Fluoroquinolone, Chloramphenicol and Tetracycline-Dharma Permana 2014

Pharmacology Antibiotics

- Fluoroquinolone- Chloramphenicol- Tetracyclline

Dharma Permana, Apt, PhD

Quinolone/Fluoroquinolone• The fluoroquinolones are a class of

synthetic antimicrobial agents which were modeled after nalidixic acid, a non-fluorinated quinolone antibiotic. Nalidixic acid was approved by the Food and Drug Administration (FDA) in 1963 for the treatment of urinary tract infections

• Broad spectrum• Bactericid• Administration : Oral and parenteral

Fluoroquinolones Mechanism of action

Work to inhibit bacterial DNA synthesis: their mechanism of action is somewhat unique in that they inhibit the bacterial DNA gyrase (Gram negative bacteria) and topoisomerase IV ( Gram Positive Bacteria ), the enzyme responsible for DNA replication.

Fluoroquinolones INHIBITION OF DNA/RNA SYNTHESIS

Fluoroquinolones Antibacterial spectrum

Gram-positive bacteria. Moderate activity against Streptococci and Staphylococci including some methicillin-resistant Staphylococci, although resistance to methicillin-resistant Staphylococci is now more frequent to quinolones.

Gram-negative bacilli. Excellent activity against pathogens seen in hospital-acquired infections such as the Enterobacteriaceae (Escherichia coli, Klebsiella species, Enterobacter species); community-acquired respiratory infections (Hemophilus influenzae and Moraxella catarrhalis); gastrointestinal infections (Salmonella, Shigella, Campylobacter, and Vibrio species) and sexually transmitted diseases (Neisseria gonorrhea and Chlamydia trachomatis). Ciprofloxacin is the most active quinolone against Pseudomonas aeruginosa.

Other. Some quinolones are used in combination with other antimycobacterial drugs for the treatment of Mycobacterium tuberculosis and Mycobacterium-avium-intracellulare.

Fluoroquinolones

Spesific agents :• 1st generation - nalidixic acid • 2nd generation - ciproloxacin, ofloxacin, norfloxacin, pefloxacin, lomefloxacin • 3rd generation - gatifloxacin, levofloxacin, moxifloxacin, sparfloxacin• 4th generation - trovafloxacin

Fluoroquinolones

Pharmacokinetics• The fluoroquinolone antibiotics are rapidly

absorbed after oral administration and reach their maximum concentrations in one to two hours. Food may decrease the rate, but not the extent of absorption.

• All fluoroquinolones are eliminated by a combination of the kidney and the liver. Good renal function is important in the elimination of all of these antibiotics, even when only small amounts of unchanged drug are detectable in the urine.

• Wide distribution to organs • Penetrate most body tissue exception of the

CNS

Oral Fluoroquinolone Pharmacokinetics data after single dose

Drugs Doses(mg)

Cmaxmg/ L

Bioavaility ( % )

T1/2 ( hour )

Renal Elimination(%)

Siproloksasin 500 1.5-3 60-80 3-5 30-50

Ofloksasin 400 3.5-3.3 85-95 5-7 70-85

Pefloksasin 400 4 > 90 10 30-60

Levofloksasin 200 2 >90 4.6 85-90

Norfloksasin 400 1.5-2 40 4.5 25-40

Moksifloksasin 400 2.5-5 82-89 12.5 26

Farmakologi & Terapi ed V, 2009

Pharmacokinetics Of Fluoroquinolones (ref ; 23, 24, 25)

FluoroquinolonesClinical Uses

• Urinary tract infections - norfloxacin, lomefloxacin, ofloxacin,

ciprofloxacin, levofloxacin, gatifloxacin, trovafloxacin

• Lower respiratory tract infections - lomefloxacin, ofloxacin, ciprofloxacin,

moxifloxacin, trovafloxacin • Skin and skin-structure infections - ofloxacin, ciprofloxacin, levofloxacin,

trovafloxacin• Urethral and cervical gonococcal infections - norfloxacin, ofloxacin, ciprofloxacin,

gatifloxacin, trovafloxacin


• Prostatitis - ciprofloxacin norfloxacin, ofloxacin,

trovafloxacin • Acute sinusitis - ciprofloxacin, levofloxacin, gatifloxacin,

moxifloxacin , trovafloxacin • Acute exacerbations of chronic bronchitis

( AECB ) - levofloxacin, sparfloxacin , gatifloxacin,

moxifloxacin, trovafloxacin • Community-acquired pneumonia ( COP ) - levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, trovafloxacin


• Ciprofloxacin is a drug of choice for prophylaxis and treatment of anthrax

• Ciprofloxacin, levofloxacin, or moxifloxacin is occasionally used for treatment of tuberculosis and atypical mycobacterial infections

Drug , Indication , Dose , Duration of therapy chart for some Fluoroquinolones (24,26) :

Drug Indication PO

dose ( mg )

Interval Duration ( days )

Ciprofloxacin Uncomplicated UTI 100 BID 3

Complicated UTI ; Acute pyelonephritis

250-500 BID 7-14

Uncomplicated N gonorrhea 500 1-dose 1-dose AECB , CAP 500-750 BID 10-14

Acute prostatitis 500 BID 14-28 Infectious diarrhoea ; Typhoid Fever(Drugs of choice for adult)

500 BID 3-5

Gatifloxacin 25 Uncomplicated UTI 400 QD 3 Uncomplicated N gonorrhea 400 1-dose 1-dose

Complicated UTI ; Acute pyelonephritis, AECB , CAP

400 QD 7-14

Levofloxacin Uncomplicated UTI ; Acute pyelonephritis

250 QD 10

AECB, CAP 500 QD 7- 14

Norfloxacin Uncomplicated and complicated UTI ; Acute pyelonephritis

400 BID 3-10

Acute prostatitis 400 BID 14-28 Lomefloxacin Uncomplicated and

complicated UTI ; Acute pyelonephritis; AECB

400 QD 3-14

Sparfloxacin AECB , CAP 400 x 1 , then 200

QD 10

Moxifloxacin AECB , CAP 400 QD 5-10 Ofloxacin Uncomplicated and

complicated UTI ; Chlamydia 200 BID 3-10

Uncomplicated N gonorrhea 400 1-dose 1-dose AECB , CAP 400 BID 7-10

Adverse effects occurrence for Fluoroquinolone

• Gastrointestinal effects. The most common adverse events experienced with fluoroquinolone administration are gastrointestinal (nausea, vomiting, diarrhea, constipation, and abdominal pain), which occur in 1 to 5% of patients.

• CNS effects. Headache, dizziness, and drowsiness have been reported with all fluoroquinolones. Insomnia was reported in 3-7% of patients with ofloxacin


• Phototoxicity. Exposure to ultraviolet A rays from direct or indirect sunlight should be avoided during treatment and several days (5 days with sparfloxacin) after the use of the drug. The degree of phototoxic potential of fluoroquinolones is as follows: lomefloxacin > sparfloxacin > ciprofloxacin > norfloxacin = ofloxacin = levofloxacin = gatifloxacin = moxifloxacin.

• Musculoskeletal effects. Concern about the development of musculoskeletal effects, evident in animal studies, has led to the contraindication of fluoroquinolones for use in children <18 years and in women who are pregnant or lactating.


• Phototoxicity (photodermatitis)

Avoid sun and U.V. radiation

exposure during therapy!!!


• Abnormalities of bone and cartilage formation.

contraindicated in children under 18 and pregnant

women!!!


• Tendon damage (tendinitis and tendon rupture). Although fluoroquinolone-related tendinitis generally resolves within one week of discontinuation of therapy, spontaneous ruptures have been reported as long as nine months after cessation of fluoroquinolone use. Potential risk factors for tendinopathy include age >50 years, male gender, and concomitant use of corticosteroids.

• Cardiovascular effects. The newer quinolones have been found to produce additional toxicities to the heart that were not found with the older compounds. Evidence suggests that sparfloxacin may have the most cardiotoxic potential.


• Hypoglycemia/Hyperglycemia. Recently, rare cases of hypoglycemia have been reported with gatifloxacin and ciprofloxacin in patients also receiving oral diabetic medications, primarily sulfonylureas. Although hypoglycemia has been reported with other fluoroquinolones (levofloxacin and moxifloxacin), the effects have been mild.

• Hypersensitivity. Hypersensitivity reactions occur only occasionally during quinolone therapy and are generally mild to moderate in severity, and usually resolve after treatment is stopped.


• Crystaluria :- Associated with fluoroquinolones except Levofloxacin , Gatifloxacin,Moxifloxacin , and Trovafloxacin . Patients are instructed to drink plenty of water.

• Liver Toxicity :- In 18 months post-approval follow up by US Food and Drug Administration (FDA) for Trovafloxacin 140 cases of liver toxicity were found


Dosage PERCENTAGE OF ADVERSE EFFECTS Severe intermediate mild

DURATION OF THE ADVERSE EFFECTS

up to one week of up to 1,000 mg daily

9% 22 % 29% several weeks to months

6 weeks of 1.000 mg daily

62 % 91% 100% months to years

more than 6 weeks on a 1,000 mg/day basis

86% 100% 100% mean duration of severe limitations and pains for 2..5years, but can be 6 years more - and in some cases the damage and destruction is permanent or ends in death.

1,500 mg/day for a week or more

100% 100% 100% Many years or permanent

FluoroquinolonesDrugs Interactions

• Do not take mineral supplements, vitamins containing iron, didanosine chewable tablets, antacids containing calcium, aluminum, or magnesium within two hours of taking fluoroquinolone antibiotics.

• Avoid taking cimetidine, cyclosporine, nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen, probenecid, sucralfate, theophylline-containing drugs, blood thinners, insulin, or multivitamins containing zinc while you are on fluoroquinolone antibiotics.

FluoroquinolonesDrugs Interactions

• Other drugs that interact with fluoroquinolones include Sucralfate, Warfarin, Antiviral agents, Phenytoin, Cyclosporine, Rifampin, Pyrazinamide, and Cycloserine

Chloramphenicol

• Broad spectrum• Bacteriostatic• Inhibit bacterial protein synthesis in

the 23S rRNA of the 50S ribosomal sub unit

• Oral, IV, im , Topical ( eye drops, ointment, eye ointment )

Chloramphenicol Antibacterial spectrum

• gram +: streptococci and staphylococci; • gram -: Neissiera, Brucella, Salmonella,

Shigella, and Haemaphilus), Mycoplasma, Nocardia, Chlamydia, Rickettsia and anaerobic bacteria (Clostridium, Bacteroides (including B. fragilis), Fusobacterium, and Veillonella).

Chloramphenicol Spesific agents :

• Chloramphenicol• Tiamphenicol

Chloramphenicol Pharmacokinetics

• Rapidly absorbed after oral administration. Peak serum levels occur approximately 30 minutes after dosing

• Widely distributed throughout the body and crosses the placenta . Highest levels are found in the liver and kidney.

• Eliminated primarily by hepatic metabolism via glucuronidative mechanisms

• Only about 5-15% of the drug is excreted unchanged in the urine

ChloramphenicolAdverse effects

• Gray baby syndrome Intravenous chloramphenicol use has been associated with

the so-called Gray baby Syndrome. This phenomenon occurs in newborn infants because they do not yet have fully functional liver enzymes (glucuronyl transferase), so chloramphenicol remains unmetabolized in the body.This causes several adverse effects, including Cyanosis and hypotension. The condition can be prevented by using the drug at the recommended doses, and monitoring blood levels

- Leukemia- Bone marrow suppression, inhibition red blood cells

maturation (This effect manifests first as a fall in hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been given

- Aplastic anemia (The most serious side effect of chloramphenicol treatment. This effect is rare, usually occurs weeks or months after chloramphenicol treatment has been stopped )

- -Vomiting- - diarrhea

Chloramphenicolclinical uses

• Thypoid fever -Chloramphenicol 4 x 500 mg, 7-14 days,

children 50-100 mg/KgBB/ days 4x1, neonatus , 25 mg/KgBB/days 4x1

-Thiamphenicol 4 x 500 mg, children 25-50 mg/KgBB/day, 4x1 )

• Meningitis (Chloramphenicol 4 x 500 mg, 4 days, children 50-100 mg/KgBB/ days 4x1

• Riketsiosis, 4 days ( alternative Tetracyclline )

• contraindicated with pregnant women!!!

ChloramphenicolDrugs interaction

• diabetes medicine, warfarin, phenytoin, phenobarbital, rifampin, macrolide antibiotic, vitamin B12, iron, folic acid.

Tetracycline• Broad spectrum• Bacteriostatic• Inhibit bacterial protein synthesis in the rRNA

of the 30 S ribosomal sub unit• They are active against many gram-positive

and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas and against some protozoa (eg, amebas).

Tetracyclinespesific agents :

These agents were first isolated from These agents were first isolated from Streptomyces aureofaciensStreptomyces aureofaciens

The following are the tetracyclinesThe following are the tetracyclines• Short-acting tetracyclinesShort-acting tetracyclines

– tetracyclinetetracycline– oxytetracyclineoxytetracycline

• Intermediate acting tetracyclinesIntermediate acting tetracyclines– demeclocyclinedemeclocycline– methacyclinemethacycline

• Long acting tetracyclinesLong acting tetracyclines– doxycyclinedoxycycline– MinocyclineMinocycline– TigecyclineTigecycline

Pharmacokinetic• Oral absorption variable (calsium , iron aluminium

inhibit absorption )• Absorption after oral administration is approximately

30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95–100% for doxycycline and minocycline. Tigecycline is poorly absorbed orally and must be administered intravenously.

• Wide tissue distribution• Cross placenta barrier• CNS penetration limited• Doxycycline excreted mainly in feses, other drugs

eliminated in the urine• T1/2 doxycycline, minocycline and tigecycline are

longer than tetracycline. Based on serum half-lives of 6–8 hours, 12 hours, and 16–18 hours, respectively. Tigecycline has a half-life of 36 hours.

• .

TetracyclineDoses

• Tetracycline: 250-500mg four times daily • Oxytetracycline: 250-500mg four times daily • Demeclocycline: 150-300mg twice daily • Doxycycline: 50-100mg once or twice daily • Minocycline: 50-100mg once or twice daily • Tigecycline, formulated for intravenous

administration only, is given as a 100-mg loading dose; then 50 mg every 12 hours

Tetracycline Clinical Uses• Primary uses First choice for m. Pneumoniae (3

weeks), chlamydia (3 weeks) , Rickettsiae and v.cholera ( 3 days )

• Secondary uses alternatif to treatment shyphilis, and gonorrhea

( 4 x 500 mg , 15 hari• Leptospirosis , 7-10 days• Acne ( menghambat produksi asam lemak dari sebum )

tetracycline 2x 250 mg, doxycycline dosis awal 200 mg/ day hari 100 mg selanjutnya 2-3 week

• doxycycline Malaria (plasmodium falcifarum ), 7 days• Amebiasis, 10 days• anthrax tetracycline 500 mg PO every 6 hours for 60

days • They are used in combination regimens to treat gastric

and duodenal ulcer disease caused by Helicobacter pylori.

• Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state.

TetracyclineContraindications and Precautions in the use of TetracyclinesContraindications and Precautions in the use of Tetracyclines

– It is not recommended for use in It is not recommended for use in pregnancy and lactation because the pregnancy and lactation because the drug can affect the bones and teeth, drug can affect the bones and teeth, causing permanent discoloration and causing permanent discoloration and sometimes arrest of growth.sometimes arrest of growth.

– Tetracyclines are also avoided in Tetracyclines are also avoided in children less than 8 (eight) years of age children less than 8 (eight) years of age because of the potential damage to the because of the potential damage to the bones and permanent discoloration of bones and permanent discoloration of the teeththe teeth

Adverse Effects of the Adverse Effects of the TetracyclineTetracycline

• GI system- nausea, vomiting, diarrhea, GI system- nausea, vomiting, diarrhea, abdominal pain, glossitis and dysphagia. abdominal pain, glossitis and dysphagia.

• Fatal hepatotoxicity related to tetracycline’s Fatal hepatotoxicity related to tetracycline’s irritating effect on the liver cells has been irritating effect on the liver cells has been reported.reported.

• Musculoskletal- Tetracyclines have an Musculoskletal- Tetracyclines have an affinity for teeth and bones; they accumulate affinity for teeth and bones; they accumulate there, leading to weakening of the bone/teeth there, leading to weakening of the bone/teeth and permanent staining and pitting.and permanent staining and pitting.

• Skin- Skin- photosensitivity and rash are photosensitivity and rash are expectedexpected..

• bone marrow depression, hypersensitivity, bone marrow depression, hypersensitivity, super infections, pain and hypertensionsuper infections, pain and hypertension

Tetracycline

Drug-Drug InteractionsDrug-Drug Interactions• Penicillin- if taken with tetracyclines, Penicillin- if taken with tetracyclines,

will decrease the effectiveness of will decrease the effectiveness of penicillin.penicillin.

• Oral contraceptives- if taken with Oral contraceptives- if taken with tetracycline, will have decreased tetracycline, will have decreased effectiveness. effectiveness.

• Digoxin- digoxin toxicity rises when Digoxin- digoxin toxicity rises when tetracyclines are used togethertetracyclines are used together

Tetracycline

Drug-Food InteractionDrug-Food Interaction• Dairy products- can complex with Dairy products- can complex with

tetracycline and render tetracycline and render unabsorbable. unabsorbable.

• Tetracyclines should then be Tetracyclines should then be given on an EMPTY stomach 1 given on an EMPTY stomach 1 hour before meals or 2-3 hours hour before meals or 2-3 hours after any meal or other after any meal or other medications.medications.

•Terima kasih

Fluoroquinolone, Chloramphenicol and Tetracycline-Dharma Permana 2014

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Transcript of Fluoroquinolone, Chloramphenicol and Tetracycline-Dharma Permana 2014