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)

Cmax
mg/ L

Bioavaility T1/2
Renal
( hour ) 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

> 90

10

30-60

Levofloksasin

200

>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)

Fluoroquinolones
Clinical 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

Fluoroquinolones
Clinical Uses
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

Fluoroquinolones
Clinical Uses
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)
Indication

PO
dose
( mg )

Interval

Duration
( days )

Uncomplicated UTI

100

BID

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

400

QD

Uncomplicated N gonorrhea

400

1-dose

1-dose

Complicated UTI ; Acute

pyelonephritis, AECB , CAP

400

QD

7-14

Uncomplicated UTI ; Acute

pyelonephritis

250

QD

10

AECB, CAP

500

QD

7- 14

Drug
Ciprofloxacin

Gatifloxacin 25 Uncomplicated UTI

Levofloxacin

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

Adverse effects occurrence for

Fluoroquinolone
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.

Adverse effects occurrence for

Fluoroquinolone
Phototoxicity
(photodermatitis)

Avoid sun and U.V.

radiation exposure
during therapy!!!

Adverse effects occurrence for

Fluoroquinolone
Abnormalities of
bone and cartilage
formation.

contraindicated in children
under 18 and pregnant
women!!!

Adverse effects occurrence for

Fluoroquinolone
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.

Adverse effects occurrence for

Fluoroquinolone
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.

Adverse effects occurrence for

Fluoroquinolone
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

Adverse effects occurrence for

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

PERCENTAGE OF ADVERSE EFFECTS

Severe
intermediate

mild

DURATION OF THE
ADVERSE EFFECTS

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..5
years, 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

Fluoroquinolones
Drugs 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.

Fluoroquinolones
Drugs 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

Chloramphenicol
Adverse effects
Gray baby syndrome
Intravenous chloramphenicol use has been associated with the socalled 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

Chloramphenicol
clinical uses
Thypoid fever ( Drugs of choice for children )
-Chloramphenicol 4 x 500 mg, 7-14 days, children 50100 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!!!

Chloramphenicol
Drugs 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).

Tetracycline
spesific agents :
These agents were first isolated from Streptomyces
aureofaciens
The following are the tetracyclines

Short-acting tetracyclines

Intermediate acting tetracyclines

Long acting tetracyclines

tetracycline
oxytetracycline

demeclocycline
methacycline
doxycycline
Minocycline
Tigecycline

Pharmacokinetic
Oral absorption variable (calsium , iron aluminium
inhibit absorption )
Absorption after oral administration is approximately
30% for chlortetracycline; 6070% for tetracycline,
oxytetracycline, demeclocycline, and methacycline;
and 95100% 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
68 hours, 12 hours, and 1618 hours, respectively.
Tigecycline has a half-life of 36 hours.
.

Tetracycline
Doses

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.

Tetracycline
Contraindications and Precautions in the use of Tetracyclines

It is not recommended for use in pregnancy

and lactation because the drug can affect the
bones and teeth, causing permanent
discoloration and sometimes arrest of growth.

Tetracyclines are also avoided in children less

than 8 (eight) years of age because of the
potential damage to the bones and permanent
discoloration of the teeth

Adverse Effects of the Tetracycline

GI system- nausea, vomiting, diarrhea, abdominal
pain, glossitis and dysphagia.
Fatal hepatotoxicity related to tetracyclines
irritating effect on the liver cells has been reported.
Musculoskletal- Tetracyclines have an affinity for
teeth and bones; they accumulate there, leading to
weakening of the bone/teeth and permanent
staining and pitting.
Skin- photosensitivity and rash are expected.
bone marrow depression, hypersensitivity, super
infections, pain and hypertension

Tetracycline
Drug-Drug Interactions
Penicillin- if taken with tetracyclines, will
decrease the effectiveness of penicillin.
Oral contraceptives- if taken with
tetracycline, will have decreased
effectiveness.
Digoxin- digoxin toxicity rises when
tetracyclines are used together

Tetracycline
Drug-Food Interaction
Dairy products- can complex with
tetracycline and render unabsorbable.
Tetracyclines should then be given on
an EMPTY stomach 1 hour before
meals or 2-3 hours after any meal or
other medications.

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