Subject: Pharmacology Topic: GENERAL CONCEPTS AND PRINCIPLES IN THE CHEMOTHERAPY OF INFECTIOUS DISEASE Lecturer: Dr.

Deo Panganiban Date of Lecture: 07/08/2011 Transcriptionist: Gilbarz, Marvs, Des Pages: 5

GENERAL CONCEPTS AND PRINCIPLES IN THE CHEMOTHERAPY OF INFECTIOUS DISEASE General Principles Proper selection of antimicrobials Identity of the pathogen Site of the infection Pharmacokinetics and pharmacodynamics of the agent Potential toxicity to the patient Possible drug interactions Cost Convenience of administration Selection of an Ideal Antimicrobial Agent: A. Necessity most important (Is it really needed?) B. Susceptibility/Sensitivity of the microorganism C. Pharmacokinetic / Pharmacodynamic factors D. Host factors 1. host defense mechanisms 2. local factors (ex. presence of pus, foreign bodies) E. Age of the patient F. Genetic factors To use drugs that can go around the genetic disease G. Pregnancy Can either increase or decrease metabolism May affect the development of the baby H. Hypersensitivities/Allergies Ex. penicillin I. CNS disorders Modification of initial antimicrobial choice Patient should be monitored after initial antimicrobial was given and dosage and the kind of drug should be changed accordingly. The following are the basis for the medication of initial antimicrobial of choice: 1. Response to therapy 2. Function of major organs systems 3. More information about nature of the infection Definition of terms: Chemotherapeutic agents Drug used for the treatment Process where you administer drug for disease of disorder

Antibiotics Antibacterials Antifungal Antiviral Antiparasitic o Antimalarial o Anthelmintic o Amoebicidal Antimicrobial Destroying or inhibiting the growth of microorganisms, especially pathogenic microbes Antiseptic Preventing or arresting the growth of the microbes on living tissues Can be taken orally or applied Disinfectant A chemical that destroys vegetative forms of harmful microbes especially on fomites Sources 1. Molds or Fungi e.g. Streptomyces spp., Penicillium spp 2. Bacteria e.g. Bacillus spp. 3. Semisynthetic or Synthetic Manufacture and amplified at laboratory Factors involved in an infectious process A. Epidemiologic Considerations: 1. Transmission interaction 2. Acquisition portal of entry a. Contact b. Inhalation c. Common vehicle d. Vector-borne 3. Patient Information a. Age, Gender, Place of residence 4. Family and personal contact 5. Occupation, hobbies 6. Contact with animals 7. Travel history 8. Dietary habits B. Infectivity - ability to cause an infection C. Virulence factors - toxins, adherence factors D. Host factors

SY 2011-2012

Approach to Antimicrobial Use A. Documentation of Infection Non-specific o Symptomatology o CBC Specific o Gram stain o Cultures identify specific pathogen B. Determine Susceptibility of the Microorganism to Antimicrobial Drugs Disk Diffusion Method o provides qualitative data, hence unable to provide information of the number of bacteria that was killed o simple, inexpensive o measure zone of inhibition o to find out which antibiotic is best for the patient Broth Dilution Method o Provides a quantitative data o Inexpensive o Measures the MIC and MBC Factors which Determine Susceptibility A. Host 1. General health Healthy vs. Immunocompromised 2. Age Young and Elderly 3. Genetic Hypogammaglobulinemia 4. Concurrent disease Diabetes Obstruction o stones support poor excretion, hence increase toxicity Foreign body o urinary catheter-potential for microbial entry o Prosthetic heart valves Abscess o acid pH o Impaired circulation B. Infecting organism 1. Intracellular vs. Extracellular Neisseria Gonorrhea- goes inside your macrophages- more difficult to treat extracellular- easier to treat with antimicrobi 2. Bacterial cell permeability Gram negative bacteria has double cell wall

3. Ability to produce inactivating enzymes e.g. Beta lactamase o resistance to penicillin is d/t the production of lactamase enzymes. Newer drugs are being made (eg: Cephalosporine) 4. Affinity to binding sites C. Antimicrobial Drug 1. Concentration at site of action dose, frequency, route 2. Appropriate duration 5-10 days 3. Culture and Sensitivity 4. Bacteriostatic vs. Bactericidal Bactericidal o when the bactericidal kills the bacteria Bacteriostatic o inhibits bacterial growth and proliferation 5. Pharmacokinetic Absorption Distribution o blood brain barrier o placental barrier o Protein binding Classification of Antimicrobial Drug A. Based on Microorganism Affected Antibacterial Antifungal Antiviral Antiparasitic o Antimalarial o Anthelmentic o Amoebicidal B. Based on Chemical Structure Beta lactam Macrolides Aminoglycosides Lincosamides Tetracyclines Sulfonamides Quinolones/ Fluoroquinolones o Increase effectivity when fluoride was added to quinolone Polypeptides Miscellaneous o Chloramphenicol C. Based on Mechanism of Action a. Inhibition of cell wall synthesis Beta-lactams Cycloserine o Antibiotic given to pTB patients Bacitracin o antibiotic Vancomycin o antibiotic 2

b. Inhibition of Ribosomal Protein Synthesis RNA, DNA, nucleus of the cell Aminoglycosides Macrolides Chloramphenicol Tetracycline Lincosamides Fusidic acid c. Inhibition of Nucleic acid Synthesis Metronidazole Sulfonamides Quinolones Trimethoprim Rifampicin d. Inhibition of Cell Membrane Function Polypetides Imidazoles Polyene Antibiotics D. Based on Mode of Action a. Primarily Bactericidal Betalactams Metronidazole Aminoglycosides Quinolones Vancomycin Rifampicin Polypeptides Isoniazid b. Primarily Bacteriostatic Chloramphenicol Lincosamides Macrolides Tetracyclines Sulfonamides Trimethoprim o usually acts synergistically with sulfamethoxazole Ethambutol Bactericidal vs. Bacteriostatic Primarily Bactericidal preferred in: o immunocompromised patients o serious, life-threatening infection Primarily Bacteriostatic not absolute dependent on organism and condition

Two Main Groups of Bactercidal Drugs: 1. Concentration dependent killing rate and extent of killing increases with increasing drug concentration ratio of the AUC* to the MIC** (AUC/MIC) correlates best with efficacy of the drug e.g. Aminoglycosides, Fluoroquinolones *Area Under Curve **Minimal Inhibitory Concentration 2. Time dependent killing increasing concentration above MBC* do not result in killing no post antibiotic effect e.g. Beta lactams, Vancomycin *Minimal Bacteriostatic Concentration- 99.9% of bacterial growth is inhibited. E. Based on Spectrum of Activity a. Narrow PenicillinG Vancomycin Aztreonam Trimethoprim 3rd Gen Cephalosporins Anti-Staphylococcal Penicillins b. Intermediate Aminoglycosides Lincosamides Macrolides Sulfonamides c. Broad both covers gram(+) and gram(-) bacteria Aminopenicillins Imipenem Cephalosporins Tetracyclines Chloramphenicol F. Based on Adverse Effect or Toxic Potential a. Hypersensitivity PenicillinG Sulfonamides b. GIT Adverse Effects Chloramphenicol Quinolones Macrolides Sulfonamides Tetracyclines c. Nephrotoxic Aminoglycosides Polypeptides Vancomycin Beta lactams

d. Ototoxic Aminoglycosides Macrolides Vancomycin e. Hematologic Chloramphenicol Beta lactams Sulfonamides f. Neurotoxic Aminoglycosides Polypeptides Penicillins Hepatotoxic Rifampicin Tetracyclines Metronidazole (amoebiasis) Sulfonamides

Prophylaxis Chemoprophylaxis o giving of antimicrobial drug to a healthy person exposed to an infectious agent to prevent that person from acquiring the infection o Rifampicin for Meningococcemia o Rifamipicin + Isoniazid for pTB o Fansidar for Malaria Surgical Prophylaxis (loading dose) o prevent infectious complications in surgically traumatized areas o e.g. Bowel surgery, Ruptured acute appendicitis Immunoprophylaxis o use of vaccines o passive for immediate protection o active for long term protection Antimicrobial Combination Rationale: 1. Synergy enhanced effect e.g. Penicillin + Aminoglycosides for Pseudomonas 2. Extended Antimicrobial Spectrum Trimethoprim + Sulfamethoxazole Amoxicillin + Clavulanic acid 3. Prevention of Resistance Rifampicin +Isoniazid 4. Treatment of Mixed Infection Intra-abdominal Infection 5. Decreased Drug Toxicity Aminoglycosides + Penicillin Mechanisms of Resistance 1. Enzymatic inactivation or modification Beta lactams Aminoglycosides 2. Altered target site: decreased affinity e.g. Methicillin-resistant Staphylococci 3. Altered permeability of bacterial cell wall Beta lactams Fluoroquinolones 4. Production of Multi Drug Resistant MDR pumps on the cell wall alternate pathway bypassing antimicrobial action Sulfonamides Trimethorpim

g.

Empiric Therapy giving of antimicrobial before actual identification or isolation of infecting microorganism based on Epidemiologic data e.g. Community-acquiredpneumonia, Urinary tract infection Selective Toxicity ability of the drug to kill the invading microorganism without harming the host cells drugs are intended to selectively affect processes in the microbial cells without affecting counterpart processes in mammalian cells e.g. Chloramphenicol o affects 70S ribosomes Sulfonamides o inhibit bacterial Folic Acid synthesis Post Antibiotic Effect (PAE) persistent suppression of bacterial growth after limited exposure to antimicrobial Mechanisms: o Post-antibiotic leukocyte enhancement o sub-inhibitory concentration may make bacteria more susceptible to phagocytic and bactericidal action of neutrophils Clinical Significance: o Allows less frequent administration Drugs with PAE vs. gram (-): o Aminoglycosides o Imipenem o Chloramphenicol o Quinolones o Rifampicin

Adverse Effects 1. Hypersensitivity reaction e.g. Beta lactams, Sulfonamides 2. Biologic Alteration of normal flora producing: o Superinfection/ Suprainfection Candidiasis o Antibiotic-associated Enterocolitis Ampicillin Tetracyclines Clindamycin /Lincomycin

3. Direct Toxic Effects Unpleasant o abdominal discomfort o Dizziness o Nausea and vomiting o Diarrhea o Tooth discoloration Severe o hearing loss, o Nephrotoxicity o Bone and tooth malformation o Inhibit antibody production Life threatening respiratory paralysis o Seizures

--------------------------------------------------------------------------------------------------------------------------------------------End of transcription This is pretty much a copy paste of docs lecture. Happy memorizing! Unedited!!! Also read your lab manual(didactics) Then you call on me and come to pray to me, and I will hear you. You will seek me and find me. When you seek, seek Me with all your heart. Jeremiah 29:12