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 immuno- compromised 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 : G- Broad 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 G- 3. 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