Transcript drug therapy of infectious diseases

DRUG THERAPY OF INFECTIOUS
DISEASES
Classification of infectious diseases
•According to onset and duration
 •According to location
 •According to item present
 •According to sequence of appearance
 •According to epidemiological factors
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Classifications according to onset and duration
Acute disease -- Rapid onset and short
duration. E.g. common cold, measles
 Chronic disease -- Slower onset and longer
duration. eg TB, leprosy
 Subchronic disease -- ermediate to acute and
chronic both in onset and duration. eg gingivitis
 Latent disease -- One characterized by periods
of activity erspersed with periods of inactivity.
E.g.: malaria, herpes simplex.
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Classification according to location
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Local infection -- Confined to
a specific area of the body.
E.g.: cystitis, vaginitis,
myocarditis.
Focal infection -- Infection
that started in one place and
later on spread to other
areas. E.g. tuberculosis,
sinus infection, infected
tooth.
Systemic (generalized)
infection - Occurring
throughout the body
Classifications according to item present
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Septicemia -- A microbe is present in the blood, is
continuously being delivered from tissues to blood and
is actively multiplying in the blood. Typical of systemic
diseases. Often fatal.
Bacteremia -- Presence of bacteria in the blood
Viremia -- Presence of virus in the blood of the body
Pyemia -- Poisoning of the blood by pus-producing
bacteria released from an abscess
Toxaemia -- Presence of bacterial toxins in the blood.
Can result in fever, diarrhea and vomiting.
Classification according to sequence of
appearance
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Primary infection - Initial infection in a healthy person
Secondary infection - Occurs after primary infection
Superinfection - A secondary infection due to the
destruction of the protective normal flora of the body
by the use of a broad spectrum antibiotic
Also defined as a secondary infection facilitated by a
primary infection e.g. HIV and AIDS
Epidemiological factors - mode of appearance,
number of cases, trends of diseases in
populations
Classifications according to epidemiological factors
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Endemic disease (endemia) - Present regularly in particular area of the
world, and total number and severity are low
Ecdemic disease (ecdemia) - A foreign disease brought to a new area by
travelers or immigrants from a foreign country
Pandemic disease (pandemia) - A disease that affects many people and
which occurs across neighboring cities, countries or continents. Affects
many people.
Epidemic disease (epidemia) - Appears suddenly, affects many people and
is confined to a particular, often the same, area. Morbidity rate and
mortality rate above what is normal.
Sporadic disease (epidemia) - Appears suddenly, in a random and unpredictable manner, affects only a few people, and limited to a few, usually
unrelated, places.
Outbreak - Few cases, often related in time and location, and sharing same
manifestations
Threat of emerging infectious diseases
Due to constant changes in our lifestyles and environments,
there are constantly new diseases that people
are susceptible to, making protection from the threat of
infectious disease urgent. Many new contagious diseases
have been identified in the past 30 years, such as
AIDS, Ebola, and hantavirus. Increased travel between
continents makes the worldwide spread of disease a bigger
concern than it once was. Additionally, many common
infectious diseases have become resistant to known
treatments.
Problems of antibiotic resistance
Because of the overuse of antibiotics, many bacteria
have developed a resistance to common antibiotics. This
means that newer antibiotics must continually be developed
in order to treat an infection. However, further
resistance seems to come about almost simultaneously.
This indicates to many scientists that it might become
more and more difficult to treat infectious diseases. The
use of antibiotics outside of medicine also contributes to
increased antibiotic resistance. One example of this is the
use of antibiotics in animal husbandry. These negative
trends can only be reversed by establishing a more rational
use of antibiotics through treatment guidelines.
Beta-Lactam Antibiotics
PENICILLINS
THE PENICILLINS ARE CLASSIFIED AS BETA-LACTAM DRUGS BECAUSE OF
THEIR UNIQUE FOUR-MEMBERED LACTAM RING.
THEY SHARE FEATURES OF CHEMISTRY, MECHANISM OF ACTION,
PHARMACOLOGIC AND CLINICAL EFFECTS, AND
IMMUNOLOGIC CHARACTERISTICS WITH CEPHALOSPORINS,
MONOBACTAMS, CARBAPENEMS, AND -LACTAMASE
INHIBITORS, WHICH ALSO ARE -LACTAM COMPOUNDS.
A penicillin culture
CEPHALOSPORINS & CEPHAMYCINS
Cephalosporins and cephamycins are similar to
penicillins chemically, in mechanism of action,
and in toxicity. Cephalosporins are more stable
than penicillins to many bacterial -lactamases
and therefore usually have a broader spectrum
of activity. Cephalosporins are not active against
enterococci and Listeria monocytogenes.
MONOBACTAMS
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These are drugs with a monocyclic -lactam ring . They are relatively resistant
to
lactamases and active against gram-negative rods (including pseudomonas
and serratia). They have
no activity against gram-positive bacteria or anaerobes. Aztreonam is the
only monobactam
available in the USA. It resembles aminoglycosides in its spectrum of
activity. Aztreonam is given
intravenously every 8 hours in a dose of 1–2 g, providing peak serum levels
of 100 g/mL. The
half-life is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate aztreonam without reaction. Occasional
skin rashes and
elevations of serum aminotransferases occur during administration of
aztreonam, but major toxicity
has not yet been reported. The clinical usefulness of aztreonam has not
been fully defined.
BETA-LACTAMASE INHIBITORS (CLAVULANIC
ACID, SULBACTAM, & TAZOBACTAM)
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These substances resemble -lactam molecules (Figure 43–7) but themselves have
very weak
antibacterial action. They are potent inhibitors of many but not all bacterial
lactamases and can
protect hydrolyzable penicillins from inactivation by these enzymes. -Lactamase
inhibitors are
most active against Ambler class A lactamases (plasmid-encoded transposable
element [TEM] lactamases in particular) such as those produced by staphylococci, H influenzae, N
gonorrhoeae,
salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class
Clactamases, which typically are chromosomally encoded and inducible, produced by
enterobacter,
citrobacter, serratia, and pseudomonas, but they do inhibit chromosomal
lactamases of legionella,
bacteroides, and branhamella.
BETA-LACTAMASE INHIBITORS (CONT’D)
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The indications for penicillin- -lactamase inhibitor combinations are
empirical therapy for
infections caused by a wide range of potential pathogens in both
immunocompromised and
immunocompetent patients and treatment of mixed aerobic and anaerobic
infections, such as intraabdominal
infections. Doses are the same as those used for the single agents except
that the
recommended dosage of piperacillin in the piperacillin-tazobactam
combination is 3 g every 6
hours. This is less than the recommended 3–4 g every 4–6 hours for
piperacillin alone, raising
concerns about the use of the combination for treatment of suspected
pseudomonal infection.
Adjustments for renal insufficiency are made based on the penicillin
component.
CARBAPENEMS
The carbapenems are structurally related to beta-lactam antibiotics.
Ertapenem, imipenem, and meropenem are licensed for use in the USA.
Imipenem has a wide spectrum with good activity against many gramnegative rods, including Pseudomonas aeruginosa, gram-positive
organisms, and anaerobes. It is resistant to most lactamases but not
metallo- lactamases. Enterococcus faecium, methicillin-resistant
strains of staphylococci, Clostridium difficile,
Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant.
Imipenem is inactivated by dehydropeptidases in renal tubules,
resulting in low urinary concentrations. Consequently, it is administered
together with an inhibitor of renal dehydropeptidase, cilastatin, for
clinical use. Meropenem is similar to imipenem but has slightly greater
activity against gram-negative aerobes and slightly less activity against
gram-positives. It is not significantly degraded by renal
dehydropeptidase and does not require an inhibitor.
Ertapenem is less active than meropenem or imipenem against
Pseudomonas aeruginosa and acinetobacter species. It is not
degraded by renal dehydropeptidase.
CARBAPENEMS (CONT’D)
The usual dose of imipenem is 0.25–0.5 g given intravenously every 6–
8 hours (half-life 1 hour). The usual adult dose of meropenem is 1 g
intravenously every 8 hours. Ertapenem has the longest half-life (4
hours) and is administered as a once-daily dose of 1 g intravenously
or intramuscularly. Intramuscular ertapenem is irritating, and for that
reason the drug is formulated with 1% lidocaine for
administration by this route. A carbapenem is indicated for infections
caused by susceptible organisms that are resistant to other available
drugs and for treatment of mixed aerobic and anaerobic infections.
Carbapenems are active against many highly penicillin-resistant
strains of pneumococci. A carbapenem is the beta- lactam antibiotic
of choice for treatment of enterobacter infections, since it is resistant
to destruction by the lactamase produced by these organisms.
Strains of Pseudomonas aeruginosa may rapidly develop resistance
to imipenem or meropenem, so simultaneous use of an
aminoglycoside is recommended for infections caused by those
organisms. Ertapenem is insufficiently active against P aeruginosa
and should not be used to treat infections caused by that organism.
Imipenem or meropenem with or without an aminoglycoside may be
effective treatment for febrile neutropenic patients.
CHLORAMPHENICOL
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It
binds reversibly to the 50S subunit of the bacterial ribosome.
Because of potential toxicity, bacterial resistance, and the
availability of other effective drugs (eg, cephalosporins),
chloramphenicol is all but obsolete as a systemic drug. It may be
considered for treatment of serious rickettsial infections, such as
typhus or Rocky Mountain spotted fever, in children for whom
tetracyclines are contraindicated, ie, those under 8 years of age. It is
an alternative to a -lactam antibiotic for treatment of meningococcal
meningitis occurring in patients who have major hypersensitivity
reactions to penicillin or bacterial meningitis caused by
penicillinresistant strains of neumococci. The dosage is 50–100
mg/kg/d in four divided doses.
Chloramphenicol is occasionally used topically in the treatment of
eye infections because of its wide antibacterial spectrum and its
penetration of ocular tissues and the aqueous humor. It is ineffective
for chlamydial infections.
CHLORAMPHENICOL. TOXICITY FOR NEWBORN INFANTS
Newborn infants lack an effective glucuronic acid
conjugation mechanism for the degradation and
detoxification of chloramphenicol. Consequently,
when infants are given dosages above 50
mg/kg/d, the drug may accumulate, resulting in
the gray baby syndrome, with vomiting, flaccidity,
hypothermia, gray color, shock, and collapse. To
avoid this toxic effect, chloramphenicol should be
used with caution in infants and the dosage limited
to 50 mg/kg/d or less (during the first week of
life) in full-term infants and 25 mg/kg/d in remature
infants.
TETRACYCLINES
Tetracyclines are broad-spectrum
bacteriostatic antibiotics that inhibit protein
synthesis. They are active against many grampositive and gram-negative bacteria, including
anaerobes, rickettsiae, chlamydiae, mycoplasmas,
and L forms; and against some protozoa, eg,
amebas. The antibacterial activities of most
tetracyclines are similar except that tetracyclineresistant strains may remain susceptible to
doxycycline or minocycline, drugs that are less
rapidly transported by the pump that is
responsible for resistance
TETRACYCLINES. CLINICAL USES
A tetracycline is the drug of choice in infections with Mycoplasma
pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are
used in combination regimens to treat gastric and duodenal ulcer
disease caused by Helicobacter pylori. In cholera, tetracyclines rapidly
stop the shedding of vibrios, but tetracycline resistance has appeared
during epidemics. Tetracyclines remain effective in most chlamydial
infections, including sexually transmitted diseases. Tetracyclines are no
longer recommended for treatment of gonococcal disease because of
resistance. A tetracycline—usually in combination with an
aminoglycoside—is indicated for plague, tularemia, and brucellosis.
Tetracyclines are sometimes employed in the treatment of protozoal
infections, eg, those due to Entamoeba histolytica or Plasmodium
falciparum. Other uses include treatment of acne, exacerbations of
bronchitis, community-acquired pneumonia, Lyme disease, relapsing
fever, leptospirosis, and some nontuberculous mycobacterial infections
(eg, Mycobacterium marinum). Tetracyclines formerly were used for a
variety of common infections, including bacterial gastroenteritis,
pneumonia (other than mycoplasmal or chlamydial pneumonia), and
urinary tract infections. However, many strains of bacteria causing these
infections now are resistant, and other agents have largely supplanted
Tetracyclines.
MACROLIDES
Erythromycin
Clarithromycin (is derived from erythromycin)
Azithromycin (differs from erythromycin and clarithromycin
mainly in pharmacokinetic properties). 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
and shortening of the duration of treatment in many
cases. 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 zithromycin given as a
500 mg loading dose, followed by a 250 mg single daily
dose for the next 4 days.
Ketolides (Telithromycin)
Aminoglycosides
Streptomycin, neomycin,
kanamycin, amikacin,
gentamicin, tobramycin,
sisomicin, netilmicin
SULFONAMIDES
Sulfonamides are infrequently used as single
agents. Formerly drugs of choice for infections
such as Pneumocystis jiroveci (formerly P carinii)
pneumonia, toxoplasmosis, nocardiosis, and
occasionally other bacterial infections, they have
been largely supplanted by the fixed drug
combination of trimethoprim-sulfamethoxazole.
Many strains of formerly susceptible species,
including meningococci, pneumococci,
streptococci, staphylococci, and gonococci, are
now resistant. Nevertheless, sulfonamides can be
useful for treatment of urinary tr
SULFONAMIDES. ORAL ABSORBABLE AGENTS
Sulfisoxazole and sulfamethoxazole are short- to
medium-acting agents that are used almost
exclusively to treat urinary tract infections. The usual
adult dosage is 1 g of sulfisoxazole four times daily or 1
g of sulfamethoxazole two or three times daily.
Sulfadiazine achieves therapeutic concentrations in
cerebrospinal fluid and in combination with
pyrimethamine is first-line therapy for treatment of acute
toxoplasmosis. Pyrimethamine, an antiprotozoal agent,
is a potent inhibitor of dihydrofolate reductase.
Sulfadoxine is available only as Fansidar, a combination
formulation with pyrimethamine, which is used as a
second-line agent in treatment for malaria
SULFONAMIDES. ORAL NONABSORBABLE
AGENTS
Sulfasalazine (salicylazosulfapyridine) is widely
used in ulcerative colitis, enteritis, and other
inflammatory bowel disease
Topical Agents
Sodium sulfacetamide ophthalmic solution or
ointment is effective treatment for bacterial
conjunctivitis and as adjunctive therapy for
trachoma. Mafenide acetate is used topically to
prevent bacterial colonization and infection of
burn wounds.
Fluoroquinolones
The important quinolones are synthetic
fluorinated analogs of nalidixic acid. They are active
against a variety of gram-positive and gram-negative
bacteria. Quinolones block bacterial DNA synthesis by
inhibiting bacterial topoisomerase II (DNA gyrase)
and topoisomerase IV.
Earlier quinolones (nalidixic acid, oxolinic acid,
cinoxacin) did not achieve systemic antibacterial
levels. These agents were useful only for treatment of
lower urinary tract infections.
Fluorinated derivatives (ciprofloxacin, levofloxacin,
and others) have greatly improved antibacterial
activity compared with nalidixic acid and achieve
bactericidal levels in blood and tissues.
Ciprofloxacin, enoxacin, lomefloxacin,
evofloxacin, ofloxacin, and pefloxacin comprise a
second group of similar agents possessing
excellent gram-negative activity and moderate to
good activity against grampositive bacteria.
Gatifloxacin, moxifloxacin, sparfloxacin, and
rovafloxacin comprise a third group of
fluoroquinolones with improved activity against
gram-positive organisms, particularly S
pneumoniae and to some extent staphylococci.
Antifungal Agents
The antifungal drugs presently available
fall into several categories: systemic
drugs (oral or parenteral) for systemic
infections, oral drugs for mucocutaneous
infections, and topical drugs for
mucocutaneous infections.
Immunologic therapies
Immunologic therapy is the treatment of disease
using medicines that boost the body’s natural immune
response.
Purpose
Immunologic therapy is used to improve the
immune system’s natural ability to fight such diseases as
cancer, hepatitis and AIDS. These drugs may also be
used to help the body recover from immunosuppression
resulting from such treatments as chemotherapy or
radiation therapy.
Description
Immunologic therapies
Most drugs in this category are synthetic versions of
substances produced naturally in the body. In their natural
forms, these substances help defend the body against
disease. For example, aldesleukin (Proleukin) is an
artificially
made form of interleukin-2, which helps white
blood cells work. Aldesleukin is administered to patients
with kidney cancers and skin cancers that have spread to
other parts of the body. Filgrastim (Neupogen) and
sargramostim (Leukine) are versions of natural
substances called colony stimulating factors, which
drive the bone marrow to make new white blood cells.
Another type of drug, epoetin (Epogen, Procrit), is a
synthetic version of human erythropoietin that stimulates
the bone marrow to make new red blood cells.
Thrombopoietin stimulates the production of platelets,
disk-shaped bodies in the blood that are important in
clotting.
Immunologic therapies cont’d
Interferons are substances the body produces
naturally using immune cells to fight infections and
tumors. The synthetic interferons carry such brand
names as Alferon, Roferon or Intron A. Some
of the interferons that are currently in use as drugs
are Recombinant Interferon Alfa-2a, Recombinant
Interferon Alfa-2b, interferon alfa-n1 and Interferon
Alfa-n3. Alfa interferons are used to treat hairy cell
leukemia, malignant melanoma and AIDS-related
Kaposi’s sarcoma, which is a form of cancer. In
addition interferons are also used for such other
conditions as laryngeal papillomatosis,
genital warts and certain types of hepatitis.
General precautions for all types of
immunologic
therapy
Regular physician visits are necessary during
immunologic therapy treatment. This gives the
physician a chance to make sure the medicine is
working and to check for unwanted side effects.
Anyone who has had unusual reactions to drugs
used in immunologic therapy should let the
physician know before resuming the drugs. Any
allergies to foods, dyes, preservatives, or other
substances should also be reported.