Transcript Respiratory Drugs Part 3

Respiratory Drugs
Part 3
XV. Respiratory anti-infective
agents
A. Introduction
• 1. Cell wall synthesis inhibitors
• One of the categories of antimicrobials
used in the treatment of respiratory
infections are the cell wall synthesis
inhibitors.
• There are numerous medications in this
class including the:
• penicillins
• cephalosporins
• monobactams
• vancomycin
a. penicillins
• The feature which all penicillins have in
common is a beta lactam ring, and it is this
ring that is necessary for the antibacterial
activity of the penicillins.
• These drugs bind to specific proteins in
bacteria called penicillin binding proteins
(PBP’s) and then prevent cross links from
forming between constituents in the
bacterial cell wall.
PBP1 and 2B in diagram b
• In addition, they activate enzymes which
cause lesions in the cell wall.
• There are 3 major categories of penicillins:
• “regular penicillins” (Penicillin G, Penicillin
V)
• Broad spectrum penicillins: amoxicillin,
ampicillin, azlocillin, carbenicillin,
mezlocillin, piperacillin and ticarcillin
• anti S. aureus penicillins: cloxacillin,
dicloxacillin, methicillin, naficillin and
oxacillin.
• None of these are effective against MRSA
(methicillin resistant S. aureus).
• Over 25% of S. aureus infections are
currently classified as MRSA.
• Most staphylocci and many gram negative
bacteria form beta lactamases (also
known as penicillinases), and this is the
major mechanism for the bacterial
resistance on penicillins.
• A possible strategy is to combine an
inhibitor of beta lactamase (sulbactam,
tazobactam, or clavulanate)) with a
penicillin.
• Examples of these combination drugs
include:
• Augmentin (amoxicillin and clavulanate)
• Unasyn (ampicillin and sulbactam)
• Timentin (ticarcillin and clavulanate)
• Zosyn (piperacillin and tazobactam)
• Adverse effects of the penicillins include
allergic reactions, anaphylaxis, nausea
and diarrhea.
b. cephalosporins
• Cephalosporins are derivatives of 7aminocephalosporanic acid.
• There are now 5 generations of
cephalosporins, based on their
introduction into clinical use.
• In general, the lower generation
cephalosporins are more effective against
staphylococcal and streptococcal
organisms.
• The higher generation cephalosporins are
more effective against gram negative
organisms (i.e. E. coli species, Klebsiella
species, Proteus species).
Examples of cephalosporins include:
• For “general use”: cefazolin (Kefzol, Ancef,
IV) and cephalixin (Keflex, oral)
• For use against anerobes, as in
prophylaxis of appendicitis: cefotetan
(Cefotan, IV)
• For use agains H. influenza: ceftriaxone
(Rocephin, IV) and cefuroxime (Ceftin,
oral)
• For use against meningitis, where
penetration of the blood brain barrier into
the central nervous system and
cerebrospinal fluid is necessary:
cefotaxime (Claforan, IV) and ceftriaxone
(Rocephin, IV)
• For use against Pseudomonas species:
ceftazidime (Fortaz)
• Their mechanism of action is similar to that
of the penicillins, they bind to PBP’s and
inhibit cell wall synthesis.
• They are less susceptible to penicillinases
due to structural differences that are
different from the penicillins.
• Similar to, but less frequent than the
penicillins, the cephalosporins have a
range of allergic effects from skin rashes
to anaphylactic shock.
c. monobactams
• Monobactams are monocyclic beta lactam
antibiotics, and aztreonam is the only
commercially available agent here.
• It’s mechanism of action is similar to the
other beta lactam cell wall synthesis
inhibitors.
• Aztreonam is most effective against gram
negative aerobes such as Pseudomonas
aeruginosa and various enterobacter
species.
• It is administered parenterally, and its
adverse effects include GI disturbances,
headache, and skin rashes.
d. vancomycin
• Vancomycin is active against gram
positive, but not gram negative bacteria.
• It is indicated for infections caused by
MRSA (pneumonia, as well as skin
infections, peritonitis, endocarditis).
• There are numerous resistant bacilli
emerging, including vancomycin
intermediate Staphylococcus aureus
(VISA) and vancomycin resistant
Staphylococcus aureus (VRSA).
• Adverse effects include chills, fever
ototoxicity and diffuse flushing from rapid
intravenous infusion (called red man
syndrome).
2. Bacterial protein synthesis
inhibitors
• There are numberous medications that are
inhibitors of bacterial protein, that have
applications in the treatment of respiratory
infections including:
•
•
•
•
•
the tetracyclines
the macrolides and ketolides
the streptogramins
linezolid
the aminoglycosides
• Antimicrobial agents that inhibit bacterial
protein synthesis have actions that are
centered on the ribosome.
• In humans, as well as other eukaryotes,
there are 80S ribosomes consisting of a
small (40S) and large (60S) subunit.
• In prokaryotes (bacteria), there are 70S
ribosomes consisting of a small (30S) and
a large (50S) subunit.
• The S stands for Svedberg unit, which
measures the rate of sedimentation (S) in
a centrifuge, and NOT the size, therefore
the fragments are not additive.
• These drugs are targeted for the 70S
bacterial ribosomes, and do not cause
major effects on protein synthesis in
humans.
a. the tetracyclines
• The tetracyclines are also broad spectrum
antibiotics that are the drug of choice in
the treatment of infections with Rickettsia,
Chlamydia, and Mycoplasma species.
• They are also used in the treatment of
cholera, acne, Lyme disease,
exacerbations of bronchitis and community
acquired pneumonia.
• Members of this family include
tetracycline, doxycycline, and minocycline.
• GI effects are fairly common (nausea,
diarrhea), as is enhanced skin sensitivity
to UV light.
• Tetracyclines are usually contraindicated
in pregnancy, they lead to fetal tooth
enamel dysplasia and bone growth
irregularities.
b. Macrolides
• Macrolide antibiotics contain a large
lactone ring attached to various sugars.
• They have good oral bioavailability,
although the absorption of some are
impeded by food.
• They are active against a few gram
positive bacteria ( MSSA), gram negative
species (i.e.Hemophillus influenzae), and
atypical bacteria (i.e. Legionella,
Mycoplasma).
• The prototype of the macrolides is
erythromycin. Newer macrolides include
azithromycin (Zithromax) and
clarithromycin (Biaxin).
•
c. Streptogramins
• The combination of 2 streptogramins
quinupristin and dalfopristin (Synercid) are
active against gram positive cocci,
including Streptococcus pneumoniae,
MSSA, and MRSA.
• It is indicated in the treatment of
pneumonias and is administered
parenterally.
• This combination of drugs inhibits a
cytochrome P450, and therefore increases
the plasma concentration of cyclosporine,
diazepam, warfarin and terfenadine
d. oxazolidinones
• Linezolid is the first in a new class of
antibiotics called oxazolidinones.
• Headache and GI disturbances are the
most commonly reported adverse effects
associated with linezolid administration.
e. aminoglycosides
• Aminoglycosides inhibit protein synthesis
by binding to the smaller subunit of
ribosomes.
• This blocks the formation of the initiation
complex necessary to begin translation of
the mRNA.
• The prototype for aminoglycosides is
gentamicin. Other aminoglycosides
include tobramycin and amikacin.
• Aminoglycosides are administered either
parenterally (IM or IV), or by inhalation as
they are very poorly absorbed through the
GI tract.
• When administered alone,
aminoglycosides are effective against
gram negative species (especially
Enterobacter species).
• For the treatment of infection from gram +
species, aminoglycosides are generally
combined with a cell wall synthesis
inhibitor (i.e. a penicillin).
3. Sulfonamides
• Today, sulfonamides have limited uses
due to bacterial resistance.
Sulfamethazole is used in the treatment of
UTI’s (urinary tract infections).
• Sulfamethoxazole combined with
trimethoprim ( Bactrim, Septra) is used in
the treatment of respiratory and urinary
tract infections.
• Sulfonamides are inhibitors of
tetrahydrofolic acid (often referred to as
simply, folic acid).
• Bacteria require folic acid to synthesize
proteins and the nucleic acids DNA and
RNA.
• Sulfonamide side effects include
hypersensitivity reactions and GI
disturbances.
• Trimethoprim may cause
granulocytopenia, leukopenia or
megaloblastic anemia.
4. Fluoroquinolones
• The fluoroquinolones inhibit 2 enzymes
involved in bacterial DNA synthesis:
• DNA gyrase, which is necessary to “relax”
supercoiled DNA so that replication can
occur;
• and topoisomerase IV, which is involved in
the separation of already replicated DNA
during cell division.
• Fluoroquinolones include ciprofloxacin
(Cipro), levofloxacin (Levaquin),
lomefloxacin (Maxaquin), norfloxacin
(Noroxin) and ofloxacin (Floxin). Newer
fluoroquinolones include gemifloxacin
(Factive) and moxifloxacin (Avelox).
B. Mycobacterium tuberculosis
• One-third of the world's population is
infected with Mycobacterium tuberculosis,
according to the World Health
Organization (WHO), with an estimated 8
million new cases of tuberculosis and
nearly 2 million deaths each year.
• There are approximately 10 million people
who are co-infected with Mycobacterium
tuberculosis and HIV, with over 90% of
these individuals residing in developing
nations.
• Worldwide, tuberculosis is the most
common opportunistic infection
affecting HIV positive individuals, and it
is the most common cause of death in
patients with AIDS.
• In these HIV patients, TB may be located
in the brain, bones, kidneys, larynx, or
lymph nodes.
• New guidelines for the treatment of TB
were released in 2003, jointly, by the
Centers for Diseases Control and
Prevention (CDC), the American Thoracic
Society (ATS), and the Infectious
Diseases Society of America.
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•
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The first-line drugs include:
isoniazid, INH (INH)
rifampin, RIF (Rimactane)
rifabutin, RFB (Mycobutin)
ethambutol, EMB (Myambutol)
pyrazinamide, PZA (Tebrazid)
• The recommendation for treatment for
drug susceptible tuberculosis is INH,
RIF, PZA, and EMB daily for 8 weeks,
followed by INH and RIF daily for 18
weeks or INH and RIF twice-weekly for 18
weeks.
• Drug-resistant TB is TB that is resistant
to at least one first-line drug.
• The second-line drugs that are used,
along with the first-line drugs when drugresistant TB is present or suspected,
include:
• streptomycin, SM (Streptomycin)
• cycloserine, (Seromycin)
• ethionamide, (Trecator-SC)
• Multidrug-resistant TB (MDR TB) is TB
that is resistant to at least two of the firstline drugs, isoniazid and rifampicin.
• The treatment of multidrug-resistant TB
involves using the most active of the
second-line drugs:
• the fluoroquinolones (i.e ciprofloxacin,
levofloxacin)
• various injectable aminoglycosides
(capreomycin, CM; kanamycin, KM).
• Patients on TB medications should receive
a vitamin and mineral supplement in order
to prevent depletions.
• The results of a study published in May
2008 in the Journal of Infectious Diseases
demonstrated that vitamin and mineral
supplements can reduce the risk of
recurrence of TB.
• This study was conducted by Eduardo
Villamor, MD, of the Harvard School of
Public Health in Tanzania, using doses of
vitamins A, B-complex, C, E, and selenium
or placebo in 887 patients receiving
tuberculosis therapy, and followed for a
median of 43 months.
• Approximately half of these patients (471)
were also HIV-coinfected.
• The study demonstrated that
supplementation was associated with
reduced rates of TB recurrence.
• In this study, there was a decreased risk of
TB recurrence, 45% overall and 63% in
HIV-infected patients.
• Vitamin and mineral supplementation is an
inexpensive addition to TB therapy to
reduce relapses and increase survival.
C. Pneumocystis pneumonia
(PCP)
• Pneumocystis carinii has previously been
classified as a protozoan, however, other
researchers claim it is a fungus, and
should be re-named as Pneumocystis
jiroveci.
• The pneumocystis microorganism is
commonly found in the lungs of healthy
individuals and is communicable via air
borne transmission.
• It causes disease when immunity is
compromised (i.e. individuals with CD4
lymphocyte count less than 200/mm3).
• In the U.S. prior to the 1980s, there were
less than one hundred cases of PCP each
year.
• In the first decade of the HIV epidemic in
the U.S., more than 100,000 cases of
PCP were reported.
• It is the most common opportunistic
infection in patients with HIV infection
in the U.S.
Treatments for PCP:
• 1. inhaled aerosol pentamidine
isoethionate (NebuPent)
• This is normally administered for
prophylaxis of PCP, but has been used
also during acute illness.
• It can also be administered IV or IM, but
not orally.
• There are less severe adverse effects
associated with inhaled aerosol treatment
(bronchospasm, sore throat, cough,
shortness of breath, wheezing)
• as compared with IV or IM treatment
(hypoglycemia in over 60% of patients,
hypotension, pancreatitis, nephrotoxicity,
anemia, leukopenia).
• Mechanism of action: It prevents RNA and
DNA synthesis.
2.
trimethoprim,TMP/sulfamethoxaz
ole, SMX (Bactrim, Septra)
• This is normally administered for the
treatment of PCP.
• It is available in 80 mg TMP/400 mg SMX
tablets or 80 mg TMP/400 mg SMX per 5
ml for injection.
• The most common adverse effects
associated with TMP/SMX include:
nausea, vomiting, rash.
• Mechanism of action:
• The combination of these 2 agents
prevents the synthesis of RNA and DNA
by inhibiting 2 different enzymes in the
biosynthetic pathway in various bacteria,
as well as the protozoa which causes
PCP.
• Sulfamethoxazole is a sulfonamide which
prevents the synthesis of folate from
PABA by inhibiting the enzyme
dihydropteroate synthetase.
• Trimethoprim inhibits the enzyme
dihydrofolate reductase, which prevents
the synthesis of tetrahydrofolate from
folate.
• PABA → folate → tetrahydrofolate →
purines, pyrimidines in RNA, DNA
D. Other Pneumonias
1. Community-acquired pneumonia
• Community–acquired pneumonias
develop in people that are in contact with a
group of individuals.
• These pneumonias do not include those
contracted in hospitals and nursing
homes, which are classified as nosocomial
pneumonias.
• Community–acquired pneumonias are
normally caused by:
• Streptococcus pneumoniae
• Haemophilus influenzae
• Chlamydia pneumoniae
• Mycobacterium pneumoniae
• Legionella pneumophila.
a. Streptococcus pneumoniae
• Streptococcus pneumoniae aka
pneumococcal pneumonia, is the most
common of the bacterial pneumonias.
• It may be carried and spread, by healthy
individuals, who do not experience illness.
• Streptococcus pneumoniae is transmitted
by airborne droplets (coughing, sneezing).
• Children under age 2 and adults over 65
are now routinely vaccinated in an attempt
to prevent this disease.
• The 2007 Infectious Diseases Society of
America/American Thoracic Society
guidelines recommend either a β-lactam, a
macrolide, or a fluoroquinolone, for the
treatment of Streptococcus pneumoniae.
• Penicillin had been the β-lactam of choice
in treating this type of pneumonia.
• It may still be effective, however,
significant resistance (between 20 – 40%)
to this drug has developed.
• Augmentin, which is a combination of the
β-lactam amoxicillin with the β-lactamase
inhibitor clavulanate is often prescribed.
• In addition, ticarcillin clavulanate
(Timentin) is effective, but is only
administered IV or IM.
• There are 2 components to this
medication, similar to Augmentin. It
contains the β-lactam ticarcillin and the βlactamase inhibitor clavulanate.
• Resistance associated with the
macrolides, mostly clarithromycin (Biaxin)
and azithromycin (Zithromax) are
increasing.
• Telithromycin remains active against
Streptococcus pneumoniae.
• The second generation fluoroquinolones
(ciprofloxacin and ofloxacin) as well as the
third generation levofloxacin, are poorly
active against Streptococcus pneumoniae.
• Antibiotic resistance has been less
common when using the fourth generation
moxifloxacin and gemifloxacin.
b. Hemophilus influenzae
• Hemophilus influenzae is an opportunistic
bacteria which often causes pneumonia in
people suffering from COPD.
• Antibiotic resistance is now seen with
many of the β-lactams.
• Combination drugs which include a βlactam and a β-lactamase inhibitor such as
piperacillin with tazobactam (Taxocin,
Zosyn) or ticarcillin clavulanate (Timentin)
are effective.
• Third generation cephalosporins such as
cefdinir (Omnicef) and cefditoren
(Spectracef) are recommended.
• Fluoroquinolones that are recommended
include gatifloxacin (Tequin), gemifloxacin
(Factive), and moxifloxacin (Avelox).
• c. Chlamydia pneumoniae
•
Chlamydia pneumoniae accounts for a
small percentage of community-acquired
pneumonia and is most commonly seen in
two distinct age groups: teenagers and
adults over age 60.
• This type of pneumonia is not usually
severe and generally doesn’t require the
patient to be hospitalized.
• Chlamydia pneumoniae is generally
treated with either a macrolide:
azithromycin (Zithromax), clarithromycin
(Biaxin); or a tetracycline: doxycycline.
• Chlamydia pneumoniae has been
implicated the development of
atherosclerosis, as is has been found
within plaques in the walls of coronary
arteries.
d. Mycoplasma pneumoniae
• Mycoplasma pneumoniae cause a
pneumonia that is often referred to as
"atypical” or “walking” pneumonia.
• Symptoms of this pneumonia include
fever, headache, and nonproductive
cough.
• It accounts for up to 20% of all bacterial
pneumonias.
• It tends to be found in places where young
people congregate (dorms, army barracks)
and occurs at unusual times of the year
(summer and fall).
• It is usually a slow developing pneumonia,
with an incubation period of up to 3 weeks.
• The macrolides erythromycin (E-mycin),
clarithromycin (Biaxin) and azithromycin
(Zithromax) are commonly prescribed.
• e. Legionella pneumophila
•
Legionnaire’s disease is a serious,
often fatal pneumonia caused by the
bacterium Legionella pneumophilia.
• The first outbreak of this disease occurred
in 1976 at an American Legion convention
in Philadelphia, PA, where more that 200
people became ill and 34 died.
• The bacterium grew in the standing water
in the air conditioning system and was
distributed throughout the building.
• It is not transmitted by human to human
contact, only by aerosol.
• There was an outbreak of in the summer
of 2008 in Syracuse, N.Y. The bacterium
was located in a cooling tower at
Community General Hospital.
• According to Onondaga County Health
Commissioner Dr. Cynthia Morrow, there
were 10 reported cases of Legionnaires
Disease in the area surrounding the
hospital.
• About 70% of those individuals who
contact Legionnaire’s disease are heavy
smokers, and/or elderly, and/or have some
predisposing illness.
• Each year in the U.S. between eight and
eighteen thousand people are hospitalized
with Legionnaire’s disease.
• The majority of cases seem to be in the
summer (maybe due to re-starting of air
conditioning units after sitting all winter).
• The drugs of choice in treating
Legionnaire’s disease, according to the
CDC, are the macrolides erythromycin (Emycin), clarithromycin (Biaxin) and
azithromycin (Zithromax).
2. nosocomial pneumonia
• Nosocomial refers to hospital acquired,
and these pneumonias are found in
patients who are: extremely ill, and/or
intubated, and/or immunocompromised,
and/or have cardiopulmonary disease.
• Nosocomial pneumonias are usually
caused by: Pseudomonas aeruginosa and
Staphylococcus aureus (especially
methicillin resistant).
a. Pseudomonas aeruginosa
• According to the CDC, Pseudomonas
aeruginosa is one of the most common
gram-negative bacterium causing
pneumonia in hospitalized patients.
• To minimize the emergence of resistance,
multidrug therapy is recommended in the
treatment of Pseudomonas aeruginosa
pneumonia.
• The recommended treatment includes at
least two drugs: an aminoglycoside and
either an extended spectrum penicillin with
pseudomonal activity or a cephalosporin.
• Aminoglycosides commonly prescribed
include gentamicin (G-Mycin, Garamycin).
• Aerosolized antibiotics to treat
Pseudomonas aeruginosa pneumonia
have, in the past, generally only been
used in cystic fibrosis patients.
• Until recently, there has not been sufficient
data to support their use in either hospitalacquired pneumonia (HAP) or ventilator
acquired pneumona (VAP) caused by
Pseudomonas aeruginosa.
• In a recent Phase II study (Journal of
Antimicrobial Chemotherapy 2009
64(2):229-238), intubated and
mechanically ventilated patients with HAP
or VAP
• were randomized to receive either the
aerosolized aminoglycoside Amikacin (400
or 800 mg) or placebo every 12 hours for
between 7 and 14 days.
• High levels of the drug were found in the
fluid lining the epithelial surface of the
lower respiratory tract, without
compromising safe serum levels.
• Based on the results of this trial, a Phase
III trial is currently underway.
• spectrum penicillins include ticarcillin
clavulanate (Timentin) and piperacillin with
tazobactam (Taxocin, Zosyn).
• Carbapenems, which are structurally
related to the β-lactam antibiotics, have
good activity against Pseudomonas
aeruginosa.
• Imipenem is a carbapenem which is often
combined with the fluoroquinolone
levofloxacin (Levaquin) for prevention of
emergence of resistance during treatment.
• Doripenem is a new carbapenem which is
2-4 times more potent than imipenem
against Pseudomonas aeruginosa.
• Tomopenem is another new carbapenem
whose use is associated with a very low
tendency for the emergence of resistance.
• One of the recommended cephalosporins
is ceftazidime (Fortraz, Tazidime).
• In addition, ceftobiprole is a fifth
generation cephalosporin which completed
Phase III trials in June 2009.
• Seventy patients with Pseudomonas
aeruginosa pneumonia were randomized
to receive either ceftobiprole or a
combination therapy of
ceftazidime/linezolid.
• The results were quite similar: they was a
77% cure rate for ceftobiprole as
compared to 76% for those receiving the
combination therapy.
• Polymyxins are peptide antibiotics that act
like detergents.
• They attach to and breach membranes,
causing the leakage of intracellular
contents.
• Polymyxin E (colistin) has been used both
alone and in combination therapy.
• Administered systemically, it has serious
neurotoxic and nephrotoxic adverse
effects, so it is generally reserved for the
most serious infections caused by MDR
Pseudomonas aeruginosa.
• A Phase III trial for an aerosolized
versions of aztreonam for the treatment of
hospital-acquired pneumonia (HAP) or
ventilator acquired pneumona (VAP)
caused by Pseudomonas aeruginosa has
recently been completed, and is currently
under review by the FDA.
• A Phase III trial for an aerosolized
liposomal formulation of ciprofloxacin for
the same treatment is underway (as of
November 2009).
b. Staphylococcus aureus
(methicillin resistant)
• Vancomycin had been the cornerstone for
the treatment of methicillin resistant
Staphylococcus aureus (MRSA).
• However, there are vancomycin
intermediate Staphylococcus aureus
(VISA) and vancomycin resistant
Staphylococcus aureus (VRSA) that have
emerged.
• vancomycin sensitive and vancomycin intermediate S. aureus
(VSSA and VISA, respectively), showing thickening of the cell wall in
the resistant isolate
• The combination of the 2 streptogramins
quinupristin-dalfopristin (Synercid) is
active against gram positive cocci,
including MRSA.
MRSA
MRSA sensitive to Synercid
• Linezolid is the first in a new class of
antibiotics called oxazolidinones.
• Linezolid blocks the formation of the
initiation complex in protein synthesis
• It is indicated for use against many of the
same drug resistant gram positive cocci
that quinupristin-dalfopristin is used for
(i.e. MRSA).
• It is available in both oral and parenteral
formulations, and it is suggested that its
use be limited to treatment of infections
caused by multidrug resistant gram
positive bacteria.
linezolid (Zyvox)