ANTIMIKROBA DAN

ANTIVIRAL

Dimas P.Nugraha
Bagian Farmakologi FK UR
 A antimicrobial therapy-disease progression timeline
Stages of disease progression are below the horizontal arrow;
categories of antimicrobial therapy are above the arrow.
 Prophylactic Therapy

Prophylaxis involves treating patients who are

not yet infected or have not yet developed
disease
The goal of prophylaxis is to prevent infection
in some patients or to prevent development
of a potentially dangerous disease in those
who already have evidence of infection
Ideally, a single, effective, nontoxic drug is
successful in preventing infection by a
specific microorganism or eradicating an
early infection
 Prophylaxis is used in
immunosuppressed patients such as
those with
- HIV-AIDS or are
- post-transplantation and
- anti-rejection medications
The efficacy of prophylaxis in these
patients is based on excellent
evidence
Infections for which prophylaxis is given includ
Prophylaxis may be used to protect healthy persons from acquisition of
 Pre-Emptive Therapy

used as a substitute for universal

prophylaxis and as early targeted therapy
in high-risk patients who already have a
laboratory or other test indicating that an
asymptomatic patient has become infected
The principle is that delivery of therapy
prior to development of symptoms
(presymptomatic) aborts impending
disease, and the therapy is for a short and
defined duration
 Empirical Therapy in the Symptomatic Patient

The reflex action to associate fever with treatable infections and prescr
 Initiation of optimal empirical
antimicrobial therapy should rely on the
clinical presentation, which may suggest
the specific microorganism, and
knowledge of the microorganisms most
likely to cause specific infections in a
given host
Simple and rapid laboratory techniques
are available for the examination of
infected tissues.
 Definitive Therapy with Known Pathogen

Once a pathogen has been isolated and

susceptibilities results are available, therapy
should be streamlined to a narrow targeted
antibiotic
Monotherapy is preferred to decrease the risk
of antimicrobial toxicity and selection of
antimicrobial-resistant pathogens
Both experimental and clinical evidence have
shown that unnecessarily prolonged therapies
lead to the emergence of resistance
 There are special circumstances where evidence is
unequivocal in favor of combination therapy. The
principles behind such antimicrobial use include:
preventing resistance to monotherapy
accelerating the rapidity of microbial kill
enhancing therapeutic efficacy by use of synergistic
interactions or enhancing kill by a drug based on a
mutation generated by resistance to another drug
paradoxically, reducing toxicity (i.e., when full efficacy
of a standard antibacterial agent can only be achieved
at doses that are toxic to the patient, and a second
drug is co-administered to exert additive effects)
Post-Treatment Suppressive Therapy

In some patients, after the initial disease is

controlled by the antimicrobial agent,
therapy is continued at a lower dose
This is because in these patients the
infection is not completely eradicated and
the immunological or anatomical defect that
led to the original infection is still present.
This is common in AIDS patients and post-
transplant patients, for example. The goal is
more as secondary prophylaxis
 Mechanisms of Resistance to Antimicrobial Agents

reduced entry of antibiotic into pathogen

SULFONAMIDE
Structural formulas of selected sulfonamides
and para-aminobenzoic acid
MECHANISM OF ACTION
Sulfonamides competitively inhibit
Actions of sulfonamides and trimethoprim.

Katzung
 Antimicrobial Activity

Sulfonamides inhibit both gram-positive and gram-ne

 Farmakokinetik
S
 The sulfonamides are classed based on the extent
or rapidity with which they are absorbed and
excreted:
(1) Agents that are absorbed and excreted rapidly,
such as sulfisoxazole and sulfadiazine;
(2) Agents that are absorbed very poorly when
administered orally and hence are active in the
bowel lumen, such as sulfasalazine;
(3)Agents that are used mainly topically, such as
sulfacetamide, mafenide, and silver sulfadiazine;
(4) long-acting sulfonamides, such as sulfadoxine,
that areabsorbed rapidly but excreted slowly.
 Rapidly Absorbed and Eliminated Sulfonamides

Sulfisoxazole
Sulfisoxazole acetyl is tasteless and hence
preferred for oral use in children.
Sulfisoxazole acetyl is marketed in
combination with erythromycin ethylsuccinate
for use in children with otitis media
Sulfisoxazole currently is preferred over other
sulfonamides by most clinicians when a
rapidly absorbed and rapidly excreted
sulfonamide is indicated.
Sulfamethoxazole
The clinical uses of sulfamethoxazole
are the same as those for
sulfisoxazole
In the U.S., it is marketed only in
fixed-dose combinations with
trimethoprim
Sulfadiazine
In adults and children who are being
treated with sulfadiazine, every
precaution must be taken to ensure
fluid intake adequate to produce a urine
output of at least 1200 mL in adults and
a corresponding quantity in children.
If this cannot be accomplished, sodium
bicarbonate may be given to reduce the
risk of crystalluria.
 Poorly Absorbed Sulfonamides

Sulfasalazine
It is used in the therapy of ulcerative
colitis and regional enteritis
 Sulfonamides for Topical Use

Sulfacetamide
Solutions of the sodium salt of the drug
are employed extensively in the
management of ophthalmic infections
Silver Sulfadiazine
The compound is used topically to
reduce microbial colonization and the
incidence of infections from burns. It
should not be used to treat an
established deep infection.
Mafenide
it effectively prevents colonization
of burns by a large variety of
gram-negative and gram-positive
bacteria.
It should not be used in treatment
of an established deep infection
 Long-Acting Sulfonamides

Sulfadoxine
It is used in combination with pyrimethamine
(500 mg sulfadoxine plus 25 mg pyrimethamine
as FANSIDAR) for the prophylaxis and treatment
of malaria caused by mefloquine-resistant
strains of Plasmodium falciparum.
However, because of severe and sometimes
fatal reactions, including the Stevens-Johnson
syndrome, and the emergence of resistant
strains, the drug has limited usefulness for the
treatment of malaria.
 Sulfonamide Therapy
URINARY TRACT INFECTIONS
Many urinary tract infections are caused by
sulfonamide-resistant microorganisms.
Trimethoprim sulfamethoxazole, a quinolone,
trimethoprim, fosfomycin, or ampicillin are the
preferred agents.
Sulfisoxazole may be used in areas where the
prevalence of resistance is not high or when the
organism is known to be sensitive.
The usual dose is 24 g initially, followed by 12 g,
orally four times a day for 510 days. Patients with
acute pyelonephritis should not be treated with a
sulfonamide.
TOXOPLASMOSIS
The combination of pyrimethamine and
sulfadiazine is the treatment of choice for
toxoplasmosis
Pyrimethamine is given as a loading dose of
75 mg followed by 25 mg orally per day, with
sulfadiazine 1 g orally every 6 hours, plus
folinic acid 10 mg orally each day for at least
36 weeks. Patients should receive at least 2
L of fluid intake daily to prevent crystalluria.
Nocardiosis
Sulfonamides are of value in the
treatment of infections due to
Nocardia spp.
A number of instances of complete
recovery from the disease after
adequate treatment with a
sulfonamide have been recorded.
Sulfisoxazole or sulfadiazine may be
given in dosages of 6-8 g daily
USE OF SULFONAMIDES FOR PROPHYLAXIS
The sulfonamides are as efficacious as oral
penicillin in preventing streptococcal
infections and recurrence of rheumatic fever
in susceptible subjects and are used in
patients who are hypersensitive to penicillin.
Untoward responses usually occur during the
first 8 weeks; serious reactions after this time
are rare. White blood cell counts should be
checked weekly during the first 8 weeks
 Adverse Reactions

DISTURBANCES OF THE URINARY TRACT

The incidence of crystalluria is low with more
soluble agents (e.g., sulfisoxazole).
Crystalluria has occurred in volume-depleted
patients with the acquired immune deficiency
syndrome (AIDS) who were given sulfadiazine
for Toxoplasma encephalitis.
Fluid intake should be sufficient to ensure a
daily urine volume of at least 1.2 L (in adults).
Urinary alkalinization may be helpful if urine
volume or pH is unusually low.
DISORDERS OF THE
HEMATOPOIETIC SYSTEM
Although rare, acute hemolytic
anemia can occur.
This may reflect an immune reaction
or may be due to glucose-6-
phosphate dehydrogenase
deficiency. Agranulocytosis occurs in
~0.1% of patients who receive
sulfadiazine and also can occur with
HYPERSENSITIVITY REACTIONS
Erythema nodosum,
erythema multiforme of the Stevens-
Johnson type,
Behets syndrome,
exfoliative dermatitis, and
photosensitivity.
Some adverse reactions to sulfonamides
 Contraindications:
Due to the danger of
 TRIMETHOPRIM
SULFAMETHOXAZOLE
ANTIBACTERIAL SPECTRUM
Most gram-negative and gram-positive
microorganisms are sensitive to trimethoprim, but
there is significant regional variation in the
susceptibility of Enterobacteriaceae to
trimethoprim because of the spread of resistance.
Efficacy of TrimethoprimSulfamethoxazole in
Combination
A synergistic interaction between these drugs is
apparent even when microorganisms are resistant
to sulfonamide, but maximal synergism occurs
when microorganisms are sensitive to both drugs.
Synergism between trimethoprim and sulfamethoxazole on the
inhibition of growth of Escherichia coli.
 Mechanism of action

The synergistic antimicrobial activity

of cotrimoxazole results from its
inhibition of two sequential steps in
the synthesis of tetrahydrofolic acid:
Sulfamethoxazole inhibits the
incorporation of PABA into
dihydrofolic acid precursors, and
Trimethoprim prevents reduction of
dihydrofolate to tetrahydrofolate
Inhibition of tetrahydrofolate synthesis by sulfonamides and
trimethoprim
 ABSORPTION, DISTRIBUTION, AND
EXCRETION
After a single oral dose of the
combined preparation, peak blood
concentrations of trimethoprim
usually occur by 2 hours, whereas
peak concentrations of
sulfamethoxazole require 4 hours.
The half-lives of trimethoprim and
sulfamethoxazole are ~11 and 10
hours
 Trimethoprim is distributed and concentrated
rapidly in tissues, and ~40% is bound to
plasma proteinin the presence of
sulfamethoxazole.
The volume of distribution of trimethoprim is
almost nine times that of sulfamethoxazole.
The drug readily enters CSF and sputum. High
concentrations of each component also are
found in bile. About 65% of sulfamethoxazole is
bound to plasma protein.
 About 60% of administered trimethoprim and
from 25% to 50% of administered
sulfamethoxazole are excreted in the urine in
24 hours.
Two-thirds of the sulfonamide is unconjugated.
Metabolites of trimethoprim also are excreted.
The rates of excretion and the concentrations
of both compounds in the urine are reduced
significantly in patients with uremia.
Administration and fate of the
cotrimoxazole
 THERAPEUTIC USES
Urinary Tract Infections
Treatment of uncomplicated lower urinary
tract infections with trimethoprim
sulfamethoxazole often is highly effective for
sensitive bacteria, usually for a minimum of 3
days.
The combination is especially useful in chronic
and recurrent infections of the urinary tract.
Trimethoprim also is found in therapeutic
concentrations in prostatic secretions, and
trimethoprimsulfamethoxazole is often
effective for bacterial prostatitis.
Bacterial Respiratory Tract Infections
Trimethoprimsulfamethoxazole is effective for acute
exacerbations of chronic bronchitis. Administration of
8001200 mg sulfamethoxazole plus 160240 mg
trimethoprim twice a day appears to be effective in
decreasing fever, purulence and volume of sputum, and
sputum bacterial count.
Trimethoprim sulfamethoxazole should not be used to
treat streptococcal pharyngitis because it does not
eradicate the microorganism.
It is effective for acute otitis media in children and acute
maxillary sinusitis in adults caused by susceptible strains
of Haemophilus influenzae and Streptococcus
pneumoniae.
Gastrointestinal Infections
Trimethoprimsulfamethoxazole appears to be
effective in the management of carriers of
sensitive strains of Salmonella typhi and other
Salmonella spp., but failures have occurred.
Chronic disease of the gallbladder may be
associated with a high incidence of failure to
clear the carrier state.
Acute diarrhea owing to sensitive strains of
enteropathogenic Escherichia coli can be
treated or prevented with either trimethoprim
or trimethoprim plus sulfamethoxazole
Infection by Pneumocystis jiroveci
High-dose therapy (trimethoprim 15
mg/kg/day plus sulfamethoxazole 100
mg/kg/day in three or four divided doses)
is effective for this severe infection in
patients with AIDS.
Adjunctive glucocorticoids should be
given in patients with a Po2 of <70 mm
Hg or an alveolararterial gradient of >35
mm Hg.
Typical therapeutic applications of co-trimoxazole (sulfamethoxazole
plus trimethoprim)
Some adverse reactions to
cotrimoxazole
 Drug interactions:
Prolonged
Viruses are obligate intracellular parasites. They lack both a cell wall
Therapy for viral diseases is further complicated by the fact that the c
Antiviral Agents
(Nonretroviral)
1.Neuraminidase inhibitors
Administration and metabolism of
oseltamivir and zanamivir
Adverse effects:
2.Inhibitors of viral uncoating
The therapeutic spectrum of the adamantine derivatives,
Administration and metabolism of
amantadine and rimantadine
 Adverse effects:

The side effects of amantadine are mainly

associated with the CNS. Minor neurologic
symptoms include insomnia, dizziness,
and ataxia. More serious side effects have
been reported (for example, hallucinations
and seizures).
The drug should be employed cautiously
in patients with psychiatric problems,
cerebral atherosclerosis, renal
impairment, or epilepsy.
 Rimantadine causes fewer CNS
reactions, because it does not
efficiently cross the blood-brain
barrier. Both drugs cause
gastrointestinal intolerance.
Amantadine and rimantadine should
be used with caution in pregnant and
nursing mothers, because they have
been found to be embryotoxic and
teratogenic in rats.
 3.Ribavirin
Ribavirin is a synthetic guanosine analog. It is
effective against a broad spectrum of RNA and
DNA viruses.
For example, ribavirin is used in treating infants
and young children with severe RSV infections.
[Note: It is not indicated for use in adults.]
Ribavirin is also effective in chronic hepatitis C
infections when used in combination with
interferon--2b.
Ribavirin may reduce the mortality and viremia
of Lassa fever.
Administration and metabolism of
ribavirin
Adverse effects
Treatment of Hepatic Viral Infections

The hepatitis viruses thus far

identified A, B, C, D, and each have
a pathogenesis specifically involving
replication in and destruction of
hepatocytes.
Of this group, hepatitis B and
hepatitis C are the most common
causes of chronic hepatitis, cirrhosis,
and hepatocellular carcinoma
 A. Interferon
Interferon is a family of naturally occurring,
inducible glycoproteins that interfere with the
ability of viruses to infect cells.
Although interferon inhibits the growth of
many viruses in vitro, its activity in vivo
against viruses has been disappointing
The antiviral mechanism is incompletely
understood. It appears to involve the induction
of host cell enzymes that inhibit viral RNA
translation, ultimately leading to the
degradation of viral mRNA and tRNA.
Some approved indications for
interferon
 Adverse effects
Adverse effects include flu-like
symptoms on injection, such as
fever, chills, myalgias, arthralgias,
and gastrointestinal disturbances.
Fatigue and mental depression are
common
 B.Lamivudine

This cytosine analog is an inhibitor of

both hepatitis B virus (HBV) DNA
polymerase and human
immunodeficiency virus (HIV) reverse
transcriptase
Replicative cycles of DNA Herpes
Virus
Replicative cycles of RNA
Influenza virus
 Anti-Herpesvirus Agents

Infection with herpes simplex virus type 1 (HSV-1) typically causes dis
Acyclovir and Valacyclovir

Acyclovir inhibits viral DNA synthesis

 Acyclovir resistance in HSV has
been linked to one of three
mechanisms:
- impaired production of viral
thymidine kinase,
- Altered thymidine kinase substrate
specificity (e.g., phosphorylation of
thymidine but not acyclovir),
- Altered viral DNA polymerase
 Therapeutic Uses

In
Summary of selected antiviral
agents
Alhamdulillah.....

Pembelajar yang BERHASIL adalah

pembelajar yang MAU belajar
Berubah secara ADAPTIF