Antimicrobial Agents
I.
Background
a. As Respiratory Care Practitioners, we commonly treat respiratory
infections due to:
i. pneumonia
ii. acute and chronic bronchitis
iii. bronchiectasis
iv. cystic fibrosis
b. Infections may be caused by:
i. bacteria
ii. fungi
iii. protozoa
iv. viruses
II.
Definition of Terms
Term
Antibiotic
Definition
a substance produced by microorganisms
that is capable of inhibiting or killing bacteria
and other microorganisms
Anti-infective (antimicrobial)
chemicals that are toxic to bacteria and other
microorganisms, but that are not produced
by microorganisms or derived from
organisms originally
(made in the laboratory)
a drug that inhibits the growth of a
microorganism
a drug that kills the microorganisms
a. useful against a wide range of
organisms, both gram-negative and
gram-positive
useful against only a few organisms
Bacteriostatic
Bactericidal
Broad Spectrum
Narrow Spectrum
III. Modes of Action of Antibiotics
a. Inhibition of Cell Wall Synthesis
i. Bacteria have rigid cell walls to protect themselves
1. most other cells have membranes
ii. Without a cell wall, fluid would move into the cell due to a
high osmotic pressure
1. the cell would explode
b. Alteration of cell wall permeability
i. Disruption of membrane function upsets the necessary flow
and storage of cell material required for growth and life
c. Inhibition of Protein Synthesis
i. Crucial to a cells growth and function
d. Inhibition of Nucleic Acid Synthesis
i. DNA synthesis is necessary for life
ii. Inhibits further DNA replication or formation of mRNA
IV.
Sensitivity and Resistance
a. Kirby-Bauer disk diffusion test
i. In the lab, technicians will spread a sample of the infective
material onto a plate of nutrient substance (usually agar, a
type of gel made from algae) and allow the species of
bacteria to grow for twenty-four hours
ii. With a sufficient population of bacteria grown on the plate in
the form of a "lawn", the lab will perform two main operations
1. Identify the species of bacteria with the following
techniques
a. examination of lawn characteristics (color,
texture, growth pattern, etc.)
b. gram-staining
i. simplest and most common method
c. microscopic examination
d. metabolic requirement "footprints"
e. DNA sequencing
2. Determines the bacterial population’s sensitivity to a
range of antibiotics
a. This can be done by placing small disks of filter
paper or agar impregnated with various types of
antibiotics onto the bacterial lawn. The bacteria
are allowed to incubate for a day or two, and then
the plate is examined to see whether the bacterial
growth is inhibited by the antibiotics on each disk
b. Sensitive
i. In this case, a clear, circular "halo"
(technically known as a "plaque," or zone of
inhibition) will appear around the antibiotic
disk, indicating an absence of bacteria
ii. The antibiotic has inhibited their growth
and/or killed them, meaning that this
particular antibiotic should be effective
against the infection
c. Intermediate
i. A somewhat cloudy plaque indicates that
not all the bacteria in the area around the
disk have been killed
ii. This means that there are some members of
the bacterial population that are sensitive to
this particular antibiotic, but others that are
genetically immune to its effects
iii. If an antibiotic to which the bacteria show
"intermediate" sensitivity is used, it is likely
that the sensitive members of the bacterial
population will be killed, and the resistant
ones will survive, resulting in the selection
of a population resistant to that particular
antibiotic
d. Resistant
i. In this case, the filter paper will have no
discernable plaque around it, meaning that
the bacteria are growing normally, even in
the presence of the antibiotic
ii. An antibiotic producing no plaque will most
likely be ineffective against the bacteria
causing the infection
Pseudomonas aeruginosa being strongly inhibited by three different types of
antibiotic, moderately inhibited by one (center bottom of the plate) and
unaffected by the six antibiotic disks with no plaque around them.
b. ETest Strip
i. A commercially prepared strip creates a gradient of antibiotic
concentration when placed on an agar plate
ii. Used to determine the minimum inhibitory concentration
(MIC)
1. the least concentration of antimicrobial that prevents
visible growth
ETest meniscus - the MIC corresponds to the point where the bacterial growth crosses
the numbered strip.
c. Broth Macrodilution
i. Defined aliquots of bacteria are inoculated into a nutrient
broth containing a dilution series of antibiotic concentrations
ii. A small sample can be removed from the test-tubes with no
growth to inoculate agar plates
iii. Used to determine the minimum inhibitory concentration
(MIC)
1. the least concentration of antimicrobial that prevents
visible growth
In this case, bacterial growth of Staph aureus occurred at a Tetracycline
concentration of 0.8 mcg/ml but not at 1.6 mcg/ml. Thus, the minimum
inhibitory concentration is read as 1.6 mcg/ml
iv. Used to determine the minimum bactericidal concentration
(MBC)
1. the lowest concentration of antimicrobial agent that
prevents growth of an organism on an agar plate after a
24 hour incubation
V.
Resistance to Antibiotics
a. Bacteria can adapt themselves to become resistant to antimicrobial
actions
i. Enzymes to Inactivate Antibiotics
1. Some bacteria can produce an enzyme to inactivate an
antibiotic
a. beta-lactamase (penicillinase)
i. Staphylococcus aureus
ii. Haemophilus influenzae
ii. Substitute Binding Proteins
1. Some bacteria substitute the proteins used for cell wall
synthesis making the antibiotic incapable of binding to
the cell wall
iii. Alterations in Bacterial Wall Permeability
1. prevents or slows the entrance of the antibiotic into the
bacterial wall
iv. Cell Pumps to Remove Antibiotics
1. bacteria may have pumps to actively remove antibiotics
from the cell
a. Pseudomonas aeruginosa
b. Staph aureus
VI.
Classification of Antibiotics
a. Beta-Lactam Antibiotics - antibiotics which have a beta-lactam ring
in its molecular structure
i. Penicillins
1. Penicillin was discovered in 1928 by Alexander Fleming
2. Classification
a. natural penicillins
i. penicillin G
ii. penicillin V
b. penicillinase-resistant agents
i. oxacillin
ii. nafcillin
iii. cloxacillin
iv. dicloxacillin
c. aminopenicillins
i. ampicillin
ii. amoxicillin
d. carboxypenicillins
i. carbenicillins
ii. ticarcillin
e. uredopenicillins
i. mezlocillin
ii. piperacillin
f. penicillin plus ß-lactamase inhibitors
i. amoxicillin-clavulanic acid
ii. ampicillin-sulbactam
iii. ticarrcillin-clavulanic acid
iv. piperacillin-tazobactam
3. Penicillin allergy
a. skin rash to anaphylactic shock
b. more common with parenteral vs. oral
administration
4. Uses
a. Streptococcal species
b. Staphylococcal species
c. Haemophilus influenzae
d. Pseudomonas aeruginosa
e. Gonococcal and syphilis causing organisms
ii. Cephalosporins
1. First Generation
a. Very active against gram-positive cocci (e.g.
pneumococci, streptococci, staphylococci)
b. Activity against gram-negative bacteria is
variable
c. Commonly Used Agents
i. Cefaclor (Ceclor)
ii. Cephalexin (Keflex)
iii. Cephadroxil (Duricef)
iv. Cephalothin (Keflin)
v. Cephradine (Velosef)
vi. Cephapirin (Cephadyl)
vii. Cefazolin (Ancef)
2. Second Generation
a. Remain fairly active against gram-positive
organisms that are susceptible to first generation
drugs
b. Show more activity against gram-negative
organisms (Enterobacter, Klebsiella, H.
influenzae, M. catarrhalis)
c. Commonly Used agents
i. Cefamandole (Mandole)
ii. Cefotetan (Cefotan)
iii. Cefoxitin (Mefoxin)
iv. Cefuroxine (Zinacef)
v. Cefonicid (Monocid)
vi. Cefprozil (Cefzil)
vii. Loracarbef (Lorabid)
viii. Cefmetazole (Zefazone)
3. Third Generation
a. Variable activity against gram-positive organisms
b. Show expanded gram-negative activity
c. Ceftazidime and cefoperazone are active against
Pseudomonas aeruginosa
d. Commonly Used Agents
i. Cefoperazone (Cefobid)
ii. Ceftazidime (Fortaz)
iii. Cefixime (Suprax)
iv. Ceftriaxone (Rocephin)
v. Cefdinir (Omnicef)
vi. Cefotaxine (Claforan)
vii. Ceftibuten (Cedax)
viii. Cefpodoxime (Vantin)
ix. Cefipime (Maxipime)
x. Ceftizoxime (Cefizox)
4. Fourth Generation
a. Cefepime (Maxipime)
i. Only agent available in the U.S.
b. Has extended gram-positive and gram-negative
coverage
i. P. aeruginosa
ii. MSSA
iii. Neisseria species
iv. H. influenzae
v. S. pneumoniae
vi. S. pyogenes
c. Uses
i. Urinary tract infection
ii. Skin and soft tissue infection
iii. Nosocomial pneumonia
iv. Other serious bacterial infections
5. Toxicity and Hazards
a. Well tolerated as a group
b. Minor GI complaints
c. Nephrotoxicity - acute tubular necrosis
d. IV – thrombophlebitis
e. IM – painful
6. Uses
a. Important for their broad-spectrum activity
against many common pathogenic gram-positive
cocci and some gram-negative organisms
iii. Carbapenems
1. Agents
a. imipenem-cilastatin (Primaxin)
b. meropenem (Merrem IV)
2. Uses
a. Broad spectrum activity against gram-positive and
gram-negative organisms
iv. Monobactam
1. Agent
a. aztreonam (Azactam)
b. Uses
i. Effective against a wide range of gramnegative aerobic organisms
b. Aminoglycosides
i. Derived from different species of Streptomyces
ii. Activity – bactericidal against gram-negative organisms
iii. Mode of Action
1. act by prevention and distortion of bacterial protein
synthesis
iv. Commonly Used Agents
1. Streptomycin
2. Amikacin (Amikin)
3. Gentamicin (Garamycin)
4. Neomycin (Neosporin)
5. Tobramycin (Nebcin)
6. Netilmicin (Netromycin)
7. Kanamycin (Kantrex)
8. Paramomycin (Humatin)
v. Uses
1. Gentamicin, tobramycin, netilmicin, and amikacin are
used to treat gram-negative bacillary pneumonias
2. Inhalation of these agents is commonly used to control
Pseudomonas infection in Cystic Fibrosis
vi. Toxicity
1. Nephrotoxicity - damage to renal tubules
2. Otoloxicity - dizziness, nausea
3. Produce mild neuromuscular blockage
c. Tetracyclines
i. Derived from Streptomyces species
ii. Bacteriostatic or bactericidal, depending on dosage
iii. Mode of Action
1. Act by interfering with bacterial protein synthesis
iv. Agents
1. Tetracycline (Achromycin)
2. Oxytetracycline (Terramycin)
3. Demeclocycline (Declomycin)
4. Methacycline (Rendomycin)
5. Doxycycline (Vibramycin)
6. Minocycline (Minocin)
v. Toxicity and Hazards
1. G-I irritation - nausea, vomiting, diarrhea
2. Bone marrow depression
3. Hypersensitivity - skin rash to anaphylaxis
4. Oral and Vaginal candidiasis
5. Children
a. growth retardation
b. tooth discoloration in children under 8 years old
vi. Uses
1. Useful for managing mycoplasmal and other atypical
pneumonias
2. Acute infections superimposed on chronic bronchitis
d. Fluoroquinilones
i. Mode of Action
1. inhibition of an enzyme needed for bacterial DNA
synthesis
ii. Agents
1. Ciprofloxacin (Cipro)
2. Norfloxacin (Noroxin)
3. Ofloxacin (Floxin)
4. Enoxacin (Penetrex)
5. Lomefloxacin (Maxaquin)
iii. Uses
1. Broad spectrum antibacterial activity
2. Useful against infections associated with chronic
bronchitis and cystic fibrosis
3. Strong activity against H. influenzae, Legionella
pneumophilia, M. pneumoniae, N. meningitides,
Bordetella pertussis, and Pseudomonas aeruginosa
iv. Administration
1. Oral administration give suitably high lung tissue levels
2. Limit use to several weeks to avoid bacterial resistance
e. Polymyxins
i. Derived from Bacillus polymyxa
ii. Mode of Action
1. alteration of cell membrane permeability
iii. Agents
1. Polymyxin B
2. Polymyxin E
iv. Uses
1. Very effective against Pseudomonas aeruginosa and
other gram-negative bacteria
v. Administration
1. IV
2. IM
3. INH (not FDA approved use)
4. Topical
a. Ointment
b. Ophthalmic solution
vi. Toxicity
1. Very toxic to the kidneys and nervous system
f. Macrolide Antibiotics
i. Mode of Action
1. Inhibits protein synthesis
ii. Agents
1. Erythromycin
2. Clarithromycin (Biaxin)
3. Azithromycin (Zithromax)
4. Dirithromycin (Dynabac)
5. Troleandomycin (Tao)
iii. Uses
1. Used for respiratory, genital, GI, and skin/soft tissue
infections
2. Drug of choice in treating Mycoplasma and Legionella
pneumonias
iv. Toxicity
1. Oral administration can cause GI upset, anorexia, and
diarrhea
g. Other Antibiotics
i. Vancomycin
1. Mode of Action
a. Inhibits cell wall synthesis
b. Inhibits RNA synthesis
2. Use
a. Reserved for use with severe staphylococcal or
other infections including methicillin-resistant S.
aureus (MRSA) not responsive to other
antimicrobials
3. Administration
a. Oral
b. IV
4. Toxicity
a. Otoxicity
i. May cause deafness
b. Nephrotoxicity
c. Hypotension
d. Renal failure
e. Wheezing and dyspnea
f. Vasculitis
ii. Clindamycin
1. Mode of Action
a. Inhibits protein synthesis
2. Uses
a. Anaerobic infections of the respiratory tract
i. Necrotizing pneumonia
ii. Lung abscess
iii. Empyema
iv. Aspiration pneumonia
b. AIDS-related illnesses
i. Toxoplasma encephalitis
ii. Pneumcystis carinii pneumonia
3. Side Effects
a. nausea
b. vomiting
c. diarrhea
h. Sulfonamides (Sulfamethoxazole) - lab produced chemical agent
i. Agent
1. Trimethoprim - Sulfamethoxazole (TMP-SMX)
ii. Uses
1. used in combination to treat Pneumocystis carinii
pneumonia in AIDS patients
2. chronic urinary tract infections
iii. Side Effects
1. rash
2. fever
3. leukopenia
i. Antimycobacterial Agents
i. Agents
1. Isoniazid (PO,IM)
2. Rifampim (PO, IV)
3. Rifabutin (PO)
4. Pyrazinamide (PO)
5. Ethambutol (PO)
6. Streptomycin (IM) - 1st drug available for the treatment
of TB
ii. Typical Regimen for low INH resistance rate <4%
1. INH+RIF (or RFB) + PZA + B6 daily for 2 months, then
INH + RIF (or RFB) + B6* daily for an additional 4
months
a. *INH causes B6 deficiency which is a coenzyme
for fat, carbohydrate and fat metabolism
iii. See text, page 297, Table 14-8, guidelines for treatment
iv. Adverse Effects
1. hepatic toxicity
a. most common
2. optic neuropathy
3. rifampin changes body fluids to a deep orange hue
j. Antifungal Agents
i. Background
1. Potentially pathogenic fungi (candida albicans) are
normally found in the body (mouth, sputum, stools,
vagina)
2. The presence of fungi doesn’t normally cause disease
unless the normal bacterial flora is depressed due to
a. Broad spectrum antibiotics
b. Inhaled corticosteroids
c. Immuno-compromise (HIV)
3. Fungal infections are commonly seen in ICU patients on
mechanical ventilation undergoing long term antibiotic
therapy
ii. Agents
1. Amphotericin B
a. Mode of Action
i. Increases fungal cell wall permeability
b. Uses
i. Standard drug used to treat severe fungal
infections
c. Administration
i. Oral
1. not absorbed from GI tract
ii. parenteral
1. IV
iii. topical
1. cream
2. lotion
3. oral suspension
d. Toxicity
i. Toxic side effects have limited its systemic
use
1. nephrotoxicity
2. fever
3. hypotension
4. metabolic acidosis
2. Nystatin (Mycostatin)
a. Mode of Action
i. Increases fungal cell wall permeability
b. Uses
i. Effective against Candida albicans
1. treatment of oral infection (“thrush”)
c. Administration
i. Oral suspension
ii. topical
1. cream
2. ointment
3. powder
3. Ketoconazole (Nizoral) - Candida sp.
4. Fluconazole (Diflucan) - Candida sp.
5. Itraconazole (Sporanox) - Candida sp., Aspergillus sp.
k. Antiviral Agents
i. Several agents are available for treating viral infections
ii. Mode of Action
1. All of them act by inhibiting steps involved in viral
replication
iii. Uses
1. herpes simplex virus (HSV)
a. Type I
i. fever blisters
ii. cold sores
b. Type II
i. genital herpes
2. herpes zoster (HZV)
a. shingles
3. varicella-zoster virus (VZV)
4. influenza A and B
5. HIV
6. cytomegalovirus (CMV)
iv. Agents
1. Acyclovir - HSV, HZV
2. Ganciclovir - CMV
3. Fomiversin - CMV
4. Valacyclovir – HSV, VZV
5. Valganciclovir - CMV
6. Amantadine – Influenza A
7. Penciclovir – HSV, HZV,
8. Cidofovir - CMV
9. Rimantadine – Influenza A
10. Famciclovir - HSV, VZV
11. Foscarnet – HSV, VZV, resistant CMV
12. Oseltamivir (Tamiflu) – Influenzae A and B