Download Antimicrobials and Resistance

Antimicrobial Agents
&
Mechanisms of Resistance
BY
Prof. DR. Zainalabideen A. Abdulla,
DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)
Learning Objectives
Chemotherapeutic agents
Any drug used to treat any condition or disease
Antimicrobial agents
Chemotherapeutic agents used to treat infectious
diseases:
- Anti-Bacterial
- Anti-Viral
- Anti-Fungal
- Anti-Protozoal
Antibiotic (AB)
- A substance produced by a microorganism that is
effective in killing or inhibiting the growth of other
organisms
- Anti-Bacterial
Examples:
- Mould-produced: Erythromycin, Chloramphenicol
- Bacteria-produced: Penicillin, Cephalosporin
(mainly soil bacteria)
Types of Antibiotics/Antimicrobials
1. Natural AB
e.g. Peniciilin G
2. Semisynthetic AB,
e.g. Modified AB (Ampicillin, Carbenicillin)
3. Synthetic Antimicrobials
e.g. Monobactam (Aztreonam)
Antibacterial Agents
Bacteriostatic: Inhibit growth of bacteria
- Should NOT be used in immunocompromised or leukopenic patients
Bactericidal: Kill bacteria
Selective toxicity: Affect microorganisms NOT
human cells
Cont./…
Antibacterial Agents
Narrow-spectrum antibiotic: Destroy (affect) either
gram positive or gram negative bacteria
- Examples: Vancomycin: G+
Colistin
: GBroad spectrum antibiotic: Destroy (affect) both
gram positive and gram negative bacteria
- Examples: Ampicillin
Chloramphenicol
Tetracycline
Competitive inhibitors
- Example Sulfonamide
- See the Figure
- Inhibition of Nucleic Acid synthesis
Inhibition of cell wall synthesis
- Interfere with synthesis and cross-linking
of peptidoglycan
- Human cells NOT affected; WHY?
Penicillins
- Beta-lactam drugs
- Actively dividing bacteria
- Bactericidal
- Natural penicillin:
• Penicillin-G, Penicillin-V
• Against: G+ such as Strep., some anaerobes,
Spirochetes
G-: N. meningitidis, H. influenzae
-Aminopenicillin & Extended: G- infection
Cephalosporins
1. First generation: G+
2. Second generation: Increased activity G3. Third generation: Greater G- & Pseudomonas
4. Fourth generation: G+ & G- ; P. aeruginosa
5. Fifth generation (e.g. Ceftaroline) G+
including methicillin-resistant Staph. and G-
Monobactams
- Beta-lactam drug
- Active against gram negative rods
Not against gram positive bacteria
Not against anaerobes
Example: Aztreonam
Carbapenems
- Beta lactam drug
- Active against most G+, G-, and anaerobes
- Examples
• Imipenem: Inactivated by dihydropeptidase
(renal tubules); protected by Cilastatin
• Meropenem: Not inactivated by DHP enzyme
• Ertapenem: Not P. aeruginosa, long acting
Damage to cell membrane
Tetracyclines
- Broad-spectrum
- Action on ribosome (inhibit protein synthesis)
- Bacteriostatic
- Effective against:
• G+ and G- bacteria
• Chlamydia
• Mycoplasma
• Rickettsias
• Vibrio cholera
• Spirochete (Borrelia, Treponema pallidum)
Aminoglycosides
- Broad-spectrum (against many G-, some G+,
NOT anaerobes, WHY?):
• Enterobacteriaceae
• V. cholera
• P. aeruginosa
- Bactericidal
- Inhibit protein synthesis
- Ototoxic, Nephrotoxic
Macrolides
- Inhibit protein synthesis
- • Bacteriostatic (low doses)
• Bactericidal (Higher doses)
- Effective against:
. Many G+, some G- bacteria
. Chlamydia
. Mycoplasma
. T. pallidum
. Legionella
Fluoroquinolones
- Bactericidal
- Inhibit DNA synthesis
- Example: Ciprofloxacin; effective against:
. Enterobacteriaceae
. P. aeruginosa
Multidrug therapy
- To kill all bacteria, and to prevent resistance
- Example:
Mycobacterium tuberculosis:
(isoniazid + rifampin + pyrazinamide +
ethambutol)
Synergism
Degree of killing that is far greater than that
achieved by either drug alone or the sum of
both
Example: Co-trimoxazole (Trimethoprim +
sulfamethoxazole)
Antagonism
Degree of killing that is less than that achieved
by either drug alone
Example: Penicillin + Tetracycline (WHY ?)
Antifungal Agents
- Toxic to patients (WHY?)
- Mechanism of action:
1. Binding cell membrane sterol
e.g. Nystatin, Amphotericin-B
2. Interfere with sterol synthesis
e.g. Clotrimazole, miconazole
3. Blocking mitosis, or nucleic acid synthesis
e.g. Griseofulvin, 5-flucytosine
Antiprotozoal Agents
- Toxic to human cells (WHY?)
- Mechanism of action
1. Interfere with DNA and RNA synthesis
e.g. Chloroquine, pentamidine, quinacrine
2. Interfere with protozoal metabolism
e.g. Metronidazole (Flagyl)
Antiviral Agents
- Few agents available
- WHY?- see your textbook
- Examples:
• Anti-HIV: Zidovudine (azidothymidine “AZT”);
1989
Drug resistance
- Drug resistant bacteria (Superbugs)
- Superbugs USUALLY Multidrug Resistant
- Viruses/HIV, Fungi, Protozoa, Helminthes
(Also, Multidrug Resistant)
- See the Table
Important Resistant Bacteria
• MRSA, MRSE
• VISA, VRSA;
What to do?
• VRE (UTI)
• P. aeruginosa
• Clostridium difficile
• Acinetobacter baumanni
• Klebsiella pneumonia
• M. tuberculosis (MDR-TB)
Mechanisms of bacterial resistance
- Lack specific target, e.g. M. pneumoniae
- Intrinsic resistance: Natural
- Acquired resistance: Changed/Acquired
- FOUR mechanisms (See the Table)
- Resistance Factor (R- Factor); Conjugation
- MDR Pumps (Transporter/ Efflux Pump)
Beta-Lactamases
- Beta-lactam antibiotics with Beta-lactam ring
- Two types:
1. Penicillinases
2. Cephalosporinases
- Some bacteria produce one or both enzymes
Prevention of Beta-lactamase action
Combine antibiotics with Inhibitors:
Examples:
Clavulanic acid + Amoxicillin = Augmentin
Clavulanic Acid + Ticarcillin = Timentin
Sulbactam + Ampicillin = Unasyn
Tazobactam + Piperacillin = Zosyn
Strategies against drug resistance
- Education, Prudent use
- Proper prescription (most unnecessary)
- First: Narrow spectrum & inexpensive
- Complete the full coarse as prescribed
- No need for prophylactic unless by clinician
- Good infection control and prevention
Empiric therapy
To “ guess”; “educated guess”:
• Pocket chart/Antibiogram (Clinical Microbiology Lab)
• Allergy
• Age
• Pregnancy
• Inpatients
• Site of infection, e.g. Brain, bladder?
• Drug cross-reaction
• Toxic side effects
• Immune status
• Cost
Undesirable effects of antimicrobial agents
• Selecting for drug-resistant organisms
• Allergy
• Toxic, e.g. Chloramphenicol Aplastic Anemia
Streptomycin
Deafness
• Superinfection “population explosion”
- By opportunistic or secondary invaders
- Example: C. difficile antibiotic-associated/
pseudomembranous colitis
Candida albicans Yeast vaginitis