Principles of Anti-Microbial Therapy PDF

PRINCIPLES OF ANTI-MICROBIAL THERAPY: Chemotherapy: treatment of infections with specific drugs that selectively suppress/ kill the infecting microorganism without significantly affecting the host.’ The basis of selective microbial toxicity: - the action of the drug on a component of the microbe (e....

PRINCIPLES OF ANTI-MICROBIAL THERAPY: Chemotherapy: treatment of infections with specific drugs that selectively suppress/ kill the infecting microorganism without significantly affecting the host.’ The basis of selective microbial toxicity: - the action of the drug on a component of the microbe (e.g. bacterial cell wall) or metabolic processes (e.g. folate synthesis) that is not found in the host. - high affinity for certain microbial biomolecules (e.g. trimethoprim for bacterial dihydrofolate reductase). Antibiotics: substances produced by some microorganisms that inhibit the growth of or kill other microorganisms. Chemotherapeutic agents: this term was restricted to synthetic compounds that kill or inhibit the growth of microorganisms without affecting host cells. Now it is used for both synthetic and microbiologically produced drugs. Antimicrobial agent (AMA): term used to designate synthetic as well as naturally obtained drugs that attenuate microorganisms. ANTIMICROBIAL PHARMACODYNAMIC: A- Bacteriostatic versus Bactericidal Activity: 1- Bactericidal drugs kill bacteria. In general, cell wall-active agents are bactericidal. Bactericidal drugs are necessary for: a. Patients with severe infections b. Patients with severe or debilitating diseases c. Patients who are immunocompromised 2- Bacteriostatic Drugs inhibit the growth of bacteria. Drugs that inhibit protein synthesis are bacteriostatic. Bacteriostatic drugs should not be used in immunocompromised patients. B- Susceptibility Testing - Minimum inhibitory concentration (MIC): Bacteriostatic activity is usually expressed as the lowest concentration (MIC) at which the drug inhibits growth of the susceptible microorganism. - Minimal bactericidal concentration (MBC): Bactericidal activity expressed as the minimal bactericidal concentration which is the lowest concentration at which the drug kills microorganism. Dr. Hamad Alshabi PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) PARAMETERS (Basis for Selection of Dose and Dosing Schedule) - concentration-dependent killing (Cdk): means that killing effect of a drug is high when ratio of peak concentration to MIC (CMAX /MIC) is more. This type of killing behavior is exhibited by aminoglycosides. These drugs produce better action when used as a large single dose as compared to same daily dose divided into 2-3 portions. - time-dependent killing (Tdk): means antimicrobial action depends on the length of time the concentration remains above the MIC (T/MIC). This is exhibited by β-lactams and macrolides. For these drugs multiple daily doses are preferred over single dose. - concentration and time-dependent killing: means antimicrobial action depends on the area under the curve (AUC), above the MIC. Both the higher the concentration and the longer the concentration remains above MIC are important. This is exhibited by fluoroquinolones. Post antibiotic effect (PAE): Post antibiotic effect is the antibacterial effect that persists after drug concentration falls below the minimum inhibitory concentration. Antimicrobial drugs with long post antibiotic effect such as aminoglycosides and fluoroquinolones require only one dose per day. CHEMOTHERAPEUTIC SPECTRA: This term refers to the types of microorganisms that are affected by the drugs. A. Narrow-spectrum antibiotics: Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. Example: isoniazid. B. Extended-spectrum antibiotics Dr. Hamad Alshabi Extended spectrum is the term applied to antibiotics that are modified to be effective against gram-positive organisms and also against a significant number of gram-negative bacteria. Example: ampicillin C. Broad-spectrum antibiotics: Drugs affect a wide variety of microbial species and are referred to as broad- spectrum antibiotics. Example: tetracycline, fluoroquinolones. CHOICE OF ANTIMICROBIAL AGENT: Types of Antimicrobial Therapy The use of antimicrobial chemotherapy—falls into one of three general categories: prophylaxis, empiric use, and definitive therapy. Prophylactic Therapy: antibiotics given to prevent an infection that has not yet developed. This is used for patients at significant risk. Empiric therapy: Empiric therapy is administered when an infection is suspected but the spe- cific causative organism and its susceptibility in that patient are not known, with the antibiotics used based on the typical pathogens associated with the infectious syndrome(s). The rationale for this is 2-reasons: - Definitive identification and susceptibility of the causative microorganism(s) is typically delayed by at least 24 to 48 h from patient presentation, and - For many infections, a delay in treatment until definitive identification of the infecting pathogen would be considered harmful to the patient. Dr. Hamad Alshabi Definitive Therapy: If a pathogen has been identified and susceptibility results are available, the optimal antibiotic regimen for that patient should be selected—the definitive therapy. Adverse Consequences of Antibiotic Use: 1- Hypersensitivity reactions. 2- Direct toxicity. 3- Superinfection 4- Antibiotic Resistance. SUPERINFECTION This refers to the appearance of a new infection as a result of antimicrobial therapy. Drug therapy, particularly with broad-spectrum antimicrobials or combinations of agents and for long duration can lead to alterations of the normal microbial flora of the upper respiratory, intestinal, and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. ANTIBIOTIC RESISTANCE: Resistance is defined as the unresponsiveness of a microorganism to an antimicrobial agent (AMA). The resistance may be: 1. Natural. No target site in the bacteria. 2. Acquired: microbes that initially respond to an AMA later develop resistance to the same AMA by mutation or gene transfer. The transfer of genes for drug resistance occurs by the following mechanisms: Conjugation, Transduction and Transformation. Mechanisms of resistance: 1- Modification of target sites 2- Decreased accumulation: Decreased uptake or increased efflux of an antibiotic Dr. Hamad Alshabi 3- Enzymatic inactivation. Prevention of development of resistance to antimicrobial agents: a. Use AMA only when indicated/ necessary. b. Selecting right AMA. c. Give correct dose d. Give for correct duration. e. Judicious combination of AMA when the pathogen is noted to develop resistance to an individual drug rapidly e.g. Tuberculosis, leprosy, H. pylori. Combination of Antimicrobial Agents: It is the simultaneous use of two or more antimicrobial agents for the treatment of certain infectious diseases. Indications/advantages of antimicrobial combinations 1- To provide broad-spectrum empiric therapy in seriously ill patients. 2- To treat polymicrobial infections 3- To decrease the emergence of resistant strains 4- To decrease dose-related toxicity by using reduced doses of one or more components of the drug regimen. 5- To obtain enhanced inhibition or killing (synergism). Disadvantages of antimicrobial combinations 1. Increased toxicity, e.g. vancomycin with tobramycin may cause enhanced nephrotoxicity. 2. Increased cost. 3. Decreased antibacterial activity due to improper combinations, e.g. in pneumococcal meningitis, activity of penicillin G (bactericidal) against pneumococci will be decreased if combined with tetracycline (bacteriostatic). 4. Increased likelihood of superinfection. 5. Irrational combination of AMAs can lead to development of resistance. Clinical failure of antimicrobial therapy—Inadequate clinical or microbiologic response to antimicrobial therapy can result from: - laboratory testing errors, - problems with the drug (eg, incorrect choice, poor tissue penetration, inadequate dose), - the patient (poor host defenses, undrained abscesses), or - the pathogen (resistance, superinfection). Dr. Hamad Alshabi