperazone (Cefobid,Cefozone 500-1000 mg / vial)

• Demonstrate less activity against gram-positive organisms and an increased spectrum of gram-negative activity because of greater ß-lactamase stability

IV-Fourth generation cephalosporins:

-Cefepime) Maxipime 500,1000 mg/vial) -Cefpirome) Cefrom, 500,1000 mg/vial)

• They have a greater spectrum of activity against gram-positive organisms than the third generation cephalosporins

• They also have a greater resistance to ß- lactamases than the third generation cephalosporins

Pharmacokinetics

• 1st generation cephalosporins & cefaclor, are best absorbed from an empty stomach

• First- and second-generation cephalosporins are excreted primarily by the kidney. Dosage adjustment is required for patients with renal insufficiency

• Because of their excellent staph & strept coverage, the first-generation agents have proved to be excellent choices for the treatment of many skin and soft-tissue infections

• Most comparative studies have not shown major differences in clinical efficacy of different cephalosporins in treating skin infections

• The second-generation agents have been effectively used to treat cellulitis when the causative organisms are H. influenzae or Enterobacteriaceae. They offer no advantage for the treatment of gram-positive aerobic organisms over the first-generation agents

• The third-generation agents have also been used successfully to treat cellulitis, soft-tissue abscesses, and diabetic foot ulcers

Adverse effects

• The most frequent adverse reactions to cephalo-sporins are gastrointestinal

• Skin reaction: urticaria, maculopapular eruptions and pruritus have been reported in frequencies varying from 1% to 3%

• Approximately 5% to 10% of patients allergic to penicillins also will be allergic to cephalosporins

ß-LACTAM ANTIBIOTIC/ß-LACtaMASE INHIBITOR

COMBINATIONS • In 1940, soon after the introduction of

penicillin, Abraham and Chain in Oxford discovered an enzyme (penicillinase) capable of inactivating penicillin & later other ß-lactam antibiotics e.g. cephalosporins; therefore the name was changed to ß-lactamase

• ß-lactamase inhibitors, when combined with existing ß-lactam antibiotics, act synergistically to inhibit ß-lactamases

Formulations available:

• Amoxicillin-clavulanate (Augmentin, Megamox,Hibiotic,156*-375-625-1000-1200 tab & vial)

• Ampicillin-sulbactam (Unasyn, Unictam,250*-375-750-

1500 tab & vial)

Antibacterial activity

• In vitro activity is significant for Staph, Haemophilus, Klebsiella, E. coli, and Proteus

Pharmacokinetics

• Bioavailability of amoxicillin/clavulanic acid are unaffected by food

• Serum concentrations are higher and half-lives of the combinations are prolonged in patients with renal impairment, thereby necessitating dosage adjustments

Dermatologic indications • Ideally suited for the treatment of serious

infections of the skin and soft tissue when polymicrobial organisms are suspected

• Amoxicillin/clavulanic acid is the recommended oral agent after animal or human bites in which both aerobic and anaerobic organisms may be pathogens

• These drugs often have no advantage for infections caused by single pathogens

Adverse effects

• Gastrointestinal complaints are common, with diarrhea occurring more frequently with use of amoxicillin/clavulanic acid (10%)

• Sulbactam has been associated with pain at the intramuscular injection site, usually lasting 5 minutes to 1 hour. To minimize this, the powder may be diluted with lidocaine before injection

MACROLIDES• Erythromycin(Erythrocin,Erythrocid,Erythrin, 200*-250-500 tab) ,

the prototype of the macrolide antibiotics, was isolated in 1952 from the metabolic products of a strain of Streptomyces erythreus obtained from the soil samples in the Philippines

• The new macrolides are: -Clarithromycin (Klacid,125*-250-500 tab)

- Azithromycin (Zithromax,Azrolid,Zisrocin ,200*-250-500 tab)

Mode of action

They penetrate the cell walls of

susceptible bacteria and reversibly bind to the 50S subunit of the ribosome, inhibiting RNA-dependent protein synthesis

Antibacterial activity• In vitro, clarithromycin is generally equivalent to

or 2-4 fold more potent than erythromycin against gram +ve organisms such as Staph & Strept

• In contrast, the activity of azithromycin against gram +ve organisms is 2-4 fold less active than erythromycin

• Clarithromycin and azithromycin possess increased activity against several gram -ve pathogens

• Azithromycin is 4-8 times more potent than erythromycin against Mycoplasma

Pharmacokinetics• Erythromycin has an erratic oral

bioavailability.The major advantage offered by the new macrolides is their consistent oral bioavailability

• Clarithromycin is well absorbed, with or without food.The absorption of azithromycin is decreased with food and should be taken 1 hour before or 2 hours after a meal

• Clarithromycin is extensively metabolized and cleared by the kidney. As renal function declines, the half-life increases. Therefore, dosage modifications are recommended in patients with severe renal impairment

• Only 20% of azithromycin is excreted unchanged in the urine, so dosage adjustments in patients with renal impairment are not necessary

Dermatologic indications

• Azithromycin was compared with erythromycin in 82 patients with pyoderma, abscess, infected wound, ulcer, or erysipelas.S. aureus was the most common pathogen

• The dose of azithromycin was 1 gm on day 1, followed by 250 mg every day for 4 days compared with erythromycin 500 mg every 6 hours

• Clinical response rates were 86% for patients receiving azithromycin and 82% for patients receiving erythromycin

• In a randomized trial of 146 patients with mild to moderate skin infections, clarithromycin 250 mg taken twice daily was compared with oral erythromycin 250 mg four times a day for 7 to 14 days.The most frequently isolated organisms were S. aureus and S. pyogenes

• Clinical success was seen in 96% of the clarithromycin-treated patients compared with 94% in erythromycin-treated patients

Drug interactions

• Erythromycin & Clarithromycin inhibit the hepatic cytochrome P- 450 enzyme system leading to a decrease in the metabolic clearance of several drugs e.g. theophylline, phenytoin, digoxin, warfarin, nonsedating antihistamines , and methylprednisolone

• Azithromycin does not affect the cytochrome P- 450

Adverse effects

• Nausea, abdominal pain and diarrhea

•

• Azithromycin and clarithromycin appear to be well tolerated. Both cause fewer adverse gastrointestinal reactions (approximately 3% of patients) than erythromycin ) 5.8%)

FLUOROQUINOLONES• The first quinolone, nalidixic acid, was

introduced in 1962• It had numerous clinical limitations, such as

rapid emergence of resistance, narrow spectrum of activity, and frequent side effects

• However, the introduction of a fluorine atom resulted in second-, third-, and fourth-generation fluoroquinolones, which have improved coverage of gram-positive organisms

Quinolone generations

I-First generation:Nalidixic acid (Nalidram,500 tab)

II-Second generation:   Lomefloxacin (Lomex,Lomeflox,400 mg tab)

Norfloxacin (Noroxin,Epinor, 400 mg tab)

Ofloxacin (Tarivid,Ofloxacin, Kirol,200 mg tab)

Ciprofloxacin(Ciprobay,Ciprofloxacin,Mifoxin,Serviflox,Rancif,Ciprofar,250-500-750 tab)10 generics

III-Third generation:   Levofloxacin (Tavanic,Leoxin,Unibiotic,150-500 mg tab)

Sparfloxacin (Sparcin,Spara,200 mg tab)

Gatifloxacin (Tequin,400 mg tab or vial)

Moxifloxacin (Avalox,400 mg tab)

IV-Fourth generation: Trovafloxacin (Trovan tab & vial not available in Egypt)

Mode of action:

• Inhibition of bacterial DNA gyrase resulting in the interference of DNA replication

Antimicrobial activity

•As a group, they have adequate activity against methicillin-sensitive and methicillin- resistant S. aureus, levofloxacin is the most active

•Levofloxacin and is more active against streptococcal species compared with the other fluoroquinolones

• Ciprofloxacin, ofloxacin, and levofloxacin are active against Mycobacterium spp., including M. tuberculosis

• Ofloxacin is also active against Chlamydia trachomatis and U. urealyticum

• The fluoroquinolones show no appreciable activity against anaerobic bacteria

Pharmacokinetics

• The fluoroquinolones are mainly excreted renally. Therefore, in patients with impaired renal function dosage adjustments are necessary

Dermatologic indications

• Fluoroquinolones achieve appropriate concentrations in the skin and its appendages, making them ideal agents for the treatment of severe skin infections caused by multiresistant gram-negative bacteria such as abscesses, cellulitis, ulcers and wound infections

Drug interactions

• All fluoroquinolones show a significant decrease in absorption , when they are administered together with aluminum-, magnesium-, and calcium-containing antacids and iron- and zinc-containing products . These drugs should be taken at least 2 hours after the administration of the fluoroquinolone

• May increase caffeine, cyclosporine,

theophylline and warfarin level

• May prolong QT if used concomitantly

with antiarrhythmics

• May increase risk of CNS stimulation and

convulsions if used concomitantly with

nonsteroidal anti-inflammatory drugs

• May lead to hypoglycemia and/or

hyperglycemia if used with antidiabetics

Adverse effects

• In animals, fluoroquinolones impair cartilage formation; therefore the routine use of these agents is not recommended for children or for pregnant or nursing mothers

• The most common adverse reactions are nausea, abdominal discomfort, vomiting, diarrhea, mild headache, dizziness, agitation, and sleep disturbances

Dosing

• The recommended total daily doses: norfloxacin, 800 mg; ciprofloxacin, 500 to 1500 mg; ofloxacin, 400 to 800 mg; lomefloxacin, 400 mg; and levofloxacin, 500 mg

RIFAMYCINS

• The rifamycins were first isolated in 1957 from a soil isolate, Nocardia mediterranei

• The substance was nicknamed Riffi after the title of a then popular French movie, “LeRiffi.”

•

• Mode of action

• Rifamycins inhibit bacterial RNA synthesis by interacting directly with RNA polymerase. Mammalian RNA polymerases are not affected

Types of Rifamycins

• Rifampin or rifampicin (Rimactan, Rifadin,Rifactin2%*-150-300 mg cap)

• Rifabutin (Ansamycin,Not available in Egypt) is used to treat M. avium in AIDS

Antimicrobial activity

• Rifampin is active against staphylococci (both coagulase-

negative[comensals] and coagulase-positive) strains

• It is not particularly active against aerobic gram-negative bacilli E.coli

Pharmacokinetics

• Absorption is impaired if the drug is taken during or right after a meal. Food with a high fat content can interfere with absorption

• Rifampin has good penetration into abscesses and can enter living phagocytes and kill intracellular bacteria

• Rifampin is metabolized by the liver. Its half-life is prolonged in patients with hepatic disease. The dosage does not need to be adjusted for renal insufficiency

• Rifampin crosses the placenta readily and is not approved for use in pregnant women

Dermatologic indications

• Cutaneous tuberculosis remains the primary indication for rifampin therapy

• Rifampin is the only bactericidal drug to M. leprae. In 15 to 30 days no bacteria can be found

• Rifampin is bactericidal to gram-ve cocci and is an excellent agent in treating pyodermas

• Rapid emergence of resistance has been observed when monotherapy is employed. Therefore rifampin should only be used in conjunction with another gram-positive agent

• In a study, patients with recurrent furunculosis in

whom at least three courses of conventional systemic antistaphylococcal therapy had failed were given rifampin and cloxacillin for 7 to 10 days; 31 of 32 patients were cured

• Cutaneous leishmaniasis and rhinoscleroma also respond well to rifampin because it easily penetrates the cell membrane and attacks intracellular pathogens

• The usefulness of rifampin in psoriasis remains controversial

• Rifampin is used in treatment of pruritus in

patients with primary biliary cirrhosis. The mechanism may be enhanced hepatic microsomal function that perhaps accelerates metabolism of pruritogenic metabolite of bile acids

• Rifampin leads to reduced absorption of several compounds. Some notable problems include:

- Decreased efficacy of oral contraceptives

- Decreased prothrombin time in patients

receiving warfarin

- Addisonian crisis in patients taking

glucocorticoids

Adverse effects

• The most obvious inconvenience is orange-red discoloration of urine and permanent staining of soft contact lenses

• Rifampin passes into the breast milk. However, no problems were reported in nursing babies

• Gastrointestinal complaints• Increased liver function tests• Hypersensitivity reactions characterized by a flu-

like syndrome

Dosage

• The recommended daily dosage is usually 10 to 20 mg/kg (600 mg maximum) in a single daily administration

• The dosage recommended for elimination of staphylococcal carriage is higher

• For prophylaxis for exposure to Neisseria meningococcus, the recommended dosage is 600 mg every 12 hours for 2 days

TETRACYCLINES• Types of Tetracyclines

I-The short-acting agents: -Oxytetracycline (Oxytetracid,Oxytetrine,250 mg cap) -Tetracycline (Hostacycline,Tetracid,500 mg cap)

II-The intermediate-acting compound is demeclocycline(not available in Egypt)

III-The long-acting compounds: -Doxycyline (Vibramycin,Farcodoxin,Tolexin,Doxy,100 mg cap)

-Minocycline (minocine,50-10 mg tab)

Mode of action:

Inhibition of protein synthesis by binding

to the 30S ribosomal subunit

Pharmacokinetics

• The tetracyclines are better absorbed in the fasting state except for doxycycline and minocycline

• Absorption of tetracyclines is impaired by the concurrent ingestion of dairy products, aluminum hydroxide gels, calcium, magnesium, iron or zinc salts

• Both doxycycline and minocycline are lipid soluble, allowing superior tissue penetration

• The tetracyclines, except doxycycline, should not be used in patients with renal failure as renal failure prolongs the half-life of most tetracyclines except doxycycline

• These drugs should be used cautiously in patients with hepatic failure because of potential hepatotoxicity

Dermatologic indications

• The major use of tetracycline has been for the treatment of acne. These drugs inhibit P. acne

• Tetracycline is also used in the treatment of acne rosacea and perioral dermatitis

• Less conventional uses for the tetracyclines include the combination of tetracycline and nicotinamide for treatment of bullous pemphigoid, dermatitis herpetiformis and linear IgA bullous dermatosis

Nondermatologic indications

• Chlamydia nonspecific urethritis, lymphogranuloma venereum and as an alternate therapy for primary syphilis

Drug interactions

• Tetracyclines potentiate the effects of oral anticoagulants

• Barbiturates, phenytoin, and carbamazepine decrease the serum half-life and serum concentration of doxycycline

Adverse effects

• In children brown discoloration of the teeth and depression of bone growth may occur so tetracyclines are contraindicated during pregnancy and in children younger than 9 years of age

• The most commonly described are epigastric burning, nausea, and vomiting

• The drugs are hepatotoxic, particularly in patients receiving larger doses

• Tetracycline derivatives can produce mild to severe phototoxic reactions

• Hypersensitivity reactions have been described ranging from mild exanthem to Stevens-Johnson syndrome

TRIMETHOPRIM-SULFAMETHOXAZOLE

• In the mid-1970s a combination of trimethoprim and sulfamethoxazole became available. It is a fixed dose ratio of one part trimethoprim (TMP) to five parts sulfamethoxazole (SMX)

Mode of action

• The two components of this drug provide sequential inhibition of enzymes involved in the bacterial (but not human) synthesis of tetrahydrofolic acid and thereby disrupts nucleic acid synthesis

Antimicrobial activity

Many gram-positive aerobic cocci are inhibited by TMP-SMX in vivo. This includes many S. aureus, S. pyogenes, and S. viridans

Dermatologic indications

• An alternate choice for treatment of pyodermas, chancroid, and lymphogranuloma venereum

• TMP-SMX has been used to treat acne vulgaris in tetracycline- and erythromycin-resistant patients

Drug interactions

• TMP-SMX should be used with caution in patients taking methotrexate because it can interfere with folic acid availability

Adverse effects

• Common adverse effects of TMP-SMX are gastrointestinal and hypersensitivity reactions

CLINDAMYCIN

• Clindamycin (Dalacin C, Clindacin,150 mg cap) is a derivative of lincomycin that has an increased antibacterial potency and is better absorbed than its parent

Mode of action

• Clindamycin binds to the 50S portion of the ribosome and inhibits protein synthesis by blocking transpeptidation

Antimicrobial activity

• Clindamycin is active against most anaerobic organisms (including most Propionibacterium), most gram-positive cocci and certain protozoa

• The spectrum of activity includes many S. aureus, S. pneumoniae, S. pyogenes (although increased resistance of this organism has been increasingly reported)

Pharmacokinetics

• Clindamycin is mainly metabolized in the liver. Dose adjustment is needed for patients with severe liver failure

Dermatologic indications• Clindamycin has been successfully used

to treat many skin and soft-tissue infections, such as cellulitis, folliculitis, furunculosis, carbuncles, impetigo, ecthyma and hidradenitis suppurativa

• Clindamycin is effective at low dose in preventing recurrent staphylococcal skin infections

• Clindamycin is used in topical preparations for the treatment of acne. The risk of pseudomembranous colitis has limited oral usage in this condition

Drug interactions

• Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular agents (e.g., ether, tubocurarine, pancuronium)

• Antagonism has been observed between erythromycin and clindamycin in vitro

Adverse effects

• The most serious adverse effect is pseudomembranous colitis due to Clostridium difficile toxin. The reported incidence ranges from 0.1% to 10%. Ampicillin and cephalosporins have been associated with a similar risk

• The most frequently reported adverse effect to clindamycin is a generalized morbilliform eruption

• Other gastrointestinal side effects include anorexia, nausea, vomiting, diarrhea, and elevated hepatocellular enzymes

Dosage

• The usual adult oral dosage of clindamycin is 150 to 450 mg every 6 hours

• Acne vulgaris has been treated with 150 mg every 12 hours

NEW ANTIBIOTICS

1-LINEZOLID• Linezolid (Zyvox) has been approved by

the FDA in April 2000

• Linezolid is a synthetic antibiotic belonging to a new class of antimicrobials called the oxazolidinones

Mode of Action

• Linezolid disrupts bacterial growth by binding to 50 S ribosomal subunit inhibiting the initiation process in protein synthesis

• Linezolid is bacteriostatic against enterococci and staphylococci, and bactericidal for the majority of streptococci

Pharmacokinetics

• Linezolid is highly absorbed when administered orally & not affected by food

• This allows conversion from intravenous to oral therapy as soon as the patient is clinically stable; thus, it provides an advantage over comparative therapy that can be delivered only parenterally e.g. vancomycin

• Linezolid is metabolized via hepatic oxidation

• Presently, no dosage adjustment is recommended for patients with renal insufficiency; however, linezolid is removed by hemodialysis and should be administered following dialysis

Antimicrobial activity

• Gram-positive infections in adult patients• Other pathogens include penicillin-resistant S.

pneumoniae, vancomycin-sensitive E. faecalis, vancomycin-resistant E. faecalis, methicillin-susceptible Staphylococcus epidermidis and methicillin-resistant S. epidermidis, Corynebacterium

• It is recommended that coverage for gram-negative organisms be added when indicated

• The safety,efficacy& dosage have not been established in children younger than 18 years

Adverse Effects

• Two % of patients have the following: rash, headache, diarrhea, nausea, vomiting, insomnia, constipation and fever

• FDA has recently reported cases of myelosuppression

• Price   Zyvox (linezolid) 600mg

20 tablets     $1,168.77 

Comparitive studies

Linezolid X Clarithromycin

Cure rate 91% 93%

Linezolid X Vancomycin

Cure rate 73.2% 73.1%

• Dosing

• The dosage regimen for linezolid is 400 mg or 600 mg every 12 hours for a duration of to 28 days, with an intravenous or oral route of administration, based on the indication

• The 400-mg dose is approved for uncomplicated skin infections; however, because many other antibiotic therapies are available, the use of linezolid for this indication should be discouraged in order to reduce the potential for developing bacterial resistance

2-QUINUPRISTIN-DALFOPRISTIN(SYNERCID)

• It was approved by the FDA in September 1999

• Quinupristin-dalfopristin is a streptogramin

antibiotic produced by Streptomyces pristinaepiralis

• It is available in an IV form only

Mode of action

• The combination of quinupristin and dalfopristin is synergistic, and is generally bactericidal

• The main target is the bacterial 50S

ribosome, with the formulation acting to inhibit protein synthesis

Pharmacokinetics • It is eliminated mainly by the liver

• Quinupristin-dalfopristin demonstrates a prolonged postantibiotic effect, which is the phenomenon of continued suppression of bacterial growth after serum levels have fallen below the minimum inhibitory concentration.The duration of this effect may be up to 10 hours

Drug Interactions

• The plasma levels of some drugs will be raised e.g. cyclosporin, methylprenisolone & diazepam

Adverse Reactions

• Pain and inflammation at the infusion site are common but require discontinuation of treatment in fewer than 10 percent of patients

• The most common side effects of quinupristin-

dalfopristin have been arthralgias (9 %) and myalgias (6 %)

• A 500-mg vial of quinupristin-dalfopristin costs approximately $107

Antimicrobial activity

Results obtained in treating complicated skin in fections:

• Quinupristin and dalfopristin:68%

• Vancomycin:71%

• Cephazolin:71%

Dosage:

• The recommended infusion volume and duration is 250 mL given over 60 minutes

3-DAPTOMYCIN

Cubicin • It was Approved by the FDA in September

2003

• It is derived from the fermentation of Streptomyces roseosporus

Mode of action

• Rapid depolarization of bacterial cell membrane due to K efflux and that this associated with a disruption of DNA, RNA and protein synthesis resulting in death

Antibacterial activity

• Gram positive organisms even if they MRSA or VRSA

• It is NOT active against Gram negative organisms

Pharmacokinetics

• IV administration only

• 78% excreted via kidney

• Reduce dose for patients with creatinine clearance <30 ml/min

• significant post antibiotic effect

Dermatological indications

• Complicated skin and soft tissue infections due to susceptible organisms

Adverse effects

• GI effects are the most commonly reported adverse reactions occurring in 3% to 6%

• Elevations in serum (CPK) were reported in 3% with no symptoms of myopathy. Monitor CPK weekly

Dosage

• 4 mg/kg of daptomycin should be administered over a 30-minute period by IV infusion once every 24 hours for seven to 14 days