-PHA LEC - LE2- 03 - Principles of Antimicrobial Therapy (v2).pdf

PHARMACOLOGY LECTURE 03 - Principles of Antimicrobial LE Therapy...

PHARMACOLOGY LECTURE 03 - Principles of Antimicrobial LE Therapy 02 Ronaldo Marcelo Macaraig TABLE OF CONTENTS “The God of War hates those who hesitate” -Euripides, I. INTRODUCTION B. Based on Mode of Action 480-406 B.C. II. DEFINITION OF TERMS C. Based on Spectrum of → We should never delay treatment when we have an A. Chemotherapy Activity infection B. Antibiotics D. Based on Toxic/Adverse “The essence of war is violence. Moderation in war is C. Antimicrobials Effect Potential imbecility.” -British Sea Lord John Fisher D. Superinfections VII. REASONS OF USING → If we fall to an infection, the violence is on us. If we are E. Iatrogenesis COMBINATION OF winning in an infection, we bring violence to the F. Nosocomial Infections ANTIMICROBIAL G.Selective Toxicity AGENTS infectious organism.” H. Post-antibiotic Effect A. Synergy I. Mutant-Preventing B. Extended Antimicrobial II. DEFINITION OF TERMS Concentration Spectrum A. CHEMOTHERAPY III. FACTORS TO C. Prevention of Resistance The use of synthetic chemicals to destroy infective agents CONSIDER IN THE D. Treatment of Mixed Refers to treatment of disease by chemicals that kill cells, RATIONAL CHOICE OF Infection ANTIMICROBIALS E. Treatment of Severe both good and bad, but specifically those of microorganisms A. Factors Related to the Infection or cancerous tumors Infecting (Etiologic) F. Disadvantages of Organism Antimicrobial B. ANTIBIOTICS B. Epidemiological Factors Combinations Greek: anti – against; bios – life C. Factors Related to the VIII. ANTIMICROBIAL Technically, substances produced by one microorganism Host PROPHYLAXIS IV. WEAPONS AND IX. REASONS FOR that kill, or prevent the growth, of another microorganism AMMUNITION AGAINST ANTIMICROBIAL The role of using one microorganism against another INFECTION FAILURE microorganism was an accidental discovery. V. MOLECULAR BASIS OF X. RATIONAL → In 1928, Alexander Fleming observed that a mold on a CHEMOTHERAPY THERAPEUTIC Staphylococcus culture plate created a bacteria-free VI. GENERAL STRATEGY FOR circle around itself. CLASSIFICATION OF PROVEN OR → Penicillium fungus prevented the growth of ANTIMICROBIALS SUSPECTED Staphylococcus (another living organism) bacteria in the A. Based on Mechanism of INFECTIOUS DISEASES Action XI. REVIEW QUESTIONS uncovered petri dish XII. FORMATIVE QUIZ → Further experiments showed that a mold culture prevented the growth of Staphylococci, even when LEGEND diluted 800 times ⭐ 💬 📖 📋 IMPORTANT LECTURE BOOK PREVIOUS TRANS The term “Antibiotic” was coined by Nobel laureate Selman Abraham Waksman → A researcher who discovered other antibiotics. His LEARNING OBJECTIVES research prompted the discovery of Streptomycin, and To define the terminology related to antimicrobial therapy. several other antibiotics such as actinomycin, clavacin, To discuss the principles involved in the rational choice of streptothricin, grisein, neomycin, fracidin, candicidin, antimicrobials. candid, and others. To illustrate these principles by way of common clinical situations that the student will most likely encounter. C. ANTIMICROBIALS To integrate these principles with knowledge acquired in the different basic medical sciences. Antimicrobial VS Antibiotics Antimicrobials I. INTRODUCTION → Refers to all agents against microorganisms “The art of war is of vital importance to the State. It is a Antibiotic matter of life and death, a road to safety or to ruin. → Derived from microorganisms Therefore, it is a subject that must be thoroughly studied.” - → An antibiotic is an antimicrobial Sun Tzu VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 1 of 14 TE | Dela Paz  → Synthetic agents for infections are also antimicrobials but Widely used for flus, colds, and other are not antibiotics because they are not derived from bacterial infections living organisms. → Stimulates immune system → ↑ WBC count → Effective when taken over long periods of time Antibacterial and antifungal properties → Often used for the treatment of sinus and ear infections, sore throats, and Goldenseal vaginal infections → Lowers blood sugar levels → Contraindicated in pregnancy Figure 1. Toxicity and Effectiveness of Natural, Semi-synthetic, Antiseptic, antibiotic, and antiviral and Synthetic Antimicrobials [Lecture PPT] Myrrh properties Oldest and most controversial natural 📋 Natural Antimicrobials Mainly fungal sources antibiotic → Less effective, but have more toxic elements in them → Very common during the 19th century for bacterial infections 📋 Semi-synthetic Antimicrobials Chemically-altered natural compound Documented to be very effective against fungal infections like ringworm 📋 Synthetic Antimicrobials Chemically designed in the laboratory Has ability to inhibit the growth of → Aim in developing synthetic antimicrobials is to develop bacteria and viruses effective drugs that have less toxicities Colloidal silver Very popular → Celebrities like Gwyneth Paltrow Natural VS Synthetic Antibiotics swear by colloidal silver as a germ-fighting miracle cure Natural antibiotics in our daily life which have very little or no → According to Mayo Clinic, colloidal side effects silver “isn’t considered safe or effective” Table 1. Summary of Natural Antibiotics and their Features Adverse effect: Argyria Natural Antibiotic → Would turn user color blue Effective on various microbes including Cathelicidins Olive leaf extract viruses → During sickness human body can Has antifungal property create their own natural antibiotics Garlic Antiviral agent which are basically natural peptides Can boost immunity → Distributed in tissue and WBC Natural antibiotics → Have the ability to inhibit microbial Work against certain strains of oral in mammals bacteria growth and fight infections Green tea Human Cathelicidins Active ingredient: epigallocatechin gallate (EGCG) → Surround the bacterial cell and Has the ability to kill 96% of all cause leakage of intracellular Pneumococcus bacteria, 92% of all contents Neisseria, Proteus, and Staphylococcus bacteria In time, discovered that it has adverse effects but has definite antimicrobial Oregano oil properties Can eliminate 83% of Streptococcus and 78% of Enterococcus, which are linked to rheumatic fever, anorexia, scarlet fever, toxic shock syndrome, wound infection, cystitis, and strep throat Popular in other countries for its viral Echinacea and antibacterial infections VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 2 of 14 TE | Dela Paz  📋 Occurs simultaneously with the initial infection Superinfection → There is only one infectious agent at the start. But as you give an antimicrobial, it destroys the normal flora, hence, another microorganism can invade and cause another 📋 infection. Develops following the initial infection Steps in a Superinfection Figure 2. Human cathelicidins surrounding the bacterial cell membrane resulting to leakage of intracellular contents [Lecture PPT] Synthetic Antibiotics commonly used in the clinics: → Sulfonamides → Quinolones → Nitrofurans → Isoniazid → Methenamine Figure 4. Development of superinfection [Lecture PPT] D. SUPERINFECTIONS Infection caused by alteration of normal flora due to the (A) Initially, there are numerous normal flora (blue) and a few intake of antimicrobials microorganisms that could potentially cause an infection → Antimicrobials will kill or prevent the growth of bacteria. 📋 (red). However, in (A) the normal flora dominates. However, the normal bacterial flora of our body may also In a healthy individual, the normal flora (blue) is be affected. An unwanted group of bacteria will come in dominant and maintains homeostasis and while a because of an alteration of this normal flora causing a potential pathogen (red) may coexist, it is kept in check superinfection. (B) If given an antimicrobial, the normal flora may be Infection following a previous infection, especially when destroyed. However the pathogenic or the potentially caused by microorganisms that are resistant or have pathogenic bacteria may not be destroyed. Giving the become resistant to the antibiotics used earlier 📋 potentially pathogenic flora an opportunity to grow. A sick patient taking a broad-spectrum antimicrobial Coinfection VS Superinfection would cause the destruction of the normal flora, and the pathogen is given an opportunity to grow if it is resistant to the drug. (C) Pathogenic flora becomes the dominant flora causing a 📋 difficult infection for the patient. Predominant pathogenic flora causes a superinfection on top of the original infection Figure 3. Types of Dual Infection [Lecture PPT] 📋 Difference between the two is temporal in nature Coinfection → Two infectious organisms are already causing a disease Figure 5. Oral thrush in a orthopedic patient [Lecture PPT] at the time the patient comes to you VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 3 of 14 TE | Dela Paz 📋A superinfection caused by an antibiotic given for the → Infection that may be inadvertently caused by a patient’s condition that leads to the reduction of the normal physician or surgeon or by a medical or surgical 📋 flora of the oral cavity, causing the overgrowth of Candida treatment or a diagnostic procedure Adverse drug reactions and development of resistance to antimicrobials are bound to happen due to multiple antimicrobial drug prescriptions to a single patient. F. NOSOCOMIAL INFECTION Hospital-acquired infection Not present or were incubating at the time of admittance to a healthcare facility May manifest after discharge → A few hours or a few days later, a patient may have another infection which is attributed to the hospital where he acquired the hospital flora Figure 6. Clindamycin [Lecture PPT] Statistics → Occur in: ◼ About 5% of all persons admitted to acute care hospitals in the US ◼ 8% of persons in long-term care facilities ◼ Patients who undergo surgical procedures (higher incidence) ◼ Among healthy infants, around 1-2 newborn patients may develop an infection. ◼ If a patient is placed in the neonatal ICU the infection rate goes up from 10% to 20% due to different personnel handling the patient. Figure 7. Endoscopic view of Pseudomembranous colitis [Lecture Significance PPT] → More difficult to prevent and treat Clindamycin is used for gram-positive and anaerobic ◼ Difficult to prevent, because it may come from the 📋 infections. It has no coverage for Clostridium difficile. procedures given for the treatment of the patient When using clindamycin on a patient, it is important to check ◼ E.g. bladder cystitis (urinary bladder infection) from a whether they develop diarrhea, abdominal pain, or fever. nosocomial pathogen may be secondary to insertion Pseudomembranous colitis of urinary catheter. 📋 → Overgrowth of Clostridium sp. → Signs and symptoms are unpredictable 📋 → Whitish plaques in the large intestine Signs and symptoms may not be those that you read This may have occurred secondary to the suppression of in textbooks, making them difficult to predict. the normal flora of the colon → More resistant to cure than community-acquired 📋 infections E. IATROGENESIS Results to prolonged hospital stays, thus higher cost Inadvertent and preventable induction of a disease or of medication and additional procedures complication by the medical treatment or procedures of a → These microorganisms are already resistant to the physician or surgeon antimicrobials that are being given in the hospital Examples of iatrogenesis: G. SELECTIVE TOXICITY 💬 → Medical error, poor prescription handwriting Correct prescription writing is emphasized in The antimicrobial should be harmful to the parasite, not to pharmacology the host → Negligence or faulty procedures Achieves antimicrobial killing of the infecting organism → Prescription drug interaction without damaging the human host → Adverse effects of prescription drugs Unique targets harmful to microorganisms: → Over-use of drugs leading to antibiotic resistance in → Cell wall enzymes bacteria ◼ Bacterial cell walls are different from human cell walls → Nosocomial infection → Bacterial ribosomes → Blood transfusion reaction ◼ Humans: 80S Iatrogenic infection ◼ Bacteria: 70S → Enzymes required for DNA synthesis and reproduction → Competitive antagonism of metabolic pathways VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 4 of 14 TE | Dela Paz  → Clindamycin → Ketolides → Macrolides → Rifampicin → Quinupristin/dalfopristin (probably longest PAE) Advantages of Post Antibiotic Effect: → Can extend the dosing interval ◼ Example: If an antimicrobial is usually given 4 times a day, PAE can reduce the interval to 1 or 2 times a day → Reduced cost → Less toxicity since it is given less often → Better compliance among outpatients receiving antimicrobial therapy I. MUTANT-PREVENTING CONCENTRATION (MPC) Drug concentration that prevents the growth of first-step resistant mutants Figure 8. Summary antibiotic toxicity [Lecture PPT] H. POST-ANTIBIOTIC EFFECT (PAE) Persistent suppression of bacterial growth after a brief exposure (1-2 hours) of bacteria to an antibiotic even in the absence of host defense mechanisms The killing action of an antimicrobial continues even when its plasma levels have declined below measurable levels Period of time after complete removal of an antibiotic during which there is no growth of the target organism Figure 10. Antibiotic conc. (mg/dL) vs. time (hrs) [Lecture PPT] → MIC: lower level of Area B is the MIC to prevent growth of infectious bacteria → MPC: upper level of Area B is needed to prevent development of first-step resistant mutants, which is what we want in Area C III. FACTORS TO CONSIDER IN THE RATIONAL CHOICE OF ANTIMICROBIALS A. FACTORS RELATED TO THE INFECTING (ETIOLOGIC) [Lecture PPT] Figure 9. Antibiotic conc. plotted vs. time graph ORGANISMS Minimum inhibitory concentration (MIC) Intracellular VS Extracellular Activity → Lowest concentration of the antimicrobial which prevents Example: M. tuberculosis exists in 3 different locations in the visible growth of a bacterium or bacteria human lung subpopulations: → Area above the MIC means that at these concentrations, → Inside macrophages (intracellular) there is effective killing or prevention of growth → Inside cavitary lesions (extracellular) → However, for some antimicrobials, even if blood levels → In caseations (extracellular) are already below the MIC some may continue the killing of bacteria (post-antibiotic effect) ◼ Some antimicrobials have already reached the tissues Antimicrobials that exhibit PAE (mainly seen in drugs which have concentration-dependent kill characteristics): → Aminoglycosides Figure 11. TB [Lecture PPT] → Streptogramins → Clinical significance: → Quinolones ◼ Different antimicrobials will be more effective for → Tetracyclines macrophages, cavitary lesions, and caseations VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 5 of 14 TE | Dela Paz  → Anti-TB agents: → Outer membrane is protective, with high level of ◼ First line lipopolysaccharide (LPS) content – Pyrazinamide → Distinctive feature: presence of a double membrane Active against bacilli inside macrophages surrounding each bacterial cell (intracellular) ◼ Unique outer membrane which excludes certain Can be discontinued after 2 months drugs and antibiotics from penetrating the cell which – Isoniazid and rifampicin partially explains why gram-negatives are generally Active against bacilli inside macrophages, more resistant to antibiotics than gram-positives cavitary lesions, and caseations Can be given for 6 months (min. duration of Ability to Produce Inactivating Enzymes treatment) Beta lactamases ◼ Formerly first line → Inactivate beta-lactam rings of penicillins, – Streptomycin cephalosporins, etc. Active against extracellular bacilli Acetyltransferases Effective against bacilli in cavitary walls → Inactivate chloramphenicol and linezolid Problem: resistance occurs early, Kininases and other enzymes discontinued after 2 months → Inactivate aminoglycosides Infectivity The characteristic of a disease agent that embodies capability of entering, surviving in, and multiplying in a susceptible host Prevention is important (e.g. soap, alcohol) Virulence Factors Capsule → More virulent than non-encapsulated strains → Ex: Haemophilus Influenzae Type b ◼ More virulent compared to other H. influenzae types ⭐ ◼ Prevention: HiB vaccine If an organism is very virulent, prevention becomes an important aspect of management Figure 12. Activity of anti-TB drugs according to the metabolic Bacterial proteins with enzymatic activity status of the bacilli [Lecture PPT] → Beta-lactamase: destruction of beta-lactam ring of Penicillin Bacterial Cell Wall Permeability → Protease and Neuraminidase: antiviral agents (e.g HIV) Gram-positive, gram-negative, and acid-fast bacterial cell → Hyaluronidase walls are different → Elastase → Collagenase Exotoxins → Vaccines have been developed against exotoxins that cause: ◼ Diphtheria ◼ Cholera ◼ Tetanus ◼ Botulism Endotoxins ⭐ → Lipopolysaccharide produced by gram-negative bacteria Causes morbidity in gram-negative sepsis B. EPIDEMIOLOGICAL FACTORS Figure 13. Differences between gram-positive and Transmission gram-negative bacilli [Lecture PPT] Interaction between an infectious agent and a susceptible Gram-positive: host → Peptidoglycan complex is thick and multilayered Exogenous- external to the host (e.g COVID-19) Gram-negative → Prevention requires a high standard of hygiene VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 6 of 14 TE | Dela Paz  Endogenous- already present in the body but is dormant ◼ Community-acquired Pneumonia in children (6 → Result from medical procedures where a patient is months- 3 years old): S. pneumoniae and H. exposed to their own microbial flora influenzae → Prevention requires a multi-disciplinary approach especially in immunocompromised individuals Identification of Organism: Pathognomonic Clinical Presentation for a Few Organisms Routes of Acquisition Contact → Gonorrhea, Syphilis: Intercourse ◼ Preventions: safe sex, fidelity, celibacy → Carbuncle, folliculitis: Contaminated razor blade, etc → Measles, common cold: Droplets ◼ Avoid being in the same room as the patient – Highly contagious and airborne condition ◼ Characteristics of measles: Koplik spots in buccal mucosa ◼ Measles rashes start at the hairline and go down to Figure 15. Skin rash [Lecture PPT] the extremities Meningococcal Septicemia → Prominent rash seen in the lower extremities and other ⭐ parts of the body If a patient manifests this rash and other meningeal signs and symptoms, it is considered an emergency and antibiotic treatment should be given immediately → For hospital staff that was exposed to this patient, prophylactic antibiotic (e.g Rifampicin) should be given Shotgun therapy has no role in rational therapeutics Figure 14. Koplik spots in the buccal mucosa and rashes seen → Actual etiologic agent is unknown so several antibiotics in Measles [Lecture PPT] are given in order to hit gram positive, gram negative and anaerobes Inhalational → Dangerous because these combination of antimicrobials → Tuberculosis can destroy the normal flora → Can be transmitted in crowded areas Common-vehicle Patient Information → AIDS and Hepatitis B: IV needle ◼ Drug dependents who use the same IV needle may Good history and physical examination be susceptible to AIDS → Gives pertinent information about the status of a patient ◼ Do not recap used needles → Salmonella and Hepatitis A: Ingestion SUMMARY OF EPIDEMIOLOGICAL FACTORS 📋 ◼ Common vehicle is food handled by a patient Transmission Vector-borne → Exogenous: external to host → Malaria (arthropod-borne) → Endogenous: from a previously normal flora ◼ Prevention: mosquito nets Acquisition → Contact: gonorrhea, syphilis, measles Documentation of an Infection → Inhalation: TB ⭐ Antimicrobial therapy should NOT be chosen on the basis of → Common vehicle: Salmonella, Hepa A/B, AIDS → Vector borne: malaria nonspecific methods of diagnosis and “probabilities” alone. Documentation of an Infection This can cause more harm than good Specimen Identification Specific Methods: Patient Information → Culture and Sensitivity Testing ◼ Sensitivity testing will tell you what are the effective drugs against the cultured organism C. FACTORS RELATED TO THE HOST → Gram stain General Health ◼ Determine if an organism is gram positive or gram Severely malnourished individual negative → Antibiotics alone cannot give the optimal treatment → Most common etiologic agent causing the infection needed ◼ Urinary Tract Infection: E.coli → Nutritional status must be built ◼ Community-acquired Pneumonia: S. pneumoniae Obese individual VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 7 of 14 TE | Dela Paz  → Some drugs which are lipophilic, may stay in the adipose ◼ Available in clinics but not many parents know of it or tissue for a longer time are hesitant In geriatric patients: may assume that their livers and Age kidneys no longer function as they did at young adult ages Ophthalmitis in the pediatric age group may be a possible → metabolism and excretion of drugs is affected gonococcal infection in the mother Credé’s prophylaxis Genetic Factors → Antibiotic given to the pediatric age group, done by Play a role in the choice of antimicrobials washing the newborn’s eyes with 2% silver nitrate For example, the following are contraindicated in patients solution (or efficacious antimicrobial) with G6PD Deficiency: → Protect against neonatal conjunctivitis caused by N. → Quinolones gonorrhoeae → Sulfonamides and sulfones → Chloramphenicol → Chloroquine (anti malarial) → Furazolidone → Proguanil (antimalarial) → Diaminopyrimidines Drug Acetylation: Fast vs. Slow → Isoniazid ◼ Asians are fast acetylators → metabolize the drug faster ◼ Caucasians are more likely slow acetylators → Figure 16. Gonococcal ophthalmia [Lecture PPT] continuous administration can result in drug accumulation and toxicity. Roseola Infantum → Dapsone → After fever, the patient develops a rash which is NOT Concurrent Disease/s treated by antibiotics → E.g. Hepatic cirrhosis or chronic kidney disease → drugs ◼ Note: viral infections are not treated with will be poorly metabolized or excreted antimicrobials; most viral infections are self-limiting → Exanthem subitum, sixth disease, baby measles Pregnancy Generally safe → Penicillins → Cephalosporins → Macrolides (except clarithromycin) Unsafe → Aminoglycosides → Imipenem → Quinolones Figure 17. Roseola infantum [Lecture PPT] → Tetracyclines → Etiology: human herpesvirus (HHV6 & HHV7) → Sulfonamids (third trimester) Tetanus neonatorum Drug Allergy → Position of a patient with spasms (trismus) Recall lecture on ADRs → once a patient is suspected to → Tetanus vaccines are given to the mother while pregnant have a drug allergy, we must NOT give the drug again. to prevent this High index of suspicion is important and already enough for ◼ Protective for the infant us not to prescribe. IV. WEAPONS AND AMMUNITION AGAINST INFECTIOUS ORGANISMS Main weapons: Antimicrobials → Weapons of mass destruction as they kill many organisms, both infecting organisms and normal flora. Figure 18. Tetanus neonatorum with trismus [Lecture PPT] → Understanding this is helpful in preventing superinfections Vaccine preventable diseases: → Less common: Measles, Diphtheria, Mumps, Rubella (German Measles) → More common: Varicella (Chicken pox) VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 8 of 14 TE | Dela Paz  V. MOLECULAR BASIS OF CHEMOTHERAPY Table 2. Ribosomal Protein Synthesis Inhibitors[2025📋] Selective toxicity: where we target the invading organisms 23S of 50S 50S 30S but not the host. Oxazolidinones Macrolides Aminoglycoside Potential targets: Lincosamides Erythromycin Tetracycline → Most efficient: Biochemical differences between the Chloramphenicol Azithromycin Glycylcycline organism/bacteria and host Streptogramin ◼ Class II and Class III biochemical reactions in most Fusidic Acid antimicrobial drugs Clindamycin Targeted Biochemical Reactions: → Class II: used to make small molecules, e.g. amino acids, nucleotides, etc. (causes non-production of essential amino acids, growth factors, vitamins) ◼ INHIBITED by: folate antagonists, pyrimidine and pure analogues ◼ If bacteria cannot produce this, they cannot replicate and will die → Class III: small molecules build larger molecules, e.g. proteins, nucleic acids, peptidoglycan (in bacteria) Figure 20. (L) The 50S Ribosome (purple circle) composed of ◼ E.g. penicillin attacks the pg layer of bacteria, which the 23S Sub Subunit, 5S Sub Subunit, and 34 other proteins; ⭐ human host cells do not possess (R) Red arrow on the right shows an Aminoglycoside agent; Class I (e.g. Krebs Cycle) is NOT targeted as it is used Red arrow below shows an Aminoglycoside acting on the 30S commonly by both humans and bacteria ribosomal subunit[Lecturer] ◼ An antimicrobial targeting Class I would also affect the human host cell 📋 RIBOSOMAL PROTEIN SYNTHESIS INHIBITORS MNEMONICS VI. GENERAL CLASSIFICATION OF ANTIMICROBIALS Buy AT 30 : 30S subunit inhibitors A. BASED ON MECHANISM OF ACTION → Aminoglycosides (cidal) → Tetracyclines (static) Inhibitors of Cell Wall Synthesis CCEL (sell_ at 50 : 50 S subunit inhibitors Examples: → Chloramphenicol (static) → Beta lactams (penicillins, cephalosporins, penems, etc.) → Clindamycin (static) → Glycopeptides (vancomycin) → Erythromycin (macrolides, static) → Bacitracin → Lincosamides (variable) → Cycloserine It is important to know the different components of the cell Inhibitors of Nucleic Acid Synthesis wall in developing an antimicrobial By inhibiting nucleic acid synthesis, there is no formation of DNA or RNA → no bacterial replication → Examples: ◼ Quinolones ◼ Rifampicin ◼ Imidazoles Inhibitors of Cell Membrane Function Cause leakage of intracellular compounds by acting on the cell membrane → Examples ◼ Imidazoles ◼ Polyene antibiotics - bind to well wall sterols Figure 19. Comparisons of bacterial envelopes [Lecture PPT] – Nystatin – Amphotericin B Inhibitors of Ribosomal Protein Synthesis ◼ Polymyxin 50s subunit: macrolides (erythromycin), fusidic acid ◼ Daptomycin → At the 23s ribosomal RNA of 50s subunit: oxazolidinones, lincosamides, chloramphenicol Production of Antimetabolites 30s subunit: aminoglycoside Take advantage of ta bacterial weakness: they cannot absorb folic acid from the environment and must synthesize their own VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 9 of 14 TE | Dela Paz  → Folic acid: Vitamin B complex, readily available in fruits ◼ Tetracyclines and vegetables ◼ Trimethoprim → Examples: Antagonistic effect of cidal-static drug combinations are ◼ Trimethoprim: inhibits Dihydrofolate reductase demonstrated in in vivo studies ◼ Sulfamethoxazole: sulfonamide that inhibits → Avoid giving combination of cidal-static drugs at the Dihydropteroate synthetase same time ◼ Cotrimoxazole: Trimethoprim + Sulfamethoxazole → If it cannot be avoided, given an interval of two (2) hours – Exhibits a 2-step inhibition in the synthesis of folic between each drug acid ⭐ C. BASED ON SPECTRUM OF ACTIVITY Suggestion for appropriate antimicrobial drug depends on the clinical situation Narrow - spares many of the normal flora in the human body → Penicillin G - for gram positives and some anaerobes → Aztreonam - for gram negatives, almost no effect on gram positives → Vancomycin - for gram positive cocci → Trimethoprim - for gram negatives Figure 21. Pathway of Folic Acid synthesis. Inability to produce → Third generation Cephalosporins - for gram negatives folic acid hinders synthesis of purine, thus, DNA synthesis [Lecturer] → Antistaphylococcal Penicillins - for gram positives Intermediate Production of Nucleic Acid Analogs → Aminoglycosides Antiviral agents that act as nucleic acid analogs → Lincosamides → Analog: structurally similar to a real nucleic acid even if → Macrolides it’s NOT → no correct DNA and replication process → Sulfonamides Examples: Broad - more rational if there is no access to a laboratory → Zidovudine → For gram positives, gram negatives, and some → Ganciclovir anaerobes → Acyclovir → Aminopenicillins ◼ analog of purine guanosine ◼ Amoxicillin → Vidarabine → Chloramphenicol → Tetracyclines → Second generation cephalosporins → Imipenem D. BASED ON TOXIC/ADVERSE EFFECT POTENTIAL Hypersensitivity reaction Figure 22. Acyclovir as an analog of guanosine [Lecture PPT] → Beta lactams – Penicillins, cephalosporins B. BASED ON MODE OF ACTION* → Sulfonamides Microbicidal - killing action ◼ On a per use basis, sulfonamides may have greater → Beta lactams or equal hypersensitivity reactions as beta lactams → Quinolones when taken by your patients → Aminoglycosides Nephrotoxicity → Rifampicin ◼ Aminoglycosides → Polypeptides ◼ Glycopeptides (Vancomycin) → Glycopeptides (vancomycin) ◼ Tetracycline Primarily Microbiostatic ◼ Polymyxin → Do not kill but inhibit growth and replication of ◼ Cephaloridine microorganisms → cannot produce widespread infection ◼ Be especially careful when giving aminoglycosides, → Static agents can only be given to patients with a normal glycopeptides, and tetracyclines because of high immune system nephrotoxic potentials → Examples: Ototoxicity ◼ Chloramphenicol ◼ Aminoglycosides ◼ Macrolides ◼ Macrolides ◼ Sulfonamides ◼ Vancomycin ◼ Lincosamides Hepatotoxicity VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 10 of 14 TE | Dela Paz  →Isoniazid 💬 “If I were the physician treating these patients with these →Rifampicin illnesses, I would not be comfortable if I use only one →Pyrazinamide - most hepatotoxic antimicrobial. So, I would want to extend the spectrum of →Tetracycline antimicrobial coverage.“ →Erythromycin estolate - estolate salts are the most ⭐ hepatotoxic among erythromycins PREVENTION OF RESISTANCE The first three are anti TB agents. If a patient Combination therapy in: presents to you with jaundice and is currently taking → Tuberculosis (quadruple anti-Koch’s) all three, the first thing to advise is to stop all these → Hansen’s disease (two or more drugs) three drugs, and may introduce them one by one. Mycobacterial etiologic agents Hematologic toxicity → Natural resistance: a predictable random mutation on → Chloramphenicol untreated Mycobacterium tuberculosis → Sulfonamides Neurotoxicity Table 3. Chances of developing a resistant strain during → Aminoglycosides monotherapy → Beta lactams Drug Given Mutant/Resistant Strain → Polymyxin - no longer used systemically Isoniazid 1 in 104 Rifampicin 1 in 107 *Note: all classifications are part of the three (3) most important Pyrazinamide 1 in 103 classification of antimicrobials, except MODE of action. Ethambutol 1 in 105 Streptomycin 1 in 104 VII. REASONS FOR USING COMBINATIONS OF ANTIMICROBIAL AGENTS ◼ 4 drug anti-TB treatment = 1 in 104 x 107 x 103 x 105 = SYNERGY ⭐ 1 in 1019 (10 quintillion) Co-trimoxazole = sulfamethoxazole + trimethoprim The likelihood for a bacillus spontaneously → Both are folate antagonists developing resistance to 2 or more unrelated agents → Trimethoprim - inhibits dihydrofolate reductase is the product of individual drug resistance → Sulfamethoxazole - inhibits dihydropteroate synthetase probabilities → Acquired resistance: a predictable forced mutation in patients on anti-TB drugs ◼ Monotherapy - leads to resistance to the drug ◼ Amplifier effect in MDR-TB - resistance to some drugs in the combination regimen leads to the development of resistance to the remaining drugs TREATMENT OF MIXED INFECTION Two organisms that require two different antimicrobials Sepsis with a superinfection of Candida albicans (antimicrobial plus antifungal) TREATMENT OF A SEVERE INFECTION Figure 23. An example of synergism between two different Meningitis, sepsis, probable sepsis → start empiric treatment antibiotics. with combination drugs stat Together, the two drugs will create an additional zone of ⭐ inhibition; which is called the synergistic zone of inhibition. DISADVANTAGES OF ANTIMICROBIAL COMBINATIONS In effect, you are widening the antimicrobial coverage in Superinfection - the more antibiotics you give in any producing synergy. infection, will increase the likelihood of a superinfection ↑ chances of drug interactions and other metabolic effects EXTENDED ANTIMICROBIAL SPECTRUM Beta-lactam antimicrobial + aminoglycoside for sepsis VIII. ANTIMICROBIAL PROPHYLAXIS Penicillin + streptomycin for enterococcal endocarditis Conditions where prophylactic use of anti-infective drugs are Amphotericin + flucytosine for cryptococcal meningitis given: Sepsis, endocarditis, and meningitis are very serious → Surgical procedures illnesses → Surgical procedures in which anaerobic infections are common → Group B Streptococcal infections → Pneumocystis jiroveci pneumonia VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 11 of 14 TE | Dela Paz  → UTIs → E.g. Combination of Metronidazole and Diloxanide ◼ For patients with anatomic pathologies Furoate may be rational in patients with amoebiasis to ◼ Cleaning agent for the bladder improve the coverage for Entamoeba histolytica → Haemophilus influenzae type b → Meningococcal infection Table 5. Tissue vs. Luminal Amebicides. → Malaria TISSUE AMEBICIDES LUMINAL AMEBICIDES → Tuberculosis Act primarily in the bowel wall, Act primarily in the bowel lumen ◼ Given to patients who are exposed to family or liver & extraintestinal tissues community members with TB Nitroimidazoles Amides → Mycobacterium avium complex in a patient with AIDS → Metronidazole → Diloxanide Furoate → Bacillus anthracis (anthrax) → Tinidazole → Etofamide → Dental procedures in a patient with valve abnormalities → Omidazole Halogenated → Secnidazole Hydroxyquinolines Table 4. Prophylactic Use of Anti-Infective Drugs. Emetine → Iodochlorhydroxyquin DRUG USE Dehydroemetine Antibiotics Cefazolin Abductor pollicis brevis Chloroquine → Paromomycin Cefoxitin, Surgical procedures which anaerobic → Erythromycin Cefotetan infections are common → Tetracycline Ampicillin / Inadequate blood levels Group B streptococcal infections Penicillin → Make sure that the drug dose, preparation, frequency are TMP-SMX Pneumocystis jiroveci pneumonia UTIs correct and well-instructed to avoid inadequate blood H. influenzae type B levels that will not meet the minimum inhibitory Rifampin Meningococcal infection concentration to affect bacterial growth Chloroquine Poor tissue penetration Malaria mefloquine → Some antimicrobials do not penetrate the tissue well Isoniazid rifampin Tuberculosis such as blood brain barrier Mycobacterium avium complex in patients ◼ Meningitis Azithromycin with AIDS – Drug is given intrathecally through the lumbar tap Ciprofloxacin Bacillus anthracis (anthrax) and inject the drug mainly in the lumbar space to Ampicillin / Dental procedures in patients with valve circulate in the spinal fluid and reach the brain and Azithromycin abnormalities spinal cord AIDS=Acquired immunodeficiency; UTI=Urinary Tract Infection ◼ Prostatitis – Prostate and bone can be a sanctuary site for IX. REASONS FOR ANTIMICROBIAL FAILURE bacteria May manifest after discharge – Difficult to reach by antimicrobials that are usually → Cephalexin has poor coverage for H. influenzae given → In children ages 6 months - 3 years, etiologic agents are ◼ Bone Infection either H. influenzae (gram negative) or Streptococcus – E.g. osteomyelitis treated minimum of 6 weeks pneumoniae (gram positive) Drug-drug interaction → Cephalexin covers mainly gram positive and not infection → List of the more common/significant drug-drug caused by H. influenza interactions is provided → Amoxicillin may do a better job because it covers for both → Particularly if the interaction results to lower blood levels H. influenza and S. pneumonia of the antimicrobial Inadequate coverage Superinfection → Entamoeba histolytica may exist in both cysts and → Oral candidiasis in a hospitalized patient from intake of trophozoite stages, the more effective antimicrobial for antimicrobials each stage may be different → Candida oral thrush might cause on-off fever when → Trophozoite - gives signs and symptoms; invades primary disease is already treated and needs to be given tissues like bowel, liver and other extraintestinal tissues a second antimicrobial causing the signs and symptoms of disease Non-Infectious Disease → Cyst - stays in colon; relatively inactive in tissues but is → The cause of the disease might not be infectious invasive stage → E.g. Rheumatoid arthritis, carcinoma, other → If you have signs and symptoms of the disease already, non-infectious fevers of unknown origin give tissue amebicides. However, for cysts formed in Untreatable Infectious Diseases the intestinal lumen, there is still a need to give luminal → AIDS amebicides. → SARS → COVID-19 VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 12 of 14 TE | Dela Paz  → Other viral infections b) Present at the time of admittance to a health care facility Unusual Pathogens c) More difficult to prevent and treat, unpredictable, and → Pneumonias (atypical forms) caused by the following more resistant to cure than community-acquired organisms are not sensitive to penicillin: infections. ◼ Legionella d) May manifest before discharge ◼ Mycoplasma ◼ Chlamydia 4. Erythromycin binds to the 30s ribosomal subunit in order to Purulent Material or Foreign Body inhibit protein synthesis. Others reasons a) True → Failure to remove purulent material or failure to remove b) False foreign body → Vomiting due to poor taste 5. Which of the following antimicrobials differ from the other ◼ Especially in Children choices, based on MODE of action? → Adulterated and counterfeit drug a) Trimethoprim ◼ Type F Adverse Drug Reaction: Failure of Drug b) Rifampicin c) Beta lactams THE BATTLE AGAINST INFECTION d) Vancomycin The Enemy: the Infecting Organism The Weapons: 6. The risk of ototoxicity and nephrotoxicity is increased if → Antimicrobials vancomycin is given in combination with: → Immunologicals a) Macrolides → Patient’s Immune System b) Aminoglycosides The Chief Strategist: c) Penicillins → The Rational Physician d) Monobactams X. RATIONAL THERAPEUTIC STRATEGY FOR PROVEN OR 7. Which of these antimicrobials is the most hepatotoxic? SUSPECTED INFECTIOUS DISEASES a) Isoniazid History and Physical Exam b) Erythromycin estolate → Provides the explanation for the patient’s illness (working c) Tetracycline diagnosis) d) Pyrazinamide Collection of appropriate specimens to determine the etiologic agent 7) D 6) B 5) A 4) B 3) C 2) B 1) B ] Utilizing local epidemiological data Tailoring dose and route of administration of the antimicrobial 1. Term being described is natural resistance. Acquired resistance is in accordance with host factor defined as a predictable forced mutation in patients on anti-TB drugs 2. Antibiotics are antimicrobials. Moving from broad-based empiric therapy to more specific, 3. Nosocomial infections are hospital-acquired infections. It is not narrow spectrum therapy once an etiologic diagnosis is present or incubating at the time of admittance to a healthcare facility. available And may manifest after discharge. → If culture and sensitivity result is available, give 4. Erythromycin, which like Azithromycin is a macrolide, binds to the 50s antimicrobial that have a narrower spectrum subunit to inhibit protein synthesis. Monitoring response to treatment 5. Trimethoprim is bacteriostatic, while the rest are bactericidal. Assessing the risk of this infection to the community 6. Ototoxic Drugs: Macrolides, Vancomycin; Nephrotoxic Drugs: Assessing the opportunities for prevention Glycopeptides, Tetracycline, Polymyxins; Ototoxic, Nephrotoxic, Neurotoxic: Aminoglycosides. Monobactams are not nephrotoxic 7. Pyrazinamide is the most hepatotoxic. Erythromycin estolate is the XI. REVIEW QUESTIONS most hepatotoxic among erythromycins. 1. True or False. Acquired resistance is known as a predictable random mutation in an untreated TB. XII. FORMATIVE QUIZ a) True *Doc said that these will come up in the long exam/came up b) False in the previous exams* 2. True or False. Antimicrobials are antibiotics. 1. Which of the following refers to the unintentional causation a) True of an infection during the process of providing medical care b) False (such as surgery, drug treatment, hospitalization, or diagnostic testing?) 3. Which of the ff. Statements are true about nosocomial a) Iatrogenesis infections? b) Microbiostatic effect a) Community-acquired infection c) Postantibiotic effect VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 13 of 14 TE | Dela Paz  d) Selective toxicity 9. A 2-year old boy diagnosed to have pneumonia did not improve after 5 days of taking cephalexin. You need to 2. Which of the following infections will be more difficult to investigate for the possibility of the following reasons why treat? the child did not improve EXCEPT: a) Common flu a) Drug-drug interaction b) Community acquired pneumonia b) Etiological agent is H. influenzae c) Uncomplicated UTI c) Spitting of the drug because of poor taste d) Viral acute rhinitis d) Viral, not bacterial, etiology of pneumonia e) NOTA 10. Which of the following drug:MOA combination is correct? 3. Selective toxicity of antimicrobials may be achieved by a) Penicillin : inhibition of DNA synthesis attacking the following targets, EXCEPT: b) Cephalosporin : inhibition of cell wall synthesis a) Bacterial cell wall components c) Aminoglycoside : inhibition of cell wall synthesis b) DNA and RNA synthesis d) Fluoroquinolones : inhibition of cell wall synthesis c) Ribosomal protein synthesis d) Tricarboxylic acid cycle [10)B 9)A 8)C 7)C 6)C 5)B 4)D 3)D 2) E 1) A ] 4. Which of the following drug groups prevent the formation of bacterial folic acid? 1. Microbiostatic effect- does not kill organisms, but stops them from a) Carbapenems growing; Postantibiotic effect- period of time after removal of an b) Fluoroquinolones antibiotic where there is no growth of target organism; Selective toxicity- kills target organisms without damaging the human host c) macrolides 2. Nosocomial infections are more difficult to treat as they are more d) Sulfonamides resistant to cure than community-acquired infections 3. Tricarboxylic cycle, also known as the Kreb’s cycle, is a series of 5. Why are gram positive bacteria easier to treat than gram chemical reactions used by all aerobic organisms to generate energy negative bacteria? through the oxidization of acetate derived from carbohydrates, fats, and a) Absence of cell wall efflux pumps proteins into carbon dioxide. b) Lack of a protective outer cell layer 4. Sulfonamides. Metabolism of p-aminobenzoic acid (PABA) will form c) No genetic mutations are reported purines, which are important for DNA and RNA production as well as cell wall proteins. No DNA and RNA, no replication of bacteria. Folic d) Presence of inactivating enzymes acid must be synthesized by microorganisms. Isoniazid is another agent that is a competitive antagonist of a metabolic pathway, just like 6. Which of the following conditions will a combination of two sulfonamides and trimethoprim. To emphasize, trimethoprim and antimicrobials be rational? sulfonamides exhibit synergism (1+1 =3). a) Acute bacterial tonsillopharyngitis 5. Difference between gram positive and gram negative bacteria. b) Adult community-acquired pneumococcal pneumonia Gram-positive bacteria lack a hard protective outer membrane. c) Bacterial meningitis Peptidoglycan layer (that surrounds gram-positive bacteria) - capable of d) Wound infection in the thumb absorbing antibiotics and cleaning products which are fatal to them 6. Some serious bacterial infections where drug combination is rational: Sepsis, Endocarditis, and Meningitis. Bacterial meningitis is the most 7. Irving, a 24-year old movie sound editor was noted to have a common etiologic agent (Streptococcus pneumoniae, Haemophilus gram positive ear infection. From which of the following influenzae, and Neisseria meningitidis). Note: Doc said that two drug available drug groups would you select the mist rational combination should cover both gram-positive and gram-negative unless antimicrobial for Irving? culture shows only either of the two. a) Aminoglycosides 7. Lincosamides have good activity against anaerobes. All other b) Glycopeptides choices are ototoxic antimicrobials. It is not rational to use ototoxic c) Lincosamides antimicrobials when you are unsure whether the middle ear and the inner ear is infected. d) Macrolides 8. Number of children is not included in the patient host factors in choosing an appropriate antimicrobial. 8. A 28-year old female consults your clinic. You diagnose her 9. We did not mention any other drug that was given to the patient. to have pneumonia. In choosing an appropriate antimicrobial 10. Cephalosporins, like penicillins, inhibit cell wall synthesis. for her, you would LEAST consider the following: a) Previous history of drug allergy REFERENCES b) Possibility of pregnancy 2025 Lecture Transcription c) Number of her children Macaraig, Ronaldo Marcelo. (2023). Principles of d) Concurrent diseases Antimicrobial Therapy Synchronous Recording VPAA | Bonoan PHARMA LEC | LE2 - 03 Principles of Antimicrobial Therapy | Abrajano, Acejo, Adiong, Aguilar, Agustin, Alarilla, PAGE 14 of 14 TE | Dela Paz